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Ismaiah MJ, Lo EKK, Chen C, Tsui JSJ, Johnson-Hill WA, Felicianna, Zhang F, Leung HKM, Oger C, Durand T, Lee JCY, El-Nezami H. Alpha-aminobutyric acid administration suppressed visceral obesity and modulated hepatic oxidized PUFA metabolism via gut microbiota modulation. Free Radic Biol Med 2025; 232:86-96. [PMID: 40032028 DOI: 10.1016/j.freeradbiomed.2025.02.029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/17/2025] [Accepted: 02/20/2025] [Indexed: 03/05/2025]
Abstract
BACKGROUND High-fat diet (HFD) is associated with visceral obesity due to disruption in the lipid metabolism and gut dysbiosis. These symptoms may contribute to hepatic steatosis and the formation of oxidized polyunsaturated fatty acids (PUFAs). Alpha-aminobutyric acid (ABA) is an amino-acid derived metabolite, and its concentration has been correlated with several metabolic conditions and gut microbiome diversity while its direct effects on visceral obesity, lipid metabolism and the gut microbiota are not well understood. This study was designed to investigate the effect of physiological dose of ABA on diet-induced visceral obesity and lipid metabolism dysregulation by examining the fatty acids and oxidized PUFAs profile in the liver as well as the gut microbiota. RESULTS ABA administration reduced visceral obesity by 28 % and lessened adipocyte hypertrophy. The expression of liver Cd36 was lowered by more than 50 % as well as the saturated and monounsaturated FA concentration. Notably, the desaturation index for C16 and C18 FAs that are correlated with adiposity were reduced. The concentration of several DHA-derived oxidized PUFAs were also enhanced. Faecal metagenomics sequencing revealed enriched abundance of Leptogranulimonas caecicola and Bacteroides sp. ZJ-18 and were positively correlated with several DHA- and ALA-derived oxidized PUFAs in ABA group. CONCLUSION Our study revealed the modulatory effect of physiological dose of ABA on attenuating visceral obesity, reducing hepatic steatosis, and promoting the production of anti-inflammatory oxidized PUFAs that were potentially mediated by the gut microbiota.
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Affiliation(s)
- Marsena Jasiel Ismaiah
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Emily Kwun Kwan Lo
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Congjia Chen
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Jacob Shing-Jie Tsui
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Winifred Audrey Johnson-Hill
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Felicianna
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Fangfei Zhang
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Hoi Kit Matthew Leung
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China
| | - Camille Oger
- Institut des Biomolécules Max Mousseron, UMR5247, CNRS, ENSCM, Université de Montpellier, F-34093, Montpellier, France
| | - Thierry Durand
- Institut des Biomolécules Max Mousseron, UMR5247, CNRS, ENSCM, Université de Montpellier, F-34093, Montpellier, France
| | - Jetty Chung-Yung Lee
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China.
| | - Hani El-Nezami
- School of Biological Sciences, The University of Hong Kong, Pok Fu Lam Road, Hong Kong Special Administrative Region of China; Institute of Public Health and Clinical Nutrition, School of Medicine, University of Eastern Finland, Kuopio, FI-70211, Finland
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Soták M, Clark M, Suur BE, Börgeson E. Inflammation and resolution in obesity. Nat Rev Endocrinol 2025; 21:45-61. [PMID: 39448830 DOI: 10.1038/s41574-024-01047-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/30/2024] [Indexed: 10/26/2024]
Abstract
Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.
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Affiliation(s)
- Matúš Soták
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Madison Clark
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Bianca E Suur
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Emma Börgeson
- Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
- Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
- Department of Biomedicine, Aarhus University, Aarhus, Denmark.
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Ağagündüz D, Yeşildemir Ö, Koçyiğit E, Koçak T, Özen Ünaldı B, Ayakdaş G, Budán F. Oxylipins Derived from PUFAs in Cardiometabolic Diseases: Mechanism of Actions and Possible Nutritional Interactions. Nutrients 2024; 16:3812. [PMID: 39599599 PMCID: PMC11597274 DOI: 10.3390/nu16223812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/31/2024] [Accepted: 11/05/2024] [Indexed: 11/29/2024] Open
Abstract
Oxylipins are oxidized fatty acids, both saturated and unsaturated, formed through pathways that involve singlet oxygen or dioxygen-mediated oxygenation reactions and are primarily produced by enzyme families such as cyclooxygenases, lipoxygenases, and cytochrome P450. These lipid-based complex bioactive molecules are pivotal signal mediators, acting in a hormone-like manner in the pathophysiology of numerous diseases, especially cardiometabolic diseases via modulating plenty of mechanisms. It has been reported that omega-6 and omega-3 oxylipins are important novel biomarkers of cardiometabolic diseases. Moreover, collected literature has noted that diet and dietary components, especially fatty acids, can modulate these oxygenated lipid products since they are mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) or linoleic acid and α-linolenic by elongation and desaturation pathways. This comprehensive review aims to examine their correlations to cardiometabolic diseases and how diets modulate oxylipins. Also, some aspects of developing new biomarkers and therapeutical utilization are detailed in this review.
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Affiliation(s)
- Duygu Ağagündüz
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Gazi University, 06490 Ankara, Türkiye
| | - Özge Yeşildemir
- Department of Nutrition and Dietetics, Bursa Uludag University, Görükle Campus, 16059 Bursa, Türkiye;
| | - Emine Koçyiğit
- Department of Nutrition and Dietetics, Ordu University, Cumhuriyet Yerleşkesi, 52200 Ordu, Türkiye;
| | - Tevfik Koçak
- Department of Nutrition and Dietetics, Gümüşhane University, Gümüşhanevî Kampüsü, 29100 Gümüşhane, Türkiye;
| | - Buket Özen Ünaldı
- Department of Nutrition and Dietetics, Faculty of Health Sciences, Afyonkarahisar Health Sciences University, 03030 Afyonkarahisar, Türkiye;
| | - Gamze Ayakdaş
- Department of Nutrition and Dietetics, Acıbadem University, Kerem Aydınlar Campus, 34752 İstanbul, Türkiye;
| | - Ferenc Budán
- Institute of Physiology, Medical School, University of Pécs, H-7624 Pécs, Hungary
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Wang C, Deng J, Ding Z, Zhu H, Guo Z, Lu J. Maresin2 negatively regulates DC's maturation via the MAPK/NF-κB pathway in DCs. Int Immunopharmacol 2024; 140:112785. [PMID: 39088915 DOI: 10.1016/j.intimp.2024.112785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 06/05/2024] [Accepted: 07/23/2024] [Indexed: 08/03/2024]
Abstract
OBJECTIVE To observe the effects and mechanisms of Maresin2 on the function of DCs(Dendritic cells). METHOD The levels of IL-6, IL-12, TNF-α and IL-1β secreted by BMDCs (Bone marrow-derived Dendritic cells) after Maresin2 treatment were detected by ELISA. At the same time, the expressions of costimulatory molecules CD40 and CD86 on the surface, the ability of phagocytosis of ovalbumin(OVA) antigen, and antigen presentation function in BMDCs were analyzed by flow cytometry. Finally, MAPK and NF-κB pathway signaling phosphorylation in Maresin2-treated BMDCs were detected by western blot. RESULTS The secretion levels of IL-6, IL-12, TNF-α and IL-1β were significantly decreased in the Maresin2 treatment group after LPS treatment (P < 0.05). The expression levels of CD86 and CD40 were significantly decreased after Maresin2 treatment (P < 0.05). Maresin2 enhanced the phagocytosis ability of ovalbumin(OVA) (P < 0.05), but the ability of antigen presentation of BMDCs with the treatment of Maresin2 changed slightly (P > 0.05). Phosphorylation of p38, JNK, p65, ikka/β and ERK peaked at 15 min in the LPS group, while phosphorylation of p-p38 and p-ERK weakened 30 min and 60 min after treatment with Maresin2. CONCLUSIONS Maresin2 inhibits inflammatory cytokine secretion but enhances phagocytosis via the MAPK/NF-κB pathway in BMDCs, which may contribute to negatively regulating inflammation.
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Affiliation(s)
- Chaoqun Wang
- Department of Endocrinology, The First Affiliated Hospital of Naval Medical University, 200433, China
| | - Jiewen Deng
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 200433, China
| | - Zhengping Ding
- Department of Endocrinology, The People's Hospital of Akto County 845550. China
| | - Huan Zhu
- Department of Endocrinology, The First Affiliated Hospital of Naval Medical University, 200433, China
| | - Zhenhong Guo
- National Key Laboratory of Medical Immunology & Institute of Immunology, Naval Medical University, 200433, China.
| | - Jin Lu
- Department of Endocrinology, The First Affiliated Hospital of Naval Medical University, 200433, China.
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Kim N, Shin HY. Deciphering the Potential Role of Specialized Pro-Resolving Mediators in Obesity-Associated Metabolic Disorders. Int J Mol Sci 2024; 25:9598. [PMID: 39273541 PMCID: PMC11395256 DOI: 10.3390/ijms25179598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Revised: 09/02/2024] [Accepted: 09/03/2024] [Indexed: 09/15/2024] Open
Abstract
Obesity-related metabolic disorders, including diabetes, non-alcoholic fatty liver disease (NAFLD), and cardiovascular disease, increasingly threaten global health. Uncontrolled inflammation is a key pathophysiological factor in many of these conditions. In the human body, inflammatory responses generate specialized pro-resolving mediators (SPMs), which are crucial for resolving inflammation and restoring tissue balance. SPMs derived from omega-3 polyunsaturated fatty acids (n-3 PUFAs) such as resolvins, protectins, and maresins hold promise in attenuating the chronic inflammatory diseases associated with lipid metabolism disorders. Recent research has highlighted the therapeutic potential of n-3 PUFA-derived metabolites in addressing these metabolic disorders. However, the understanding of the pharmacological aspects of SPMs, particularly in obesity-related metabolic disorders, remains limited. This review comprehensively summarizes recent advances in understanding the role of SPMs in resolving metabolic disorders, based on studies in animal models and humans. These studies indicate that SPMs have potential as therapeutic targets for combating obesity, as well as offering insights into their mechanisms of action.
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Affiliation(s)
- Nahyun Kim
- Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Republic of Korea
| | - Ha Youn Shin
- Department of Biomedical Science and Engineering, Konkuk University, Seoul 05029, Republic of Korea
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Liu X, Tang Y, Luo Y, Gao Y, He L. Role and mechanism of specialized pro-resolving mediators in obesity-associated insulin resistance. Lipids Health Dis 2024; 23:234. [PMID: 39080624 PMCID: PMC11290132 DOI: 10.1186/s12944-024-02207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 07/07/2024] [Indexed: 08/02/2024] Open
Abstract
With the changing times, obesity has become a characteristic epidemic in the context of the current era. Insulin resistance (IR) is most commonly caused by obesity, and IR is a common basis of the pathogenesis of many diseases such as cardiovascular disease, nonalcoholic fatty liver disease, and type 2 diabetes, which seriously threaten human life, as well as health. A major pathogenetic mechanism of obesity-associated IR has been found to be chronic low-grade inflammation in adipose tissue. Specialized pro-resolving mediators (SPMs) are novel lipid mediators that both function as "stop signals" for inflammatory reaction and promote inflammation to subside. In this article, we summarize the pathogenesis of obesity-associated IR and its treatments and outline the classification and biosynthesis of SPMs and their mechanisms and roles in the treatment of obesity-associated IR in order to explore the potential of SPMs for treating metabolic diseases linked with obesity-associated IR.
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Affiliation(s)
- Xinru Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Tang
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Luo
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yongxiang Gao
- College of International Education, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Lisha He
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Albiach-Delgado A, Moreno-Casillas JL, Ten-Doménech I, Cascant-Vilaplana MM, Moreno-Giménez A, Gómez-Ferrer M, Sepúlveda P, Kuligowski J, Quintás G. Oxylipin profile of human milk and human milk-derived extracellular vesicles. Anal Chim Acta 2024; 1313:342759. [PMID: 38862207 DOI: 10.1016/j.aca.2024.342759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/13/2024] [Accepted: 05/20/2024] [Indexed: 06/13/2024]
Abstract
BACKGROUND Small Extracellular Vesicles (sEVs) are nano-sized vesicles that are present in all biofluids including human milk (HM) playing a crucial role in cell-to-cell communication and the stimulation of the neonatal immune system. Oxylipins, which are bioactive lipids formed from polyunsaturated fatty acids, have gained considerable attention due to their potential role in mitigating disease progression and modulating the inflammatory status of breastfed infants. This study aims at an in-depth characterization of the oxylipin profiles of HM and, for the first time, of HM-derived sEVs (HMEVs) employing an ad-hoc developed and validated ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. RESULTS The UPLC-MS/MS method covered a panel of 13 oxylipins for quantitation and 93 oxylipins for semi-quantitation. In 200 μL of HM and HMEV isolates of 15 individuals, 42 out of 106 oxylipins were detected in either HM or HMEVs, with 38 oxylipins being detected in both matrices. Oxylipins presented distinct profiles in HM and HMEVs, suggesting specific mechanisms responsible for the encapsulation of target molecules in HMEVs. Ten and eight oxylipins were quantified with ranges between 0.03 - 73 nM and 0.30 pM-0.07 nM in HM and HMEVs, respectively. The most abundant oxylipins found in HMEVs were docosahexaenoic acid derivatives (17-HDHA and 14-HDHA) with known anti-inflammatory properties, and linoleic acid derivatives (9-10-DiHOME and 12,13-DiHOME) in HM samples. SIGNIFICANCE AND NOVELTY This is the first time a selective, relative enrichment of anti-inflammatory oxylipins in HMEVs has been described. Future studies will focus on the anti-inflammatory and pro-healing capacity of oxylipins encapsulated in HMEVs, with potential clinical applications in the field of preterm infant care, specifically the prevention of severe intestinal complications including necrotizing enterocolitis.
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Affiliation(s)
- Abel Albiach-Delgado
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain; Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS-SAMID) (RD21/0012/0015), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Análisis de Vesículas Extracelulares (SAVE), Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Jose L Moreno-Casillas
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain; Servicio de Análisis de Vesículas Extracelulares (SAVE), Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Isabel Ten-Doménech
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain; Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS-SAMID) (RD21/0012/0015), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Análisis de Vesículas Extracelulares (SAVE), Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Mari Merce Cascant-Vilaplana
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Alba Moreno-Giménez
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Marta Gómez-Ferrer
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
| | - Pilar Sepúlveda
- Regenerative Medicine and Heart Transplantation Unit, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain; Centro de Investigación Biomédica en Red Enfermedades Cardiovasculares (CIBERCV), Carlos III Institute of Health, Madrid, Spain; Cardiology Service, University & Polytechnic Hospital La Fe, Avenida Fernando Abril Martorell 106, 46026, Valencia, Spain; Department of Pathology, University of Valencia, Avenida Blasco Ibáñez 15, 46010, Valencia, Spain.
| | - Julia Kuligowski
- Neonatal Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain; Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin Network (RICORS-SAMID) (RD21/0012/0015), Instituto de Salud Carlos III, Madrid, Spain; Servicio de Análisis de Vesículas Extracelulares (SAVE), Health Research Institute Hospital La Fe (IIS La Fe), Avda Fernando Abril Martorell 106, 46026, Valencia, Spain.
| | - Guillermo Quintás
- Health and Biomedicine, Leitat Technological Center, Avda Fernando Abril Martorell 106, 46026, Valencia, Spain
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Walker ME, Kodani SD, Mena HA, Tseng YH, Cypess AM, Spite M. Brown Adipose Tissue Activation in Humans Increases Plasma Levels of Lipid Mediators. J Clin Endocrinol Metab 2024; 109:1837-1849. [PMID: 38198796 PMCID: PMC11180506 DOI: 10.1210/clinem/dgae016] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 12/13/2023] [Accepted: 01/09/2024] [Indexed: 01/12/2024]
Abstract
CONTEXT Activation of brown adipose tissue (BAT) thermogenesis improves insulin sensitivity and is beneficial in obesity. Emerging evidence indicates that BAT activation increases lipid mediators that play autocrine and endocrine roles to regulate metabolism and inflammation. OBJECTIVE The goal of the study was to determine the relationship between 2 distinct approaches of BAT activation (cold exposure and mirabegron treatment) with lipid mediators in humans. METHODS Healthy female subjects (n = 14) were treated with the β3-adrenergic receptor agonist mirabegron (100 mg) daily for 28 days. A subset of female subjects (n = 8) was additionally exposed to cold temperatures (14-16 °C) for 2 hours using a cooling vest prior to initiating mirabegron treatment. A panel of lipid mediators was assessed in plasma using targeted liquid chromatography-tandem mass spectrometry, and their relationship to anthropometric and metabolic parameters was determined. RESULTS Activation of BAT with cold exposure acutely increased levels of lipoxygenase and cyclooxygenase products, including 12-hydroxyeicosapentaenoic acid, 12-hydroxyeicosatetraenoic acid (HETE), 5-HETE, 14-hydroxydocosahexaenoic acid (HDHA), an isomer of maresin 2 (MaR2), 17-HDHA, protectin D1 (PD1), and prostaglandin E2. Mirabegron treatment similarly increased these products acutely, although levels of some mediators were blunted after chronic mirabegron treatment. Selected lipid mediators, including an MaR2 isomer, 17-HDHA, 5-HETE, and 15-HETE, positively correlated with nonesterified fatty acids and negatively correlated with the respiratory quotient, while PD1, 15-HETE, and 5-HETE positively correlated with adiponectin. CONCLUSION These results indicate that selected lipid mediators may serve as biomarkers of BAT activation.
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Affiliation(s)
- Mary E Walker
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Sean D Kodani
- Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
| | - Hebe Agustina Mena
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
| | - Yu-Hua Tseng
- Section on Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center and Harvard Medical School, Boston, MA 02215, USA
- Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA
| | - Aaron M Cypess
- Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Matthew Spite
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA
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9
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Barden A, Shinde S, Beilin LJ, Phillips M, Adams L, Bollmann S, Mori TA. Adiposity associates with lower plasma resolvin E1 (Rve1): a population study. Int J Obes (Lond) 2024; 48:725-732. [PMID: 38347128 PMCID: PMC11058310 DOI: 10.1038/s41366-024-01482-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 01/16/2024] [Accepted: 01/19/2024] [Indexed: 02/17/2024]
Abstract
BACKGROUND Inadequate inflammation resolution may contribute to persistent low-grade inflammation that accompanies many chronic conditions. Resolution of inflammation is an active process driven by Specialized Pro-resolving Mediators (SPM) that derive from long chain n-3 and n-6 fatty acids. This study examined plasma SPM in relation to sex differences, lifestyle and a broad range cardiovascular disease (CVD) risk factors in 978, 27-year olds from the Australian Raine Study. METHODS Plasma SPM pathway intermediates (18-HEPE, 17-HDHA and 14-HDHA), and SPM (E- and D-series resolvins, PD1, MaR1) and LTB4 were measured by liquid chromatography-tandem mass spectrometry (LCMSMS). Pearson correlations and multiple regression analyses assessed relationships between SPM and CVD risk factors. Unpaired t-tests or ANOVA assessed the effect of sex, smoking, unhealthy alcohol consumption and obesity on SPM. RESULTS Women had higher 17-HDHA (p = 0.01) and lower RvE1 (p < 0.0001) and RvD1 (p = 0.05) levels compared with men. In univariate analysis, obesity associated with lower RvE1 (p = 0.002), whereas smoking (p < 0.001) and higher alcohol consumption (p < 0.001) associated with increased RvE1. In multiple regression analysis, plasma RvE1 was negatively associated with a range of measures of adiposity including BMI, waist circumference, waist-to-height ratio, abdominal subcutaneous fat volume, and skinfold thicknesses in both men and women. CONCLUSION This population study suggests that a deficiency in plasma RvE1 may occur in response to increasing adiposity. This observation could be relevant to ongoing inflammation that associates with CVD and other chronic diseases.
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Affiliation(s)
- Anne Barden
- Medical School, University of Western Australia, Perth, WA, Australia.
| | - Sujata Shinde
- Medical School, University of Western Australia, Perth, WA, Australia
| | - Lawrence J Beilin
- Medical School, University of Western Australia, Perth, WA, Australia
| | - Michael Phillips
- Centre for Medical Research, University of Western Australia, Perth, WA, Australia
- Royal Perth Hospital Research Foundation, Perth, WA, Australia
| | - Leon Adams
- Medical School, University of Western Australia, Perth, WA, Australia
| | - Steffen Bollmann
- School of Information Technology and Electrical Engineering, Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD, Australia
| | - Trevor A Mori
- Medical School, University of Western Australia, Perth, WA, Australia
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Gong J. Oxylipins biosynthesis and the regulation of bovine postpartum inflammation. Prostaglandins Other Lipid Mediat 2024; 171:106814. [PMID: 38280540 DOI: 10.1016/j.prostaglandins.2024.106814] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 01/08/2024] [Accepted: 01/23/2024] [Indexed: 01/29/2024]
Abstract
Uncontrolled or dysregulated inflammation has adverse effects on the reproduction, production and health of animals, and is a major pathological cause of increased incidence and severity of infectious and metabolic diseases. To achieve successful transition from a non-lactation pregnant state to a non-pregnant lactation state, drastic metabolic and endocrine alteration have taken place in dairy cows during the periparturient period. These physiological changes, coupled with decreased dry matter intake near calving and sudden change of diet composition after calving, have the potential to disrupt the delicate balance between pro- and anti-inflammation, resulting in a disordered or excessive inflammatory response. In addition to cytokines and other immunoregulatory factors, most oxylipins formed from polyunsaturated fatty acids (PUFAs) via enzymatic and nonenzymatic oxygenation pathways have pro- or anti-inflammatory properties and play a pivotal role in the onset, development and resolution of inflammation. However, little attention has been paid to the possibility that oxylipins could function as endogenous immunomodulating agents. This review will provide a detailed overview of the main oxylipins derived from different PUFAs and discuss the regulatory role that oxylipins play in the postpartum inflammatory response in dairy cows. Based on the current research, much remains to be illuminated in this emerging field. Understanding the role that oxylipins play in the control of postpartum inflammation and inflammatory-based disease may improve our ability to prevent transition disorders via Management, pharmacological, genetic selection and dietary intervention strategies.
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Affiliation(s)
- Jian Gong
- College of Life Science and Technology, Inner Mongolia Normal University, 81 Zhaowuda Road, Hohhot 010022, China.
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11
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Lu X, Li G, Liu Y, Luo G, Ding S, Zhang T, Li N, Geng Q. The role of fatty acid metabolism in acute lung injury: a special focus on immunometabolism. Cell Mol Life Sci 2024; 81:120. [PMID: 38456906 PMCID: PMC10923746 DOI: 10.1007/s00018-024-05131-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2023] [Revised: 01/06/2024] [Accepted: 01/17/2024] [Indexed: 03/09/2024]
Abstract
Reputable evidence from multiple studies suggests that excessive and uncontrolled inflammation plays an indispensable role in mediating, amplifying, and protracting acute lung injury (ALI). Traditionally, immunity and energy metabolism are regarded as separate functions regulated by distinct mechanisms, but recently, more and more evidence show that immunity and energy metabolism exhibit a strong interaction which has given rise to an emerging field of immunometabolism. Mammalian lungs are organs with active fatty acid metabolism, however, during ALI, inflammation and oxidative stress lead to a series metabolic reprogramming such as impaired fatty acid oxidation, increased expression of proteins involved in fatty acid uptake and transport, enhanced synthesis of fatty acids, and accumulation of lipid droplets. In addition, obesity represents a significant risk factor for ALI/ARDS. Thus, we have further elucidated the mechanisms of obesity exacerbating ALI from the perspective of fatty acid metabolism. To sum up, this paper presents a systematical review of the relationship between extensive fatty acid metabolic pathways and acute lung injury and summarizes recent advances in understanding the involvement of fatty acid metabolism-related pathways in ALI. We hold an optimistic believe that targeting fatty acid metabolism pathway is a promising lung protection strategy, but the specific regulatory mechanisms are way too complex, necessitating further extensive and in-depth investigations in future studies.
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Affiliation(s)
- Xiao Lu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Guorui Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Yi Liu
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Guoqing Luo
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Song Ding
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Tianyu Zhang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China
| | - Ning Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Jiefang Road 238, Wuhan, 430060, China.
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12
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Shaikh SR, Beck MA, Alwarawrah Y, MacIver NJ. Emerging mechanisms of obesity-associated immune dysfunction. Nat Rev Endocrinol 2024; 20:136-148. [PMID: 38129700 DOI: 10.1038/s41574-023-00932-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/27/2023] [Indexed: 12/23/2023]
Abstract
Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population.
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Affiliation(s)
- Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Melinda A Beck
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Yazan Alwarawrah
- Department of Paediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nancie J MacIver
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
- Department of Paediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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13
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Yu HY, Kim KK, Baek SH, Park CI, Jeon HJ, Song AR, Park HJ, Park IB, Kang JS, Kim JM, Kim TW, Jang SM, Cha JY, Kim J. Effect of YC-1102 on the Improvement of Obesity in High-Fat Diet-Induced Obese Mice. Curr Issues Mol Biol 2024; 46:1437-1450. [PMID: 38392211 PMCID: PMC10887656 DOI: 10.3390/cimb46020093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 01/30/2024] [Accepted: 02/03/2024] [Indexed: 02/24/2024] Open
Abstract
Obesity is one of the major risk factors for metabolic diseases worldwide. This study examined the effects of YC-1102, an extract derived from the roots of Rosa multiflora, on 3T3-L1 preadipocytes and high-fat diet (HFD)-induced obese mice. In vivo experiments involved the oral administration of YC-1102 (100, 150, and 200 mg/kg body weight) daily to mice for eight weeks. YC-1102 was found to downregulate the expressions of PPARγ and C/EBPα during adipogenesis, inhibiting adipocyte differentiation and upregulating the expression of PGC-1α for energy metabolism to enhance mitochondrial biogenesis and fatty acid oxidation. It has been shown that daily administration of YC-1102 to mice receiving a HFD prevented an increase in body weight and the accumulation of body fat. YC-1102 administration also reduced TG, TC, and LDL cholesterol levels, as well as glucose and leptin levels, and increased adiponectin levels, thus effectively inhibiting the metabolism of lipids. YC-1102-treated mice showed significant reductions in the mRNA expression of PPARγ and C/EBPα. The levels of PGC-1α involved in energy metabolism increased significantly in the YC-1102-treated mice when compared to the HFD-treated mice. According to the findings of this study, YC-1102 has a dual mechanism that reduces transcription factors that promote the differentiation of adipocytes and increases transcription factors that promote energy consumption.
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Affiliation(s)
- Hwa-Young Yu
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju 54907, Republic of Korea
| | - Kyoung Kon Kim
- Newgen Healthcare Co., Ltd., 56 Soyanggang-ro, Chuncheon-si 24232, Republic of Korea
| | - Sin Hwa Baek
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
| | - Cho I Park
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
| | - Hye Jin Jeon
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
| | - Ae Ri Song
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
| | - Hyun-Je Park
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
| | - Il Bum Park
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
| | - Jong Soo Kang
- Yuhan Care Co., Ltd., Seoul 07335, Republic of Korea
| | - Jung Min Kim
- Newgen Healthcare Co., Ltd., 56 Soyanggang-ro, Chuncheon-si 24232, Republic of Korea
| | - Tae Woo Kim
- Newgen Healthcare Co., Ltd., 56 Soyanggang-ro, Chuncheon-si 24232, Republic of Korea
| | - Sun Min Jang
- Newgen Healthcare Co., Ltd., 56 Soyanggang-ro, Chuncheon-si 24232, Republic of Korea
| | - Joo Young Cha
- Yuhan Care Co., Ltd., Yuhan Care R&D Center, Yongin-si 17084, Republic of Korea
- Yuhan Care Co., Ltd., Yuhan Natural Product R&D Center, Andong-si 36618, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
| | - Junghyun Kim
- Department of Oral Pathology, School of Dentistry, Jeonbuk National University, Jeonju 54907, Republic of Korea
- Non-Clinical Evaluation Center Biomedical Research Institute, Jeonbuk National University Hospital, Jeonju 57907, Republic of Korea
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14
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McGowan NG, Zhong JH, Trasande L, Hellmann J, Heffron SP. A randomized, placebo-controlled crossover trial to assess the influence of body weight on aspirin-triggered specialized pro-resolving mediators: Protocol for the DISCOVER Study. INTERNATIONAL JOURNAL OF CLINICAL TRIALS 2024; 11:53-60. [PMID: 38585621 PMCID: PMC10997378 DOI: 10.18203/2349-3259.ijct20240043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Background Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. Methods To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Results Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Conclusions Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin's role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight.
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Affiliation(s)
- Natalie G McGowan
- Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Judy H Zhong
- Department of Population Health, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Leonardo Trasande
- Department of Population Health, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- Department of Pediatrics, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- Department of Environmental Medicine, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
| | - Jason Hellmann
- Christina Lee Brown Envirome Institute, Diabetes and Obesity Center, Division of Environmental Medicine, University of Louisville School of Medicine, 500 S Preston St, Louisville, KY 40202 USA
| | - Sean P Heffron
- Leon H. Charney Division of Cardiology, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
- NYU Center for the Prevention of Cardiovascular Disease, NYU Grossman School of Medicine, 550 1 Ave, New York, NY 10016 USA
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15
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Szczuko M, Szwec-Nadworna N, Palma J, Tomasik M, Ziętek M. Increased Demand of Obese Women for Protectins, Maresin, and Resolvin D1 in the Last Trimester of Pregnancy. Nutrients 2023; 15:4340. [PMID: 37892415 PMCID: PMC10609750 DOI: 10.3390/nu15204340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Revised: 10/05/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
BACKGROUND Pregnancy is a physiological state during which inflammation occurs. This complex biological response is necessary for the implantation process as well as delivery. In turn, its suppression during gestation favors the normal course of the pregnancy. Therefore, the presence of pro-resolving mediators, EPA and DHA derivatives, The aim of this study was to investigate the changes in the levels of anti-inflammatory resolvins and their precursors in different trimesters of pregnancy with consideration of the women's weight, including overweight and obese women before pregnancy. METHODS A total of 78 women participated in this study; the mean age and BMI before pregnancy were 32.3 ± 5.52 and 27.73 ± 6.13, respectively. The patients were divided into two groups, considering their BMI before pregnancy. The extraction of eicosanoids was performed by high-performance liquid chromatography. The results obtained were subjected to statistical analysis. The levels of all studied parameters showed statistically significant differences between the study group (SG) and the control group (CG) in the different trimesters of pregnancy. Over the course of pregnancy, the levels of protection (PDX), maresin, resolvins (RvD1, RvE1), and their precursors differed in relation to the trimester of pregnancy and the division into groups considering the correct body weight before pregnancy. RESULTS Overweight or obese women had significantly lower levels of RvE1 in the third trimester and their precursors compared to normal-weight women. While the levels of PDX and RvD1 were significantly higher, this may be due to both a lower intake of products rich in omega-3 fatty acids by obese women and an increased need of obese women's bodies to quench chronic inflammatory processes associated with obesity. CONCLUSIONS Both EPA and DHA derivatives are involved in calming down inflammation during pregnancy, which was observed.
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Affiliation(s)
- Małgorzata Szczuko
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, 71-460 Szczecin, Poland;
| | - Natalia Szwec-Nadworna
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University, 71-460 Szczecin, Poland;
| | - Joanna Palma
- Department of Biochemical Sciences, Pomeranian Medical University, 71-460 Szczecin, Poland;
| | - Małgorzata Tomasik
- Department of Integrated Dentistry, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Maciej Ziętek
- Department of Perinatology, Obstetrics and Gynecology, Pomeranian Medical University, 72-010 Police, Poland;
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16
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Moens de Hase E, Petitfils C, Alhouayek M, Depommier C, Le Faouder P, Delzenne NM, Van Hul M, Muccioli GG, Cenac N, Cani PD. Dysosmobacter welbionis effects on glucose, lipid, and energy metabolism are associated with specific bioactive lipids. J Lipid Res 2023; 64:100437. [PMID: 37648213 PMCID: PMC10542644 DOI: 10.1016/j.jlr.2023.100437] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 08/14/2023] [Accepted: 08/23/2023] [Indexed: 09/01/2023] Open
Abstract
The newly identified bacterium Dysosmobacter welbionis J115T improves host metabolism in high-fat diet (HFD)-fed mice. To investigate mechanisms, we used targeted lipidomics to identify and quantify bioactive lipids produced by the bacterium in the culture medium, the colon, the brown adipose tissue (BAT), and the blood of mice. In vitro, we compared the bioactive lipids produced by D. welbionis J115T versus the probiotic strain Escherichia coli Nissle 1917. D. welbionis J115T administration reduced body weight, fat mass gain, and improved glucose tolerance and insulin resistance in HFD-fed mice. In vitro, 19 bioactive lipids were highly produced by D. welbionis J115T as compared to Escherichia coli Nissle 1917. In the plasma, 13 lipids were significantly changed by the bacteria. C18-3OH was highly present at the level of the bacteria, but decreased by HFD treatment in the plasma and normalized in D. welbionis J115T-treated mice. The metabolic effects were associated with a lower whitening of the BAT. In the BAT, HFD decreased the 15-deoxy-Δ12,14-prostaglandin J2, a peroxisome proliferator-activated receptor (PPAR-γ) agonist increased by 700% in treated mice as compared to HFD-fed mice. Several genes controlled by PPAR-γ were upregulated in the BAT. In the colon, HFD-fed mice had a 60% decrease of resolvin D5, whereas D. welbionis J115T-treated mice exhibited a 660% increase as compared to HFD-fed mice. In a preliminary experiment, we found that D. welbionis J115T improves colitis. In conclusion, D. welbionis J115T influences host metabolism together with several bioactive lipids known as PPAR-γ agonists.
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Affiliation(s)
- Emilie Moens de Hase
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium; WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
| | - Camille Petitfils
- IRSD, INSERM, INRA, INP-ENVT, Toulouse University 3 Paul Sabatier, Toulouse, France
| | - Mireille Alhouayek
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Clara Depommier
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium; WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
| | | | - Nathalie M Delzenne
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Matthias Van Hul
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium; WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Nicolas Cenac
- IRSD, INSERM, INRA, INP-ENVT, Toulouse University 3 Paul Sabatier, Toulouse, France
| | - Patrice D Cani
- Metabolism and Nutrition Research group, Louvain Drug Research Institute (LDRI), UCLouvain, Université catholique de Louvain, Brussels, Belgium; WELBIO-Walloon Excellence in Life Sciences and Biotechnology, WELBIO department, WEL Research Institute, Wavre, Belgium; Institute of Experimental and Clinical Research (IREC), UCLouvain, Université catholique de Louvain, Brussels, Belgium.
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17
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Ruggeri RM, Barbalace MC, Croce L, Malaguti M, Campennì A, Rotondi M, Cannavò S, Hrelia S. Autoimmune Thyroid Disorders: The Mediterranean Diet as a Protective Choice. Nutrients 2023; 15:3953. [PMID: 37764737 PMCID: PMC10535745 DOI: 10.3390/nu15183953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 09/06/2023] [Accepted: 09/10/2023] [Indexed: 09/29/2023] Open
Abstract
Autoimmune thyroid diseases are on the rise worldwide, and such a rapid increase is mainly driven by environmental factors related to changed lifestyles in "modern" societies. In this context, diet seems to play a crucial role. An unhealthy high-energy diet, rich in animal fat and proteins, salt and refined sugars (the so-called "Western diet") negatively influences the risk of autoimmunity by altering the immune balance and the gut microbiota composition, enhancing oxidative stress and promoting inflammation. In contrast, the Mediterranean diet represents a unique model of healthy eating, characterized by a high intake of food from vegetable sources, a low consumption of saturated fats in favor of unsaturated fats (mainly, olive oil), a moderate consumption of fish (typically, the small oily fishes) and dairy products, as well as a moderate consumption of wine at meals, and a low intake of meat. Thanks to its nutritional components, the Mediterranean Diet positively influences immune system function, gut microbiota composition, and redox homeostasis, exerting anti-oxidants, anti-inflammatory, and immunomodulatory effects. The present review was aimed at exploring the existing knowledge on the correlations between dietary habits and thyroid autoimmunity, to evaluate the role of the Mediterranean diet as a protective model.
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Affiliation(s)
- Rosaria Maddalena Ruggeri
- Department of Human Pathology of Adulthood and Childhood DETEV “G. Barresi”, Endocrinology Unit, University of Messina, 98125 Messina, Italy;
| | - Maria Cristina Barbalace
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (M.C.B.); (S.H.)
| | - Laura Croce
- Department of Internal Medicine and Therapeutics, Unit of Endocrinology and Metabolism, Laboratory for Endocrine Disruptors, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) University of Pavia, 27100 Pavia, Italy; (L.C.); (M.R.)
| | - Marco Malaguti
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (M.C.B.); (S.H.)
| | - Alfredo Campennì
- Department of Biomedical and Dental Sciences and Morpho-Functional Imaging, Unit of Nuclear Medicine, University of Messina, 98125 Messina, Italy;
| | - Mario Rotondi
- Department of Internal Medicine and Therapeutics, Unit of Endocrinology and Metabolism, Laboratory for Endocrine Disruptors, Istituti Clinici Scientifici Maugeri, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) University of Pavia, 27100 Pavia, Italy; (L.C.); (M.R.)
| | - Salvatore Cannavò
- Department of Human Pathology of Adulthood and Childhood DETEV “G. Barresi”, Endocrinology Unit, University of Messina, 98125 Messina, Italy;
| | - Silvana Hrelia
- Department for Life Quality Studies, Alma Mater Studiorum, University of Bologna, 40126 Bologna, Italy; (M.C.B.); (S.H.)
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18
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Laiglesia LM, Escoté X, Sáinz N, Felix-Soriano E, Santamaría E, Collantes M, Fernández-Galilea M, Colón-Mesa I, Martínez-Fernández L, Quesada-López T, Quesada-Vázquez S, Rodríguez-Ortigosa C, Arbones-Mainar JM, Valverde ÁM, Martínez JA, Dalli J, Herrero L, Lorente-Cebrián S, Villarroya F, Moreno-Aliaga MJ. Maresin 1 activates brown adipose tissue and promotes browning of white adipose tissue in mice. Mol Metab 2023; 74:101749. [PMID: 37271337 PMCID: PMC10331312 DOI: 10.1016/j.molmet.2023.101749] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2022] [Revised: 05/19/2023] [Accepted: 06/01/2023] [Indexed: 06/06/2023] Open
Abstract
OBJECTIVE Maresin 1 (MaR1) is a docosahexaenoic acid-derived proresolving lipid mediator with insulin-sensitizing and anti-steatosis properties. Here, we aim to unravel MaR1 actions on brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning. METHODS MaR1 actions were tested in cultured murine brown adipocytes and in human mesenchymal stem cells (hMSC)-derived adipocytes. In vivo effects of MaR1 were tested in diet-induced obese (DIO) mice and lean WT and Il6 knockout (Il6-/-) mice. RESULTS In cultured differentiated murine brown adipocytes, MaR1 reduces the expression of inflammatory genes, while stimulates glucose uptake, fatty acid utilization and oxygen consumption rate, along with the upregulation of mitochondrial mass and genes involved in mitochondrial biogenesis and function and the thermogenic program. In Leucine Rich Repeat Containing G Protein-Coupled Receptor 6 (LGR6)-depleted brown adipocytes using siRNA, the stimulatory effect of MaR1 on thermogenic genes was abrogated. In DIO mice, MaR1 promotes BAT remodeling, characterized by higher expression of genes encoding for master regulators of mitochondrial biogenesis and function and iBAT thermogenic activation, together with increased M2 macrophage markers. In addition, MaR1-treated DIO mice exhibit a better response to cold-induced BAT activation. Moreover, MaR1 induces a beige adipocyte signature in inguinal WAT of DIO mice and in hMSC-derived adipocytes. MaR1 potentiates Il6 expression in brown adipocytes and BAT of cold exposed lean WT mice. Interestingly, the thermogenic properties of MaR1 were abrogated in Il6-/- mice. CONCLUSIONS These data reveal MaR1 as a novel agent that promotes BAT activation and WAT browning by regulating thermogenic program in adipocytes and M2 polarization of macrophages. Moreover, our data suggest that LGR6 receptor is mediating MaR1 actions on brown adipocytes, and that IL-6 is required for the thermogenic effects of MaR1.
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Affiliation(s)
- Laura M Laiglesia
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
| | - Xavier Escoté
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain; Eurecat, Centre Tecnològic de Catalunya, Unitat de Nutrició i Salut, Reus, 43204 Spain
| | - Neira Sáinz
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
| | - Elisa Felix-Soriano
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
| | - Eva Santamaría
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III (ISCIII), Madrid 28029, Spain; Division of Hepatology, Center for Applied Medical Research, University of Navarra, Pamplona, Spain
| | - María Collantes
- Department of Nuclear Medicine/ Translational Molecular Imaging Unit (UNIMTRA), Clínica Universidad de Navarra, Pamplona, 31008, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Marta Fernández-Galilea
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain
| | - Ignacio Colón-Mesa
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
| | - Leyre Martínez-Fernández
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain
| | - Tania Quesada-López
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | | | | | - José M Arbones-Mainar
- Adipocyte and Fat Biology Laboratory (AdipoFat), Instituto de Investigación Sanitaria Aragón, Instituto Aragonés de Ciencias de la Salud, Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Zaragoza, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Ángela M Valverde
- Alberto Sols Biomedical Research Institute (IIBm) (CSIC/UAM), Madrid, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - J Alfredo Martínez
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - Jesmond Dalli
- William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK; Center for Inflammation and Therapeutic Innovation, Queen Mary University of London, London, UK
| | - Laura Herrero
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain
| | - Silvia Lorente-Cebrián
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Current address: Department of Pharmacology, Physiology, Legal and Forensic Medicine. Faculty of Health and Sport Science, University of Zaragoza, Zaragoza, Spain
| | - Francesc Villarroya
- Department of Biochemistry and Molecular Biomedicine, Institute of Biomedicine of the University of Barcelona, Barcelona, Catalonia, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
| | - María J Moreno-Aliaga
- University of Navarra, Center for Nutrition Research, Pamplona, 31008, Spain; University of Navarra, Department of Nutrition, Food Science and Physiology, Pamplona, 31008, Spain; Navarra Institute for Health Research (IdiSNA), Pamplona, Spain; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain.
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19
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Beyer MP, Videla LA, Farías C, Valenzuela R. Potential Clinical Applications of Pro-Resolving Lipids Mediators from Docosahexaenoic Acid. Nutrients 2023; 15:3317. [PMID: 37571256 PMCID: PMC10421104 DOI: 10.3390/nu15153317] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/16/2023] [Accepted: 07/24/2023] [Indexed: 08/13/2023] Open
Abstract
Docosahexaenoic acid (C22:6n-3, DHA) is the precursor of specialized pro-resolving lipid mediators (SPMs), such as resolvin, protectin, and maresin families which have been considered therapeutic bioactive compounds for human health. Growing evidence indicates that DHA and SPMs are beneficial strategies in the amelioration, regulation, and duration of inflammatory processes through different biological actions. The present review discusses the reported therapeutic benefits of SPMs on various diseases and their potential clinical applications.
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Affiliation(s)
- María Paz Beyer
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380000, Chile; (M.P.B.); (C.F.)
| | - Luis A. Videla
- Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago 7810000, Chile;
| | - Camila Farías
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380000, Chile; (M.P.B.); (C.F.)
| | - Rodrigo Valenzuela
- Department of Nutrition, Faculty of Medicine, University of Chile, Santiago 8380000, Chile; (M.P.B.); (C.F.)
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20
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Martínez-Fernández L, Burgos M, Sáinz N, Laiglesia LM, Arbones-Mainar JM, González-Muniesa P, Moreno-Aliaga MJ. Maresin 1 Exerts a Tissue-Specific Regulation of Adipo-Hepato-Myokines in Diet-Induced Obese Mice and Modulates Adipokine Expression in Cultured Human Adipocytes in Basal and Inflammatory Conditions. Biomolecules 2023; 13:919. [PMID: 37371501 DOI: 10.3390/biom13060919] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 05/17/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
This study analyses the effects of Maresin 1 (MaR1), a docosahexaenoic acid (DHA)-derived specialized proresolving lipid mediator with anti-inflammatory and insulin-sensitizing actions, on the expression of adipokines, including adiponectin, leptin, dipeptidyl peptidase 4 (DPP-4), cardiotrophin-1 (CT-1), and irisin (FNDC5), both in vitro and in in vivo models of obesity. The in vivo effects of MaR1 (50 μg/kg, 10 days, oral gavage) were evaluated in epididymal adipose tissue (eWAT), liver and muscle of diet-induced obese (DIO) mice. Moreover, two models of human differentiated primary adipocytes were incubated with MaR1 (1 and 10 nM, 24 h) or with a combination of tumor necrosis factor-α (TNF-α, 100 ng/mL) and MaR1 (1-200 nM, 24 h) and the expression and secretion of adipokines were measured in both models. MaR1-treated DIO mice exhibited an increased expression of adiponectin and Ct-1 in eWAT, increased expression of Fndc5 and Ct-1 in muscle and a decreased expression of hepatic Dpp-4. In human differentiated adipocytes, MaR1 increased the expression of ADIPONECTIN, LEPTIN, DPP4, CT-1 and FNDC5. Moreover, MaR1 counteracted the downregulation of ADIPONECTIN and the upregulation of DPP-4 and LEPTIN observed in adipocytes treated with TNF-α. Differential effects for TNF-α and MaR1 on the expression of CT-1 and FNDC5 were observed between both models of human adipocytes. In conclusion, MaR1 reverses the expression of specific adipomyokines and hepatokines altered in obese mice in a tissue-dependent manner. Moreover, MaR1 regulates the basal expression of adipokines in human adipocytes and counteracts the alterations of adipokines expression induced by TNF-α in vitro. These actions could contribute to the metabolic benefits of this lipid mediator.
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Affiliation(s)
- Leyre Martínez-Fernández
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
| | - Miguel Burgos
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
- IDISNA-Navarra Institute for Health Research, 31008 Pamplona, Spain
| | - Neira Sáinz
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
| | - Laura M Laiglesia
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
| | - José Miguel Arbones-Mainar
- Adipocyte and Fat Biology Laboratory (AdipoFat), Unidad de Investigación Traslacional, Instituto Aragonés de Ciencias de la Salud (IACS), Instituto de Investigación Sanitaria (IIS) Aragón, Hospital Universitario Miguel Servet, 50009 Zaragoza, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Pedro González-Muniesa
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
- IDISNA-Navarra Institute for Health Research, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - María J Moreno-Aliaga
- Department of Nutrition, Food Science and Physiology, Center for Nutrition Research, School of Pharmacy and Nutrition, University of Navarra, 31008 Pamplona, Spain
- IDISNA-Navarra Institute for Health Research, 31008 Pamplona, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
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21
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Raj RR, Lofquist S, Lee MJ. Remodeling of Adipose Tissues by Fatty Acids: Mechanistic Update on Browning and Thermogenesis by n-3 Polyunsaturated Fatty Acids. Pharm Res 2023; 40:467-480. [PMID: 36050546 DOI: 10.1007/s11095-022-03377-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 08/18/2022] [Indexed: 11/24/2022]
Abstract
Enhancing thermogenesis by increasing the amount and activity of brown and brite adipocytes is a potential therapeutic target for obesity and its associated diseases. Diet plays important roles in energy metabolism and a myriad of dietary components including lipids are known to regulate thermogenesis through recruitment and activation of brown and brite adipocytes. Depending on types of fatty acids (FAs), the major constituent in lipids, their health benefits differ. Long-chain polyunsaturated FAs (PUFAs), especially n-3 PUFAs remodel adipose tissues in a healthier manner with reduced inflammation and enhanced thermogenesis, while saturated FAs exhibit contrasting effects. Lipid mediators derived from FAs act as autocrine/paracrine as well as endocrine factors to regulate thermogenesis. We discuss lipid mediators that may contribute to the differential effects of FAs on adipose tissue remodeling and hence, cardiometabolic diseases. We also discuss current understanding of molecular and cellular mechanisms through which n-3 PUFAs enhance thermogenesis. Elucidating molecular details of beneficial effects of n-3 PUFAs on thermogenesis is expected to provide information that can be used for development of novel therapeutics for obesity and its associated diseases.
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Affiliation(s)
- Radha Raman Raj
- Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, 1955 East West Road, Honolulu, HI, 98622, USA
| | - Sydney Lofquist
- Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, 1955 East West Road, Honolulu, HI, 98622, USA
| | - Mi-Jeong Lee
- Department of Human Nutrition, Food and Animal Sciences, University of Hawaii at Manoa, 1955 East West Road, Honolulu, HI, 98622, USA.
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22
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Abstract
Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms.
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Affiliation(s)
- Catherine Godson
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland;
- The Conway Institute, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
| | - Patrick Guiry
- Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Dublin, Ireland
| | - Eoin Brennan
- Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland;
- The Conway Institute, University College Dublin, Dublin, Ireland
- School of Medicine, University College Dublin, Dublin, Ireland
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23
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Effects of Fish Oil, Lipid Mediators, Derived from Docosahexaenoic Acid, and Their Co-Treatment against Lipid Metabolism Dysfunction and Inflammation in HFD Mice and HepG2 Cells. Nutrients 2023; 15:nu15020427. [PMID: 36678298 PMCID: PMC9864948 DOI: 10.3390/nu15020427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Although fish oil (FO) and lipid mediators (LM) derived from polyunsaturated fatty acids can prevent obesity, their combined effects and cellular metabolism remain unclear. Therefore, this study aimed to examine the potential protective and metabolic effects of FO in combination with LM (a mixture of 17S-monohydroxy docosahexaenoic acid, resolvin D5, and protectin DX [3:47:50], derived from docosahexaenoic acid (DHA)) on palmitic acid (PA)-induced HepG2 cells and high-fat- diet (HFD)-induced C57BL/6J mice after 9-week treatment. Lipid metabolism disorders and inflammation induced by HFD and PA were substantially reduced after FO and LM treatment. Further, FO and LM treatments reduced lipid accumulation by increasing fatty acid oxidation via peroxisome proliferator-activated receptor α and carnitine-palmitoyl transferase 1 as well as by decreasing fatty acid synthesis via sterol regulatory element-binding protein-1c and fatty acid synthase. Finally, FO and LM treatment reduced inflammation by blocking the NF-κB signaling pathway. Importantly, the combination of FO and LM exhibited more robust efficacy against nonalcoholic fatty liver disease, suggesting that FO supplemented with LM is a beneficial dietary strategy for treating this disease.
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24
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Lamon-Fava S, Liu M, Dunlop BW, Kinkead B, Schettler PJ, Felger JC, Ziegler TR, Fava M, Mischoulon D, Rapaport MH. Clinical response to EPA supplementation in patients with major depressive disorder is associated with higher plasma concentrations of pro-resolving lipid mediators. Neuropsychopharmacology 2023; 48:929-935. [PMID: 36635595 PMCID: PMC10156711 DOI: 10.1038/s41386-022-01527-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/21/2022] [Accepted: 12/26/2022] [Indexed: 01/14/2023]
Abstract
Chronic inflammation has been implicated in the pathophysiology of major depressive disorder (MDD). Activating the resolution of inflammation through ω-3 fatty acid supplementation may prove to be a successful therapeutic strategy for the treatment of MDD. Patients with MDD, body mass index >25 kg/m2, and plasma high-sensitivity C-reactive protein ≥3 μg/mL (n = 61) were enrolled in a 12-week randomized trial consisting of 4 parallel arms: EPA 1, 2, and 4 g/d, and placebo. The supplement contained EPA and DHA in a 3.9:1 ratio. Depression symptoms were assessed using the IDS-C30 scale. Plasma fatty acids and pro-resolving lipid mediators (SPMs) were measured in 42 study completers at baseline and at the end of treatment by liquid chromatography/mass spectrometry. The response rate (≥50% reduction in IDS-30 score) was higher in the 4 g/d EPA arm than placebo (Cohen d = 0.53). In the 4 g/d EPA arm, responders had significantly greater increases in 18-hydroxyeicosapentaenoic acid (18-HEPE) and 13-hydroxydocosahexaenoic acid (13-HDHA) than non-responders (p < 0.05). Within the 4 g/d EPA arm, the increase in 18-HEPE was significantly associated with reductions in plasma hs-CRP concentrations (p < 0.05) and IDS-C30 scores (p < 0.01). In summary, response rates were greater among patients with MDD randomized to EPA 4 g/d supplementation and in those who showed a greater ability to activate the synthesis of 18-HEPE. The inverse association of 18-HEPE with both systemic inflammation and symptoms of depression highlights the activation of the resolution of inflammation as a likely mechanism in the treatment of MDD with ω-3 fatty acid supplementation.
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Affiliation(s)
- Stefania Lamon-Fava
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
| | - Minying Liu
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA
| | - Boadie W Dunlop
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Becky Kinkead
- Huntsman Mental Health Institute, Department of Psychiatry, University of Utah, Salt Lake City, UT, USA
| | - Pamela J Schettler
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | - Jennifer C Felger
- Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA
| | | | - Maurizio Fava
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - David Mischoulon
- Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA
| | - Mark Hyman Rapaport
- Huntsman Mental Health Institute, Department of Psychiatry, University of Utah, Salt Lake City, UT, USA
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25
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Xie R, Zhang Y. Association between 19 dietary fatty acids intake and rheumatoid arthritis: Results of a nationwide survey. Prostaglandins Leukot Essent Fatty Acids 2023; 188:102530. [PMID: 36586398 DOI: 10.1016/j.plefa.2022.102530] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2022] [Revised: 11/30/2022] [Accepted: 12/23/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND The relationship between dietary fatty acid intakes and rheumatoid arthritis (RA) is unclear and the available studies have focused on only a few fatty acids. This study investigated the association between the intake of 19 dietary fatty acids and RA in U.S. adults. METHODS This cross-sectional study using nationally representative data from the 2010-2020 National Health and Nutrition Examination Survey (NHANES). Multivariate linear regression model, multivariate logic regression models, smoothing curve fitting, and two-segment linear regression model were used to explore the relationships between 19 dietary fatty acids intakes with high-sensitivity C-reactive protein (Hs-CRP) and RA risk. RESULTS A total of 16,530 participants were included (1053 participants with RA). Intake of hexadecanoic acid and octadecanoic acid were significantly associated with higher Hs-CRP levels, intake of hexadecenoic acid was significantly associated with higher RA risk, and intake of docosahexaenoic acid was significantly associated with lower RA risk. In addition, there was an inverted U-shaped relationship between total monounsaturated fatty acids (MUFAs) intake and RA risk, with the inflection point reached at 15.77% . CONCLUSIONS Among the 19 dietary fatty acids, only 4 subclasses were significantly associated with Hs-CRP or RA risk. The inverted U-shaped relationship between MUFAs and RA risk may provide insights to find potential prevention strategies for RA.
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Affiliation(s)
- Ruijie Xie
- Department of Microsurgery, University of South China Affiliated Nanhua Hospital. Hengyang, China
| | - Ya Zhang
- Department of Gland Surgery, University of South China Affiliated Nanhua Hospital, Hengyang, China.
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26
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Shaikh SR, Virk R, Van Dyke TE. Potential Mechanisms by Which Hydroxyeicosapentaenoic Acids Regulate Glucose Homeostasis in Obesity. Adv Nutr 2022; 13:2316-2328. [PMID: 35709423 PMCID: PMC9776734 DOI: 10.1093/advances/nmac073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/16/2022] [Accepted: 06/13/2022] [Indexed: 01/29/2023] Open
Abstract
Dysregulation of glucose metabolism in response to diet-induced obesity contributes toward numerous complications, such as insulin resistance and hepatic steatosis. Therefore, there is a need to develop effective strategies to improve glucose homeostasis. In this review, we first discuss emerging evidence from epidemiological studies and rodent experiments that increased consumption of EPA (either as oily fish, or dietary/pharmacological supplements) may have a role in preventing impairments in insulin and glucose homeostasis. We then review the current evidence on how EPA-derived metabolites known as hydroxyeicosapentaenoic acids (HEPEs) may be a major mode of action by which EPA exerts its beneficial effects on glucose and lipid metabolism. Notably, cell culture and rodent studies show that HEPEs prevent fat accumulation in metabolic tissues through peroxisome proliferator activated receptor (PPAR)-mediated mechanisms. In addition, activation of the resolvin E1 pathway, either by administration of EPA in the diet or via intraperitoneal administration of resolvin E1, improves hyperglycemia, hyperinsulinemia, and liver steatosis through multiple mechanisms. These mechanisms include shifting immune cell phenotypes toward resolution of inflammation and preventing dysbiosis of the gut microbiome. Finally, we present the next steps for this line of research that will drive future precision randomized clinical trials with EPA and its downstream metabolites. These include dissecting the variables that drive heterogeneity in the response to EPA, such as the baseline microbiome profile and fatty acid status, circadian rhythm, genetic variation, sex, and age. In addition, there is a critical need to further investigate mechanisms of action for HEPEs and to establish the concentration of HEPEs in differing tissues, particularly in response to consumption of oily fish and EPA-enriched supplements.
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Affiliation(s)
- Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School
of Medicine, The University of North Carolina at Chapel Hill, Chapel
Hill, NC, USA
| | - Rafia Virk
- Department of Nutrition, Gillings School of Global Public Health and School
of Medicine, The University of North Carolina at Chapel Hill, Chapel
Hill, NC, USA
| | - Thomas E Van Dyke
- Center for Clinical and Translational Research, The Forsyth
Institute, Cambridge, MA, USA
- Department of Oral Medicine, Infection, and Immunity, Harvard School of
Dental Medicine, Harvard Medical School, Boston, MA, USA
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27
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da Silva Batista E, Nakandakari SCBR, Ramos da Silva AS, Pauli JR, Pereira de Moura L, Ropelle ER, Camargo EA, Cintra DE. Omega-3 pleiad: The multipoint anti-inflammatory strategy. Crit Rev Food Sci Nutr 2022; 64:4817-4832. [PMID: 36382659 DOI: 10.1080/10408398.2022.2146044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Omega 3 (ω3) fatty acids have been described since the 1980s as promising anti-inflammatory substances. Prostaglandin and leukotriene modulation were exhaustively explored as the main reason for ω3 beneficial outcomes. However, during the early 2000s, after the human genome decoding advent, the nutrigenomic approaches exhibited an impressive plethora of ω3 targets, now under the molecular point of view. Different G protein-coupled receptors (GPCRs) recognizing ω3 and its derivatives appear to be responsible for blocking inflammation and insulin-sensitizing effects. A new class of ω3-derived substances, such as maresins, resolvins, and protectins, increases ω3 actions. Inflammasome disruption, the presence of GPR120 on immune cell surfaces, and intracellular crosstalk signaling mediated by PPARγ compose the last discoveries regarding the multipoint anti-inflammatory targets for this nutrient. This review shows a detailed mechanistic proposal to understand ω3 fatty acid action over the inflammatory environment in the background of several chronic diseases.
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Affiliation(s)
- Ellencristina da Silva Batista
- Graduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Aracaju, Sergipe, Brazil
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrition Department, Federal University of Sergipe, Lagarto, Sergipe, Brazil
| | - Susana Castelo Branco Ramos Nakandakari
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | | | - José Rodrigo Pauli
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Leandro Pereira de Moura
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Eduardo Rochete Ropelle
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Laboratory of Molecular Biology of Exercise, School of Applied Sciences, UNICAMP, São Paulo, Brazil
| | - Enilton A Camargo
- Graduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Aracaju, Sergipe, Brazil
- Department of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil
| | - Dennys Esper Cintra
- Nutritional Genomics Laboratory, LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- Nutrigenomics and Lipids Research Center, CELN, School of Applied Sciences, UNICAMP, São Paulo, Brazil
- OCRC - Obesity and Comorbidities Research Center, UNICAMP, São Paulo, Brazil
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28
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Wang C, Lu J, Sun W, Merriman TR, Dalbeth N, Wang Z, Wang X, Han L, Cui L, Li X, Ji A, Li H, Ji X, He Y, Li C, Liu Z. Profiling of Serum Oxylipins Identifies Distinct Spectrums and Potential Biomarkers in Young People with Very Early Onset Gout. Rheumatology (Oxford) 2022; 62:1972-1979. [PMID: 36111871 PMCID: PMC10152281 DOI: 10.1093/rheumatology/keac507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 08/01/2022] [Accepted: 08/22/2022] [Indexed: 11/13/2022] Open
Abstract
Abstract
Objective
Oxylipins modulate inflammation via complex pathways. The oxylipin profile in gout remains unexplored. In this study, we systemically profiled oxylipins in young men and identified new oxylipin biomarkers for clinical use in differentiating gout from hyperuricemia.
Methods
Oxylipin profiling was performed in 90 men (30 very early onset gout, 30 asymptomatic HU (HU) and 30 normouricemia (NU), all aged <20 years) divided into discovery and validation sample sets. The dataset was analyzed based on orthogonal projection to latent structure-discriminant analysis (OPLS-DA). Correlation network and pathway enrichment were conducted to reveal potential oxylipin-involved pathways of gout. Candidate oxylipins were further evaluated and optimized in the validation cohort, and differential oxylipin biomarkers combined with or without serum urate were applied to construct diagnosis models.
Results
In discovery stage 21 differential oxylipins between the gout vs HU comparisons and 14 differential oxylipins between the gout vs NU comparisons were discovered. Correlation network analysis was performed and 14(S)-HDHA（14S-hydroxy-4Z, 7Z, 10Z, 12E, 16Z, 19Z-docosahexaenoic acid）was identified as a hub metabolite in both comparisons. Seven down-regulated oxylipins in gout vs HU group and five down-regulated oxylipins in gout vs NU group were validated. Diagnostic models were constructed with the above oxylipins, with 14(S)-HDHA alone acquiring area under the curve (AUC) 1 (95%CI, 1–1) in both comparisons.
Conclusion
Young men with very early onset gout have distinct oxylipin spectrums, especially those derived from AA (arachidonic acid), EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). Differential oxylipins could serve as candidate serum biomarkers in differentiating gout from hyperuricemia.
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Affiliation(s)
- Can Wang
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Jie Lu
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Wenyan Sun
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
| | - Tony R Merriman
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- University of Alabama at Birmingham Division of Clinical Immunology and Rheumatology, , Birmingham, Alabama, United States
| | - Nicola Dalbeth
- University of Auckland Department of Medicine, , Auckland, New Zealand
| | - Zhongjun Wang
- the Affiliated Hospital of Qingdao University Department of Clinical Laboratory, , Qingdao, China
| | - Xuefeng Wang
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Lin Han
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Lingling Cui
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Xinde Li
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Aichang Ji
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
| | - Hailong Li
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
| | - Xiaopeng Ji
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Yuwei He
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Changgui Li
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
| | - Zhen Liu
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, the Affiliated Hospital of Qingdao University , Qingdao, China
- Institute of Metabolic Diseases, Qingdao University , Qingdao, China
- Shandong Provincial Clinical Research Center for Immune Diseases and Gout , Qingdao, China
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Virk R, Buddenbaum N, Al-Shaer A, Armstrong M, Manke J, Reisdorph N, Sergin S, Fenton JI, Wallace ED, Ehrmann BM, Lovins HB, Gowdy KM, Smith MR, Smith GJ, Kelada SN, Shaikh SR. Obesity reprograms the pulmonary polyunsaturated fatty acid-derived lipidome, transcriptome, and gene-oxylipin networks. J Lipid Res 2022; 63:100267. [PMID: 36028048 PMCID: PMC9508350 DOI: 10.1016/j.jlr.2022.100267] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 07/27/2022] [Accepted: 08/14/2022] [Indexed: 01/13/2023] Open
Abstract
Obesity exacerbates inflammation upon lung injury; however, the mechanisms by which obesity primes pulmonary dysregulation prior to external injury are not well studied. Herein, we tested the hypothesis that obesity dysregulates pulmonary PUFA metabolism that is central to inflammation initiation and resolution. We first show that a high-fat diet (HFD) administered to C57BL/6J mice increased the relative abundance of pulmonary PUFA-containing triglycerides and the concentration of PUFA-derived oxylipins (particularly prostaglandins and hydroxyeicosatetraenoic acids), independent of an increase in total pulmonary PUFAs, prior to onset of pulmonary inflammation. Experiments with a genetic model of obesity (ob/ob) generally recapitulated the effects of the HFD on the pulmonary oxylipin signature. Subsequent pulmonary next-generation RNA sequencing identified complex and unique transcriptional regulation with the HFD. We found the HFD increased pathways related to glycerophospholipid metabolism and immunity, including a unique elevation in B cell differentiation and signaling. Furthermore, we conducted computational integration of lipidomic with transcriptomic data. These analyses identified novel HFD-driven networks between glycerophospholipid metabolism and B cell receptor signaling with specific PUFA-derived pulmonary oxylipins. Finally, we confirmed the hypothesis by demonstrating that the concentration of pulmonary oxylipins, in addition to inflammatory markers, were generally increased in mice consuming a HFD upon ozone-induced acute lung injury. Collectively, these data show that a HFD dysregulates pulmonary PUFA metabolism prior to external lung injury, which may be a mechanism by which obesity primes the lungs to respond poorly to infectious and/or inflammatory challenges.
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Affiliation(s)
- Rafia Virk
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nicole Buddenbaum
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Abrar Al-Shaer
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Michael Armstrong
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA
| | - Jonathan Manke
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA
| | - Nichole Reisdorph
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, USA
| | - Selin Sergin
- Department of Food Science and Human Nutrition, College of Agriculture and Natural Resources and College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, USA
| | - Jenifer I. Fenton
- Department of Food Science and Human Nutrition, College of Agriculture and Natural Resources and College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, USA
| | - E. Diane Wallace
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Brandie M. Ehrmann
- Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hannah B. Lovins
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA
| | - Kymberly M. Gowdy
- Division of Pulmonary, Critical Care and Sleep Medicine, The Ohio State University, Columbus, OH, USA
| | - M Ryan Smith
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, USA,Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, USA
| | - Gregory J. Smith
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Samir N.P. Kelada
- Marsico Lung Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,For correspondence: Saame Raza Shaikh
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Shaikh SR, MacIver NJ, Beck MA. Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms. Annu Rev Nutr 2022; 42:67-89. [PMID: 35995048 PMCID: PMC10880552 DOI: 10.1146/annurev-nutr-062320-115937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population.
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Affiliation(s)
- Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; , ,
| | - Nancie J MacIver
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; , ,
- Department of Pediatrics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Melinda A Beck
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; , ,
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Ketone Bodies and SIRT1, Synergic Epigenetic Regulators for Metabolic Health: A Narrative Review. Nutrients 2022; 14:nu14153145. [PMID: 35956321 PMCID: PMC9370141 DOI: 10.3390/nu14153145] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 07/21/2022] [Accepted: 07/27/2022] [Indexed: 11/17/2022] Open
Abstract
Ketone bodies (KBs) and Sirtuin-1 (SIRT1) have received increasing attention over the past two decades given their pivotal function in a variety of biological contexts, including transcriptional regulation, cell cycle progression, inflammation, metabolism, neurological and cardiovascular physiology, and cancer. As a consequence, the modulation of KBs and SIRT1 is considered a promising therapeutic option for many diseases. The direct regulation of gene expression can occur in vivo through histone modifications mediated by both SIRT1 and KBs during fasting or low-carbohydrate diets, and dietary metabolites may contribute to epigenetic regulation, leading to greater genomic plasticity. In this review, we provide an updated overview of the epigenetic interactions between KBs and SIRT1, with a particular glance at their central, synergistic roles for metabolic health.
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Al-Shaer AE, Regan J, Buddenbaum N, Tharwani S, Drawdy C, Behee M, Sergin S, Fenton JI, Maddipati KR, Kane S, Butler E, Shaikh SR. Enriched Marine Oil Supplement Increases Specific Plasma Specialized Pro-Resolving Mediators in Adults with Obesity. J Nutr 2022; 152:1783-1791. [PMID: 35349683 PMCID: PMC9258560 DOI: 10.1093/jn/nxac075] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 02/13/2022] [Accepted: 03/18/2022] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Specialized pro-resolving mediators (SPMs), synthesized from PUFAs, resolve inflammation and return damaged tissue to homeostasis. Thus, increasing metabolites of the SPM biosynthetic pathway may have potential health benefits for select clinical populations, such as subjects with obesity who display dysregulation of SPM metabolism. However, the concentrations of SPMs and their metabolic intermediates in humans with obesity remains unclear. OBJECTIVES The primary objective of this study was to determine if a marine oil supplement increased specific metabolites of the SPM biosynthetic pathway in adults with obesity. The second objective was to determine if the supplement changed the relative abundance of key immune cell populations. Finally, given the critical role of antibodies in inflammation, we determined if ex vivo CD19 + B-cell antibody production was modified by marine oil intervention. METHODS Twenty-three subjects [median age: 56 y; BMI (in kg/m2): 33.1] consumed 2 g/d of a marine oil supplement for 28-30 d. The supplement was particularly enriched with 18-hydroxyeicosapentaenoic (HEPE), 14-hydroxydocosahexaenoic acid (14-HDHA), and 17-HDHA. Blood was collected pre- and postsupplementation for plasma mass spectrometry oxylipin and fatty acid analyses, flow cytometry, and B-cell isolation. Paired t-tests and Wilcoxon tests were used for statistical analyses. RESULTS Relative to preintervention, the supplement increased 6 different HEPEs and HDHAs accompanied by changes in plasma PUFAs. Resolvin E1 and docosapentaenoic acid-derived maresin 1 concentrations were increased 3.5- and 4.7-fold upon intervention, respectively. The supplement did not increase the concentration of D-series resolvins and had no effect on the abundance of immune cells. Ex vivo B-cell IgG but not IgM concentrations were lowered postsupplementation. CONCLUSIONS A marine oil supplement increased select SPMs and their metabolic intermediates in adults with obesity. Additional studies are needed to determine if increased concentrations of specific SPMs control the resolution of inflammation in humans with obesity. This trial was registered at clinicaltrials.gov as NCT04701138.
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Affiliation(s)
- Abrar E Al-Shaer
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Jennifer Regan
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nicole Buddenbaum
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Sonum Tharwani
- The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
| | - Catie Drawdy
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Madeline Behee
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Selin Sergin
- Department of Food Science and Human Nutrition, College of Agriculture and Natural Resources and College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Jenifer I Fenton
- Department of Food Science and Human Nutrition, College of Agriculture and Natural Resources and College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA
| | - Krishna Rao Maddipati
- Department of Pathology, Bioactive Lipids Research Program, Wayne State University, Detroit, MI, USA
| | - Shawn Kane
- The University of North Carolina at Chapel Hill Family Medicine Center, Chapel Hill, NC, USA
| | - Erik Butler
- The University of North Carolina at Chapel Hill Family Medicine Center, Chapel Hill, NC, USA
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC, USA
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Dubé L, Spahis S, Lachaîne K, Lemieux A, Monhem H, Poulin SM, Randoll C, Travaillaud E, Ould-Chikh NEH, Marcil V, Delvin E, Levy E. Specialized Pro-Resolving Mediators Derived from N-3 Polyunsaturated Fatty Acids: Role in Metabolic Syndrome and Related Complications. Antioxid Redox Signal 2022; 37:54-83. [PMID: 35072542 DOI: 10.1089/ars.2021.0156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Significance: Metabolic syndrome (MetS) prevalence continues to grow and represents a serious public health issue worldwide. This multifactorial condition carries the risk of hastening the development of type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), and cardiovascular diseases (CVD). Another troubling aspect of MetS is the requirement of poly-pharmacological therapy not devoid of side effects. Therefore, there is an urgent need for prospecting alternative nutraceuticals as effective therapeutic agents for MetS. Recent Advances: Currently, there is an increased interest in understanding the regulation of metabolic derangements by specialized pro-resolving lipid mediators (SPMs), especially those derived from the long chain n-3 polyunsaturated fatty acids. Critical Issues: The SPMs are recognized as efficient modulators that are capable of inhibiting the production of pro-inflammatory cytokines, blocking neutrophil activation/recruitment, and inducing non-phlogistic (anti-inflammatory) activation of macrophage engulfment and removal of apoptotic inflammatory cells and debris. The aim of the present review is precisely to first underline key concepts relative to SPM functions before focusing on their status and actions on MetS components (e.g., obesity, glucose dysmetabolism, hyperlipidemia, hypertension) and complications such as T2D, NAFLD, and CVD. Future Directions: Valuable data from preclinical and clinical investigations have emphasized the SPM functions and influence on oxidative stress- and inflammation-related MetS. Despite these promising findings obtained without compromising host defense, additional efforts are needed to evaluate their potential therapeutic applications and further develop practical tools to monitor their bioavailability to cope with cardiometabolic disorders. Antioxid. Redox Signal. 37, 54-83.
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Affiliation(s)
- Laurent Dubé
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada
| | - Schohraya Spahis
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Karelle Lachaîne
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Hanine Monhem
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Carolane Randoll
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | - Eva Travaillaud
- Department of Nutrition, Université de Montréal, Montreal, Canada
| | | | - Valérie Marcil
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada
| | - Edgard Delvin
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Biochemistry, Université de Montréal, Montreal, Canada
| | - Emile Levy
- Research Centre, Sainte-Justine Hospital, Université de Montréal, Montreal, Canada.,Department of Nutrition, Université de Montréal, Montreal, Canada.,Institute of Nutrition and Functional Foods, Laval University, Quebec City, Canada.,Department of Pediatrics, Gastroenterology & Hepatology Unit, Université de Montréal, Montreal, Canada
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Al-Shaer AE, Pal A, Shi Q, Carson MS, Regan J, Behee M, Buddenbaum N, Drawdy C, Davis T, Virk R, Shaikh SR. Modeling human heterogeneity of obesity with diversity outbred mice reveals a fat mass-dependent therapeutic window for resolvin E1. FASEB J 2022; 36:e22354. [PMID: 35616343 PMCID: PMC10027372 DOI: 10.1096/fj.202200350r] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 04/27/2022] [Accepted: 05/06/2022] [Indexed: 11/11/2022]
Abstract
Resolvin E1 (RvE1), a specialized pro-resolving mediator (SPM), improves glucose homeostasis in inbred mouse models of obesity. However, an impediment toward translation is that obesity is a highly heterogenous disease in which individuals will respond very differently to interventions such as RvE1. Thus, there is a need to study SPMs in the context of modeling the heterogeneity of obesity that is observed in humans. We investigated how RvE1 controls the concentration of key circulating metabolic biomarkers using diversity outbred (DO) mice, which mimic human heterogeneity. We first demonstrate that weights of DO mice can be classified into distinct distributions of fat mass (i.e., modeling differing classes of obesity) in response to a high-fat diet and in the human population when examining body composition. Next, we show RvE1 administration based on body weight for four consecutive days after giving mice a high-fat diet led to approximately half of the mice responding positively for serum total gastric inhibitory polypeptide (GIP), glucagon, insulin, glucose, leptin, and resistin. Interestingly, RvE1 improved hyperleptinemia most effectively in the lowest class of fat mass despite adjusting the dose of RvE1 with increasing adiposity. Furthermore, leptin levels after RvE1 treatment were the lowest in those mice that were also RvE1 positive responders for insulin and resistin. Collectively, these results suggest a therapeutic fat mass-dependent window for RvE1, which should be considered in future clinical trials. Moreover, the data underscore the importance of studying SPMs with heterogenous mice as a step toward precision SPM administration in humans.
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Affiliation(s)
- Abrar E Al-Shaer
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Anandita Pal
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Qing Shi
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Meredith S Carson
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jennifer Regan
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Madeline Behee
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Nicole Buddenbaum
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Catie Drawdy
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Traci Davis
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Rafia Virk
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Bosco A, Dessì A, Zanza C, Pintus R, Fanos V. Resolvins' Obesity-Driven Deficiency: The Implications for Maternal-Fetal Health. Nutrients 2022; 14:nu14081662. [PMID: 35458224 PMCID: PMC9029397 DOI: 10.3390/nu14081662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/12/2022] [Accepted: 04/14/2022] [Indexed: 12/10/2022] Open
Abstract
Since pregnancy is already characterized by mild but significant inflammatory activity in physiological conditions, when complicated by obesity the probability of a persistent inflammatory state increases, with consequent multiple repercussions that add up to the complications associated with acute inflammation. In this context, the role of resolvins, specialized pro-resolving mediators (SPMs), deriving from omega-3 essential fatty acids, may be crucial. Indeed, differential production in numerous high-risk conditions associated with both childbirth and neonatal health, the correlation between maternal omega-3 intake and resolvin concentrations in maternal blood and at the placental level, and the high values found in breast milk in the first month of breastfeeding, are some of the most important hallmarks of these autacoids. In addition, a growing body of scientific evidence supports the lack of SPMs, at the level of immune-metabolic tissues, in the case of obesity. Furthermore, the obesity-related lack of SPMs seems to be decisive in the context of the current outbreak of COVID-19, as it appears to be one of the causes associated with the higher incidence of complications and negative outcomes of SARS-CoV-2 infection. The usefulness of metabolomics in this field appears clear, given that through the metabolome it is possible to observe the numerous and complex interactions between the mother, the placenta and the fetus in order to identify specific biomarkers useful in the prediction, diagnosis and monitoring of the various obstetric conditions. However, further investigations are needed in order to evaluate the possible use of some resolvins as biomarkers of maternal–fetal outcomes but also to establish adequate integration values in pregnant women with omega-3 fatty acids or with more active derivatives that guarantee optimal SPM production under risky conditions.
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Lipidomics in Understanding Pathophysiology and Pharmacologic Effects in Inflammatory Diseases: Considerations for Drug Development. Metabolites 2022; 12:metabo12040333. [PMID: 35448520 PMCID: PMC9030008 DOI: 10.3390/metabo12040333] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/29/2022] [Accepted: 04/04/2022] [Indexed: 01/26/2023] Open
Abstract
The lipidome has a broad range of biological and signaling functions, including serving as a structural scaffold for membranes and initiating and resolving inflammation. To investigate the biological activity of phospholipids and their bioactive metabolites, precise analytical techniques are necessary to identify specific lipids and quantify their levels. Simultaneous quantification of a set of lipids can be achieved using high sensitivity mass spectrometry (MS) techniques, whose technological advancements have significantly improved over the last decade. This has unlocked the power of metabolomics/lipidomics allowing the dynamic characterization of metabolic systems. Lipidomics is a subset of metabolomics for multianalyte identification and quantification of endogenous lipids and their metabolites. Lipidomics-based technology has the potential to drive novel biomarker discovery and therapeutic development programs; however, appropriate standards have not been established for the field. Standardization would improve lipidomic analyses and accelerate the development of innovative therapies. This review aims to summarize considerations for lipidomic study designs including instrumentation, sample stabilization, data validation, and data analysis. In addition, this review highlights how lipidomics can be applied to biomarker discovery and drug mechanism dissection in various inflammatory diseases including cardiovascular disease, neurodegeneration, lung disease, and autoimmune disease.
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Putman AK, Gandy JC, Contreras GA, Sordillo LM. Oxylipids are associated with higher disease risk in postpartum cows. J Dairy Sci 2022; 105:2531-2543. [PMID: 35086706 DOI: 10.3168/jds.2021-21057] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/27/2021] [Indexed: 11/19/2022]
Abstract
Postpartum diseases are a major animal welfare and economic concern for dairy producers. Dysregulated inflammation, which may begin as soon as the cessation of lactation, contributes to the development of postpartum diseases. The ability to regulate inflammation and mitigate postpartum health diseases relies, in part, on the production of inflammatory mediators known as oxylipids. The objective of this study was to examine associations between oxylipids and postpartum diseases. Plasma samples were collected from 16 cattle via coccygeal venipuncture at the following time points: 6 d before dry-off; dry-off (d 0); 1, 2, 6, and 12 d after dry-off; 14 ± 3 d before the expected calving date; and 7 ± 2 d after calving. After calving, cows were grouped according to if clinical disease was undetected throughout the sampling period (n = 7) or if they developed a disease postpartum (n = 9). Liquid chromatography-tandem mass spectrometry was used to analyze plasma concentrations of 63 oxylipid species. Of the 32 oxylipids detected, concentrations of 7 differed between cows with no detected disease and diseased cows throughout the sampling period. Thus, a variable oxylipid profile was demonstrated through 2 major physiological transitions of a lactation cycle. Further, the information gained from this pilot study using a small number of animals with diverse diseases from a single herd suggests that it may be possible to use oxylipids at early mammary involution to alert dairy producers of cows at risk for disease after calving. Future studies should be performed in larger populations of animals, including cows from diverse geographies and dairying styles, and focus on specific diseases to evaluate the utility of oxylipids as biomarkers. Furthermore, it is important to determine the clinical implications of variable oxylipid concentrations throughout the lactation cycle and if the oxylipid profile can be modulated to improve inflammatory outcomes.
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Affiliation(s)
- A K Putman
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824.
| | - J C Gandy
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824
| | - G A Contreras
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824
| | - L M Sordillo
- Department of Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing 48824
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Abstract
Coronavirus disease 2019 (COVID-19) due to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been an ongoing pandemic causing significant morbidity and mortality worldwide. The “cytokine storm” is a critical driving force in severe COVID-19 cases, leading to hyperinflammation, multi-system organ failure, and death. A paradigm shift is emerging in our understanding of the resolution of inflammation from a passive course to an active biochemical process driven by endogenous specialized pro-resolving mediators (SPMs), such as resolvins, protectins, lipoxins, and maresins. SPMs stimulate macrophage-mediated debris clearance and counter pro-inflammatory cytokine production, a process collectively termed as the “resolution of inflammation.” Hyperinflammation is not unique to COVID-19 and also occurs in neoplastic conditions, putting individuals with underlying health conditions such as cancer at elevated risk of severe SARS-CoV-2 infection. Despite approaches to block systemic inflammation, there are no current therapies designed to stimulate the resolution of inflammation in patients with COVID-19 or cancer. A non-immunosuppressive therapeutic approach that reduces the cytokine storm in patients with COVID-19 and cancer is urgently needed. SPMs are potent immunoresolvent and organ-protective lipid autacoids that stimulate the resolution of inflammation, facilitate clearance of infections, reduce thrombus burden, and promote a return to tissue homeostasis. Targeting endogenous lipid mediators, such as SPMs, offers an entirely novel approach to control SARS-CoV-2 infection and cancer by increasing the body’s natural reserve of pro-resolving mediators without overt toxicity or immunosuppression.
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Affiliation(s)
- Chantal Barksdale
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Franciele C Kipper
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Shreya Tripathy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Selvakumar Subbian
- Public Health Research Institute, New Jersey Medical School, Rutgers University, Newark, NJ, 07103, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02215, USA
| | - Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. .,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. .,Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
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Wang L, Choi HS, Su Y, Ju JH, Heo SY, Yi JJ, Oh BR, Jang YS, Seo JW. The docosahexaenoic acid derivatives, diHEP-DPA and TH-DPA, synthesized via recombinant lipoxygenase, ameliorate disturbances in lipid metabolism and liver inflammation in high fat diet-fed mice. Life Sci 2022; 291:120219. [PMID: 35041834 DOI: 10.1016/j.lfs.2021.120219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 11/24/2021] [Accepted: 12/03/2021] [Indexed: 01/06/2023]
Abstract
7S,15R-Dihydroxy-16S,17S-epoxy-docosapentaenoic acid (diHEP-DPA) and 7S,15R,16S,17S-tetrahydroxy-docosapentaenoic acid (TH-DPA) are two novel lipid mediators derived from docosahexaenoic acid (DHA) that we previously synthesized via combined enzymatic and chemical reactions. In the present study, we investigated the effects of these compounds on disturbances in lipid metabolism and liver inflammation induced by a high fat diet (HFD) in mice. Male BALB/c mice were randomly divided into four groups (n = 10/group): controls, HFD only, HFD + diHEP-DPA, and HFD + TH-DPA. Mice in HFD + diHEP-DPA and HFD + TH-DPA groups were orally administered 20 μg/kg of diHEP-DPA or TH-DPA, respectively. Measurements of adipose accumulation and liver inflammation showed that both diHEP-DPA and TH-DPA decreased adipose tissue mass and liver color depth, as well as total cholesterol, triglycerides, and low-density lipoprotein-cholesterol in the serum of HFD-fed mice compared with mice in the HFD-only group, while elevating high-density lipoprotein-cholesterol. Both of them also decreased hepatic expression of genes encoding lipid synthesis-related proteins (PPARγ, SIRT1, SREBP-1c and FASN) and increased the expression of genes encoding proteins involved in lipid degradation (PPARα and CPT-1) in the liver. Western blotting and quantitative RT-PCR confirmed that diHEP-DPA or TH-DPA administration modulated the expression of inflammation-related genes (TNF-α and IL-6) and inhibited activation of the NF-κB signaling pathway in livers of HFD-fed mice. Taken together, our data indicate that diHEP-DPA and TH-DPA ameliorate liver inflammation and inhibit HFD-induced obesity in mice.
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Affiliation(s)
- Lifang Wang
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea; Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54896, Republic of Korea.
| | - Hack Sun Choi
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju 63243, Republic of Korea.
| | - Yan Su
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea; Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54896, Republic of Korea.
| | - Jung-Hyun Ju
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea.
| | - Sun-Yeon Heo
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea.
| | - Jong-Jae Yi
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea.
| | - Back-Rock Oh
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea.
| | - Yong-Suk Jang
- Department of Bioactive Material Sciences, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54896, Republic of Korea.
| | - Jeong-Woo Seo
- Microbial Biotechnology Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Jeongeup-Si 56212, Republic of Korea.
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40
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Al-Shaer AE, Pal A, Shaikh SR. Resolvin E1-ChemR23 Axis Regulates the Hepatic Metabolic and Inflammatory Transcriptional Landscape in Obesity at the Whole Genome and Exon Level. Front Nutr 2022; 8:799492. [PMID: 35004828 PMCID: PMC8740313 DOI: 10.3389/fnut.2021.799492] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/07/2021] [Indexed: 12/20/2022] Open
Abstract
Resolvin E1 (RvE1) is an immunoresolvent that is synthesized from eicosapentaenoic acid and can bind the receptor ERV1/ChemR23. We previously showed activation of the RvE1-ChemR23 axis improves hyperglycemia and hyperinsulinemia of obese mice; however, it remains unclear how RvE1 controls glucose homeostasis. Here we investigated hepatic metabolic and inflammatory transcriptional targets of the RvE1-ChemR23 axis using lean and obese wild type (WT) and ChemR23 knockout (KO) mice. We conducted an in-depth transcriptional study by preforming whole gene-level and exon-level analyses, which provide insight into alternative splicing variants and miRNA regulation. Compared to controls, WT and KO obese mice in the absence of RvE1 displayed similar gene-level profiles, which entailed dysregulated pathways related to glucose homeostasis. Notably, obese WT mice relative to lean controls showed a robust decrease in pathways related to the biosynthesis of unsaturated fatty acids. At the exon-level, obese ChemR23 KOs compared to obese WT mice displayed changes in pathways related to hepatic lipid transport, cholesterol metabolism, and immunological functions such as complement cascades and platelet activation. Importantly, upon RvE1 administration to WT obese mice, we discovered upregulated genes in pathways relating to insulin sensitivity and downregulated genes related to regulators of TGF-β signaling. This transcriptional profile was generally not recapitulated with obese ChemR23 KO mice administered RvE1. Collectively, gene and exon-level analyses suggest RvE1 controls the hepatic transcriptional profile related to glucose homeostasis, insulin sensitivity, and inflammation in a manner that is largely dependent on ChemR23. These studies will drive future mechanistic experiments on the RvE1-ChemR23 axis.
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Affiliation(s)
- Abrar E Al-Shaer
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Anandita Pal
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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41
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Cecconello C, Clària Ribas P, Norling LV. Resolving acute inflammation; what happens when inflammation goes haywire? How can it get back in line? DIET, INFLAMMATION, AND HEALTH 2022:113-162. [DOI: 10.1016/b978-0-12-822130-3.00018-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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42
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Vander Ploeg M, Quinn K, Armstrong M, Manke J, Reisdorph N, Shaikh SR. SPM pathway marker analysis of the brains of obese mice in the absence and presence of eicosapentaenoic acid ethyl esters. Prostaglandins Leukot Essent Fatty Acids 2021; 175:102360. [PMID: 34743051 PMCID: PMC8633202 DOI: 10.1016/j.plefa.2021.102360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/17/2021] [Accepted: 08/17/2021] [Indexed: 10/19/2022]
Abstract
Obesity drives an imbalanced signature of specialized pro-resolving mediators (SPM). Herein, we investigated if high fat diet-induced obesity dysregulates the concentration of SPM intermediates in the brains of C57BL/6 J mice. Furthermore, given the benefits of EPA for cardiometabolic diseases, major depression, and cognition, we probed the effect of an EPA supplemented high fat diet on brain SPM intermediates. Mass spectrometry revealed no effect of the high fat diet on PUFA-derived brain metabolites. EPA also did not have an effect on most brain PUFA-derived metabolites except an increase of 12-hydroxyeicosapentaenoic acid (12-HEPE). In contrast, EPA dramatically increased serum HEPEs and lowered several PUFA-derived metabolites. Finally, untargeted mass spectrometry showed no effects of the high fat diet, with or without EPA, on the brain metabolome. Collectively, these results show the murine brain resists a deficiency in SPM pathway markers in response to a high fat diet and that EPA supplementation increases 12-HEPE levels.
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Affiliation(s)
- Matthew Vander Ploeg
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kevin Quinn
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO , United States
| | - Michael Armstrong
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO , United States
| | - Jonathan Manke
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO , United States
| | - Nichole Reisdorph
- Department of Pharmaceutical Sciences, University of Colorado Denver Anschutz Medical Campus, Aurora, CO , United States
| | - Saame Raza Shaikh
- Department of Nutrition, Gillings School of Global Public Health and School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.
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43
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Alqahtani S, Xia L, Jannasch A, Ferreira C, Franco J, Shannahan JH. Disruption of pulmonary resolution mediators contribute to exacerbated silver nanoparticle-induced acute inflammation in a metabolic syndrome mouse model. Toxicol Appl Pharmacol 2021; 431:115730. [PMID: 34601004 PMCID: PMC8545917 DOI: 10.1016/j.taap.2021.115730] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/08/2021] [Accepted: 09/22/2021] [Indexed: 12/18/2022]
Abstract
Pre-existing conditions modulate sensitivity to numerous xenobiotic exposures such as air pollution. Specifically, individuals suffering from metabolic syndrome (MetS) demonstrate enhanced acute inflammatory responses following particulate matter inhalation. The mechanisms associated with these exacerbated inflammatory responses are unknown, impairing interventional strategies and our understanding of susceptible populations. We hypothesize MetS-associated lipid dysregulation influences mediators of inflammatory resolution signaling contributing to increased acute pulmonary toxicity. To evaluate this hypothesis, healthy and MetS mouse models were treated with either 18-hydroxy eicosapentaenoic acid (18-HEPE), 14-hydroxy docosahexaenoic acid (14-HDHA), 17-hydroxy docosahexaenoic acid (17-HDHA), or saline (control) via intraperitoneal injection prior to oropharyngeal aspiration of silver nanoparticles (AgNP). In mice receiving saline treatment, AgNP exposure resulted in an acute pulmonary inflammatory response that was exacerbated in MetS mice. A targeted lipid assessment demonstrated 18-HEPE, 14-HDHA, and 17-HDHA treatments altered lung levels of specialized pro-resolving lipid mediators (SPMs). 14-HDHA and 17-HDHA treatments more efficiently reduced the exacerbated acute inflammatory response in AgNP exposed MetS mice as compared to 18-HEPE. This included decreased neutrophilic influx, diminished induction of inflammatory cytokines/chemokines, and reduced alterations in SPMs. Examination of SPM receptors determined baseline reductions in MetS mice compared to healthy as well as decreases due to AgNP exposure. Overall, these results demonstrate AgNP exposure disrupts inflammatory resolution, specifically 14-HDHA and 17-HDHA derived SPMs, in MetS contributing to exacerbated acute inflammatory responses. Our findings identify a potential mechanism responsible for enhanced susceptibility in MetS that can be targeted for interventional therapeutic approaches.
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Affiliation(s)
- Saeed Alqahtani
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States; National Center for Pharmaceuticals, Life Science and Environment Research Institute, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia
| | - Li Xia
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States
| | - Amber Jannasch
- Purdue Metabolite Profiling Facility, Purdue University, West Lafayette, IN, United States
| | - Christina Ferreira
- Purdue Metabolite Profiling Facility, Purdue University, West Lafayette, IN, United States
| | - Jackeline Franco
- Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, United States
| | - Jonathan H Shannahan
- School of Health Sciences, College of Health and Human Sciences, Purdue University, West Lafayette, IN, United States.
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Gemperle C, Tran S, Schmid M, Rimann N, Marti-Jaun J, Hartling I, Wawrzyniak P, Hersberger M. Resolvin D1 reduces inflammation in co-cultures of primary human macrophages and adipocytes by triggering macrophages. Prostaglandins Leukot Essent Fatty Acids 2021; 174:102363. [PMID: 34740032 DOI: 10.1016/j.plefa.2021.102363] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/04/2021] [Accepted: 10/27/2021] [Indexed: 12/21/2022]
Abstract
Obesity leads to chronic inflammation of the adipose tissue which is tightly associated with the metabolic syndrome, type 2 diabetes and cardiovascular disease. Inflammation of the adipose tissue is mainly characterized by the presence of crown-like structures composed of inflammatory macrophages in the neighborhood of adipocytes. Resolvin D1 (RvD1), a potent anti-inflammatory and pro-resolving lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid, has been shown to reduce the inflammatory tone of adipose tissue in animal models but the underlying mechanism is not clear. We investigated the effect of RvD1 on the inflammatory state of a human co-culture system of adipocytes and macrophages. For this, human mesenchymal stem cells were differentiated into mature adipocytes and overlaid with human primary macrophages. In this co-culture, 10-500 nM RvD1 dose-dependently reduced the secretion of the pro-inflammatory cytokine IL-6 (-21%) and its soluble receptor IL-6Rα (-22%), of the chemokine MCP-1 (-13%), and of the adipokine leptin (-22%). Similarly, we observed a reduction in secretion of the soluble receptor IL-6Rα (-20%), and TNF-α (-11%) when macrophages alone were treated with RvD1, while no change of cytokine secretion was observed when adipocytes were treated with RvD1. We conclude that RvD1 polarizes macrophages to an anti-inflammatory phenotype, which in turn modulates inflammation in adipocytes.
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Affiliation(s)
- Claudio Gemperle
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Syndi Tran
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Mattia Schmid
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Nicole Rimann
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Jacqueline Marti-Jaun
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Ivan Hartling
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland
| | - Paulina Wawrzyniak
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Martin Hersberger
- Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland; Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland.
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45
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Panigrahy D, Gilligan MM, Serhan CN, Kashfi K. Resolution of inflammation: An organizing principle in biology and medicine. Pharmacol Ther 2021; 227:107879. [PMID: 33915177 DOI: 10.1016/j.pharmthera.2021.107879] [Citation(s) in RCA: 184] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 03/12/2021] [Indexed: 02/07/2023]
Abstract
The resolution of inflammation has emerged as a critical endogenous process that protects host tissues from prolonged or excessive inflammation that can become chronic. Failure of the resolution of inflammation is a key pathological mechanism that drives the progression of numerous inflammation-driven diseases. Essential polyunsaturated fatty acid (PUFA)-derived autacoid mediators termed 'specialized pro-resolving mediators' (SPMs) regulate endogenous resolution programs by limiting further neutrophil tissue infiltration and stimulating local immune cell (e.g., macrophage)-mediated clearance of apoptotic polymorphonuclear neutrophils, cellular debris, and microbes, as well as counter-regulating eicosanoid/cytokine production. The SPM superfamily encompasses lipoxins, resolvins, protectins, and maresins. Our understanding of the resolution phase of acute inflammation has grown exponentially in the past three decades with the discovery of novel pro-resolving lipid mediators, their pro-efferocytosis mechanisms, and their receptors. Technological advancement has further facilitated lipid mediator metabolipidomic based profiling of healthy and diseased human tissues, highlighting the extraordinary therapeutic potential of SPMs across a broad array of inflammatory diseases including cancer. As current front-line cancer therapies such as surgery, chemotherapy, and radiation may induce various unwanted side effects such as robust pro-inflammatory and pro-tumorigenic host responses, characterizing SPMs and their receptors as novel therapeutic targets may have important implications as a new direction for host-targeted cancer therapy. Here, we discuss the origins of inflammation resolution, key discoveries and the failure of resolution mechanisms in diseases with an emphasis on cancer, and future directions focused on novel therapeutic applications for this exciting and rapidly expanding field.
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Affiliation(s)
- Dipak Panigrahy
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
| | - Molly M Gilligan
- Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Charles N Serhan
- Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, City University of New York, School of Medicine, New York, NY 10031, USA; Graduate Program in Biology, City University of New York Graduate Center, New York, NY 10016, USA
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46
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Han YH, Lee K, Saha A, Han J, Choi H, Noh M, Lee YH, Lee MO. Specialized Proresolving Mediators for Therapeutic Interventions Targeting Metabolic and Inflammatory Disorders. Biomol Ther (Seoul) 2021; 29:455-464. [PMID: 34162770 PMCID: PMC8411019 DOI: 10.4062/biomolther.2021.094] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/18/2022] Open
Abstract
Uncontrolled inflammation is considered the pathophysiological basis of many prevalent metabolic disorders, such as nonalcoholic fatty liver disease, diabetes, obesity, and neurodegenerative diseases. The inflammatory response is a self-limiting process that produces a superfamily of chemical mediators, called specialized proresolving mediators (SPMs). SPMs include the ω-3-derived family of molecules, such as resolvins, protectins, and maresins, as well as arachidonic acid-derived (ω-6) lipoxins that stimulate and promote resolution of inflammation, clearance of microbes, and alleviation of pain and promote tissue regeneration via novel mechanisms. SPMs function by binding and activating G protein-coupled receptors, such as FPR2/ALX, GPR32, and ERV1, and nuclear orphan receptors, such as RORα. Recently, several studies reported that SPMs have the potential to attenuate lipid metabolism disorders. However, the understanding of pharmacological aspects of SPMs, including tissue-specific biosynthesis, and specific SPM receptors and signaling pathways, is currently limited. Here, we summarize recent advances in the role of SPMs in resolution of inflammatory diseases with metabolic disorders, such as nonalcoholic fatty liver disease and obesity, obtained from preclinical animal studies. In addition, the known SPM receptors and their intracellular signaling are reviewed as targets of resolution of inflammation, and the currently available information on the therapeutic effects of major SPMs for metabolic disorders is summarized.
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Affiliation(s)
- Yong-Hyun Han
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Kyeongjin Lee
- Laboratory of Pathology and Physiology, College of Pharmacy, Kangwon National University, Chuncheon 24341, Republic of Korea
| | - Abhirup Saha
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Juhyeong Han
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Haena Choi
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Minsoo Noh
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Yun-Hee Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Mi-Ock Lee
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.,Bio-MAX Institute, Seoul National University, Seoul 08826, Republic of Korea
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47
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Krill Oil Treatment Increases Distinct PUFAs and Oxylipins in Adipose Tissue and Liver and Attenuates Obesity-Associated Inflammation via Direct and Indirect Mechanisms. Nutrients 2021; 13:nu13082836. [PMID: 34444996 PMCID: PMC8401900 DOI: 10.3390/nu13082836] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/12/2021] [Accepted: 08/16/2021] [Indexed: 12/31/2022] Open
Abstract
The development of obesity is characterized by the metabolic overload of tissues and subsequent organ inflammation. The health effects of krill oil (KrO) on obesity-associated inflammation remain largely elusive, because long-term treatments with KrO have not been performed to date. Therefore, we examined the putative health effects of 28 weeks of 3% (w/w) KrO supplementation to an obesogenic diet (HFD) with fat derived mostly from lard. The HFD with KrO was compared to an HFD control group to evaluate the effects on fatty acid composition and associated inflammation in epididymal white adipose tissue (eWAT) and the liver during obesity development. KrO treatment increased the concentrations of EPA and DHA and associated oxylipins, including 18-HEPE, RvE2 and 14-HDHA in eWAT and the liver. Simultaneously, KrO decreased arachidonic acid concentrations and arachidonic-acid-derived oxylipins (e.g., HETEs, PGD2, PGE2, PGF2α, TXB2). In eWAT, KrO activated regulators of adipogenesis (e.g., PPARγ, CEBPα, KLF15, STAT5A), induced a shift towards smaller adipocytes and increased the total adipocyte numbers indicative for hyperplasia. KrO reduced crown-like structures in eWAT, and suppressed HFD-stimulated inflammatory pathways including TNFα and CCL2/MCP-1 signaling. The observed eWAT changes were accompanied by reduced plasma leptin and increased plasma adiponectin levels over time, and improved insulin resistance (HOMA-IR). In the liver, KrO suppressed inflammatory signaling pathways, including those controlled by IL-1β and M-CSF, without affecting liver histology. Furthermore, KrO deactivated hepatic REL-A/p65-NF-κB signaling, consistent with increased PPARα protein expression and a trend towards an increase in IkBα. In conclusion, long-term KrO treatment increased several anti-inflammatory PUFAs and oxylipins in WAT and the liver. These changes were accompanied by beneficial effects on general metabolism and inflammatory tone at the tissue level. The stimulation of adipogenesis by KrO allows for safe fat storage and may, together with more direct PPAR-mediated anti-inflammatory mechanisms, attenuate inflammation.
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Clària J, Flores-Costa R, Duran-Güell M, López-Vicario C. Proresolving lipid mediators and liver disease. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:159023. [PMID: 34352389 DOI: 10.1016/j.bbalip.2021.159023] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 06/07/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023]
Abstract
Inflammation is a characteristic feature of virtually all acute and chronic liver diseases. It intersects different liver pathologies from the early stages of liver injury, when the inflammatory burden is mild-to-moderate, to very advanced stages of liver disease, when the inflammatory response is very intense and drives multiple organ dysfunction and failure(s). The current review describes the most relevant features of the inflammatory process in two different clinical entities across the liver disease spectrum, namely non-alcoholic steatohepatitis (NASH) and acute-on-chronic liver failure (ACLF). Special emphasis is given within these two disease conditions to gather the most relevant data on the specialized pro-resolving mediators that orchestrate the resolution of inflammation, a tightly controlled process which dysregulation commonly associates with chronic inflammatory conditions.
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Affiliation(s)
- Joan Clària
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; Department of Biomedical Sciences, University of Barcelona, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.
| | - Roger Flores-Costa
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain
| | - Marta Duran-Güell
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain
| | - Cristina López-Vicario
- Biochemistry and Molecular Genetics Service, Hospital Clínic-IDIBAPS and CIBERehd, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF-Clif) and Grifols Chair, Barcelona, Spain.
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Shen JX, Couchet M, Dufau J, de Castro Barbosa T, Ulbrich MH, Helmstädter M, Kemas AM, Zandi Shafagh R, Marques M, Hansen JB, Mejhert N, Langin D, Rydén M, Lauschke VM. 3D Adipose Tissue Culture Links the Organotypic Microenvironment to Improved Adipogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2100106. [PMID: 34165908 PMCID: PMC8373086 DOI: 10.1002/advs.202100106] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/06/2021] [Indexed: 05/15/2023]
Abstract
Obesity and type 2 diabetes are strongly associated with adipose tissue dysfunction and impaired adipogenesis. Understanding the molecular underpinnings that control adipogenesis is thus of fundamental importance for the development of novel therapeutics against metabolic disorders. However, translational approaches are hampered as current models do not accurately recapitulate adipogenesis. Here, a scaffold-free versatile 3D adipocyte culture platform with chemically defined conditions is presented in which primary human preadipocytes accurately recapitulate adipogenesis. Following differentiation, multi-omics profiling and functional tests demonstrate that 3D adipocyte cultures feature mature molecular and cellular phenotypes similar to freshly isolated mature adipocytes. Spheroids exhibit physiologically relevant gene expression signatures with 4704 differentially expressed genes compared to conventional 2D cultures (false discovery rate < 0.05), including the concerted expression of factors shaping the adipogenic niche. Furthermore, lipid profiles of >1000 lipid species closely resemble patterns of the corresponding isogenic mature adipocytes in vivo (R2 = 0.97). Integration of multi-omics signatures with analyses of the activity profiles of 503 transcription factors using global promoter motif inference reveals a complex signaling network, involving YAP, Hedgehog, and TGFβ signaling, that links the organotypic microenvironment in 3D culture to the activation and reinforcement of PPARγ and CEBP activity resulting in improved adipogenesis.
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Affiliation(s)
- Joanne X. Shen
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
| | - Morgane Couchet
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Jérémy Dufau
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
| | - Thais de Castro Barbosa
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Maximilian H. Ulbrich
- Renal DivisionDepartment of MedicineUniversity Hospital Freiburg and Faculty of MedicineUniversity of FreiburgFreiburg79106Germany
- BIOSS Centre for Biological Signalling StudiesUniversity of FreiburgFreiburg79104Germany
| | - Martin Helmstädter
- Renal DivisionDepartment of MedicineUniversity Hospital Freiburg and Faculty of MedicineUniversity of FreiburgFreiburg79106Germany
| | - Aurino M. Kemas
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
| | - Reza Zandi Shafagh
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
- Division of Micro‐ and NanosystemsKTH Royal Institute of TechnologyStockholm100 44Sweden
| | - Marie‐Adeline Marques
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
| | - Jacob B. Hansen
- Department of BiologyUniversity of CopenhagenCopenhagen2100Denmark
| | - Niklas Mejhert
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Dominique Langin
- InsermInstitute of Metabolic and Cardiovascular Diseases (I2MC)UMR1297Toulouse31432France
- Université de ToulouseUniversité Paul SabatierFaculté de Médecine, I2MCUMR1297Toulouse31432France
- Toulouse University HospitalsDepartment of BiochemistryToulouse31079France
| | - Mikael Rydén
- Department of MedicineHuddingeKarolinska InstitutetKarolinska University HospitalStockholm141 86Sweden
| | - Volker M. Lauschke
- Department of Physiology and PharmacologyKarolinska InstitutetStockholm171 77Sweden
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Andrews D, Godson C. Lipoxins and synthetic lipoxin mimetics: Therapeutic potential in renal diseases. Biochim Biophys Acta Mol Cell Biol Lipids 2021; 1866:158940. [PMID: 33839296 DOI: 10.1016/j.bbalip.2021.158940] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 12/26/2022]
Abstract
Inflammation and its timely resolution are critical to ensuring effective host defence and appropriate tissue repair after injury. Unresolved inflammation typifies many renal pathologies. The key drivers of the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. However, these are associated with undesirable side effects including immune suppression. More recently, there is growing appreciation that specialized lipid mediators [SPMs] including lipoxins promote the resolution of inflammation and endogenous repair mechanisms without compromising host defence. We discuss the pro-resolving bioactions of lipoxins and recent work that aims to harness their therapeutic potential in the context of kidney disease.
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Affiliation(s)
- Darrell Andrews
- Diabetes Complications Research Centre, Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland
| | - Catherine Godson
- Diabetes Complications Research Centre, Conway Institute and School of Medicine, University College Dublin, Dublin, Ireland.
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