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Simoes MR, Bombassaro B, Gallo-Ferraz AL, Nogueira PAS, Monfort-Pires M, Zanesco AM, Valdivieso-Rivera F, Nogueira GAS, Sponton CH, Castilho RF, Velloso LA. Balb/c mice are protected from glucose and acute cold intolerance. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167725. [PMID: 40023454 DOI: 10.1016/j.bbadis.2025.167725] [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: 10/22/2024] [Revised: 01/21/2025] [Accepted: 02/12/2025] [Indexed: 03/04/2025]
Abstract
The brown adipose tissue is a potential target for interventions aimed at treating obesity and other metabolic disorders. Both genetic and environmental factors are known to regulate brown adipose tissue function and exploring the interaction between these factors could unveil new mechanisms involved in the regulation of thermogenesis. In this study, we evaluated three genetically distinct mice strains submitted to two environmental factors known to modulate brown adipose tissue function, namely, cold exposure and the consumption of a high-fat diet. The comparison of Balb/c, C57BL/6, and Swiss mice revealed that Balb/c mice were the most glucose-tolerant and the most cold-tolerant. In addition, Balb/c presented the greatest brown adipose tissue oxygen consumption, which was independent of differences in uncoupling protein 1 expression and function. The search for uncoupling protein 1-independent mechanisms that could explain the greatest cold tolerance of Balb/c mice resulted in the identification of the N-acyl amino acid regulator, PM20D1, which had a greater gene expression in the brown adipose tissue of Balb/c mice as compared to the other two strains. The immunoneutralization of PM20D1 in Balb/c mice, resulted in increased blood glucose levels and worsening of cold tolerance. In addition, the in silico knockout of Pm20d1 impacted several metabolic processes, including thermogenesis, glucose tolerance, and insulin sensitivity. In conclusion, Balb/c mice are protected from glucose and acute cold intolerance, independently of the diet. We propose that PM20D1, in an uncoupling protein 1-independent fashion, can have an important role in this protection.
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Affiliation(s)
- Marcela R Simoes
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | - Bruna Bombassaro
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | - Ana Luisa Gallo-Ferraz
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | - Pedro A S Nogueira
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | | | - Ariane M Zanesco
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | - Fernando Valdivieso-Rivera
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil; Department of Structural and Functional Biology, Institute of Biology (IB), University of Campinas (UNICAMP), Campinas, São Paulo 13083-862, Brazil
| | - Guilherme A S Nogueira
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil
| | - Carlos H Sponton
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil; Department of Structural and Functional Biology, Institute of Biology (IB), University of Campinas (UNICAMP), Campinas, São Paulo 13083-862, Brazil
| | - Roger F Castilho
- Department of Pathology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP 13083-888, Brazil
| | - Licio A Velloso
- Obesity and Comorbidities Research Center, University of Campinas (UNICAMP), Campinas, São Paulo 13083-864, Brazil; National Institute of Science and Technology on Neuroimmunomodulation, Campinas, São Paulo 13083-864, Brazil.
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Pérez AR, Bottasso OA, Santucci NE. Immune-endocrine crossroads: the impact of nuclear receptors in Tuberculosis and Chagas disease. Front Endocrinol (Lausanne) 2025; 16:1538376. [PMID: 39991733 PMCID: PMC11842248 DOI: 10.3389/fendo.2025.1538376] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 01/13/2025] [Indexed: 02/25/2025] Open
Abstract
Nuclear Receptors (NRs) comprise a superfamily of proteins with essential roles in cell signaling, survival, proliferation, and metabolism. They act as transcription factors and are subclassified into families based on their ligands, DNA-binding sequences, tissue specificity, and functions. Evidence indicates that in infectious diseases, cancer, and autoimmunity, NRs modulate immune and endocrine responses, altering the transcriptional profile of cells and organs and influencing disease progression. Chronic infectious diseases, characterized by pathogen persistence, are particularly notable for an exaggerated inflammatory process. Unlike acute inflammation, which helps the host respond to pathogens, chronic inflammation leads to metabolic disorders and a dysregulated neuro-immuno-endocrine response. Over time, disturbances in cytokine, hormone, and other compound production foster an unbalanced, detrimental defensive response. This complexity underscores the significant role of ligand-dependent NRs. Tuberculosis and Chagas Disease are two critical chronic infections. The causative agents, Mycobacterium tuberculosis and Trypanosoma cruzi, have developed evasion strategies to establish chronic infections. Their clinical manifestations are associated with disrupted immuno-endocrine responses, pointing to a potential involvement of NRs. This review explores the current understanding of NRs in regulating immune-endocrine interactions within the context Tuberculosis and Chagas Disease. These diseases remain significant global health concerns, particularly in developing countries, highlighting the importance of understanding the molecular mechanisms underlying host-pathogen interactions mediated by NRs.
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Affiliation(s)
- Ana R. Pérez
- Laboratorio de Estudios en Enfermedad de Chagas, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
| | - Oscar A. Bottasso
- Laboratorio de Estudios en Enfermedad de Chagas, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Laboratorio de Estudios en Tuberculosis, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
| | - Natalia E. Santucci
- Facultad de Ciencias Médicas, Universidad Nacional de Rosario (UNR), Rosario, Argentina
- Laboratorio de Estudios en Tuberculosis, Instituto de Inmunología Clínica y Experimental de Rosario (IDICER)-Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)-Universidad Nacional de Rosario (UNR), Rosario, Argentina
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Tomasini S, Vigo P, Margiotta F, Scheele US, Panella R, Kauppinen S. The Role of microRNA-22 in Metabolism. Int J Mol Sci 2025; 26:782. [PMID: 39859495 PMCID: PMC11766054 DOI: 10.3390/ijms26020782] [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: 11/28/2024] [Revised: 01/14/2025] [Accepted: 01/15/2025] [Indexed: 01/27/2025] Open
Abstract
microRNA-22 (miR-22) plays a pivotal role in the regulation of metabolic processes and has emerged as a therapeutic target in metabolic disorders, including obesity, type 2 diabetes, and metabolic-associated liver diseases. While miR-22 exhibits context-dependent effects, promoting or inhibiting metabolic pathways depending on tissue and condition, current research highlights its therapeutic potential, particularly through inhibition strategies using chemically modified antisense oligonucleotides. This review examines the dual regulatory functions of miR-22 across key metabolic pathways, offering perspectives on its integration into next-generation diagnostic and therapeutic approaches while acknowledging the complexities of its roles in metabolic homeostasis.
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Affiliation(s)
- Simone Tomasini
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark; (S.T.); (U.S.S.); (R.P.)
| | - Paolo Vigo
- Resalis Therapeutics Srl, Via E. De Sonnaz 19, 10121 Torino, Italy
| | - Francesco Margiotta
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy;
| | - Ulrik Søberg Scheele
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark; (S.T.); (U.S.S.); (R.P.)
| | - Riccardo Panella
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark; (S.T.); (U.S.S.); (R.P.)
- Resalis Therapeutics Srl, Via E. De Sonnaz 19, 10121 Torino, Italy
- Pharmacology and Toxicology Section, Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy;
- European Biomedical Research Institute of Salerno (EBRIS), Via Salvatore de Renzi 50, 84125 Salerno, Italy
| | - Sakari Kauppinen
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark; (S.T.); (U.S.S.); (R.P.)
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Jain U, Srivastava P, Sharma A, Sinha S, Johari S. Impaired Fibroblast Growth Factor 21 (FGF21) Associated with Visceral Adiposity Leads to Insulin Resistance: The Core Defect in Diabetes Mellitus. Curr Diabetes Rev 2025; 21:e260424229342. [PMID: 38676505 DOI: 10.2174/0115733998265915231116043813] [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: 06/23/2023] [Revised: 09/06/2023] [Accepted: 09/20/2023] [Indexed: 04/29/2024]
Abstract
The Central nervous system (CNS) is the prime regulator of signaling pathways whose function includes regulation of food intake (consumption), energy expenditure, and other metabolic responses like glycolysis, gluconeogenesis, fatty acid oxidation, and thermogenesis that have been implicated in chronic inflammatory disorders. Type 2 diabetes mellitus (T2DM) and obesity are two metabolic disorders that are linked together and have become an epidemic worldwide, thus raising significant public health concerns. Fibroblast growth factor 21 (FGF21) is an endocrine hormone with pleiotropic metabolic effects that increase insulin sensitivity and energy expenditure by elevating thermogenesis in brown or beige adipocytes, thus reducing body weight and sugar intake. In contrast, during starvation conditions, FGF21 induces its expression in the liver to initiate glucose homeostasis. Insulin resistance is one of the main anomalies caused by impaired FGF21 signaling, which also causes abnormal regulation of other signaling pathways. Tumor necrosis factor alpha (TNF-α), the cytokine released by adipocytes and inflammatory cells in response to chronic inflammation, is regarded major factor that reduces the expression of FGF21 and modulates underlying insulin resistance that causes imbalanced glucose homeostasis. This review aims to shed light on the mechanisms underlying the development of insulin resistance in obese individuals as well as the fundamental flaw in type 2 diabetes, which is malfunctioning obese adipose tissue.
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Affiliation(s)
- Unnati Jain
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Priyanka Srivastava
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
| | - Ashwani Sharma
- Insight BioSolutions, Rue Joseph Colin, 35000 Rennes, France
| | - Subrata Sinha
- Centre of Biotechnology and Bioinformatics, Dibrugarh University, Dibrugarh, Assam 786004, India
| | - Surabhi Johari
- Department of Biosciences, Institute of Management Studies Ghaziabad (University Courses Campus), NH09, Adhyatmik Nagar, Ghaziabad, Uttar Pradesh, India
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Wu CJ, Liu H, Tu LJ, Hu JY. Peroxisome proliferator-activated receptor gamma mutation in familial partial lipodystrophy type three: A case report and review of literature. World J Diabetes 2024; 15:2360-2369. [PMID: 39676812 PMCID: PMC11580599 DOI: 10.4239/wjd.v15.i12.2360] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Revised: 09/22/2024] [Accepted: 10/23/2024] [Indexed: 11/18/2024] Open
Abstract
BACKGROUND Familial partial lipodystrophy disease (FPLD) is a collection of rare genetic diseases featuring partial loss of adipose tissue. However, metabolic difficulties, such as severe insulin resistance, diabetes, hypertriglyceridemia, and hypertension frequently occur alongside adipose tissue loss, making it susceptible to misdiagnosis and delaying effective treatment. Numerous genes are implicated in the occurrence of FPLD, and genetic testing has been for conditions linked to single gene mutation related to FPLD. Reviewing recent reports, treatment of the disease is limited to preventing and improving complications in patients. CASE SUMMARY In 2017, a 31-year-old woman with diabetes, hypertension and hypertriglyceridemia was hospitalized. We identified a mutation in her peroxisome proliferator-activated receptor gamma (PPARG) gene, Y151C (p.Tyr151Cys), which results in a nucleotide substitution residue 452 in the DNA-binding domain (DBD) of PPARG. The unaffected family member did not carry this mutation. Pioglitazone, a PPARG agonist, improved the patient's responsiveness to hypoglycemic and antihypertensive therapy. After one year of treatment in our hospital, the fasting blood glucose and glycosylated hemoglobin of the patient were close to normal. CONCLUSION We report a rare PPARG mutation, Y151C, which is located in the DBD of PPARG and leads to FPLD, and the preferred agent is PPARG agonists. We then summarized clinical phenotypic characteristics of FPLD3 caused by PPARG gene mutations, and clarified the relationship between different mutations of PPARG gene and the clinical manifestations of this type of FPLD. Additionally, current treatments for FPLD caused by PPARG mutations are reviewed.
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Affiliation(s)
- Chao-Jun Wu
- Basic Medical College, Army Medical University, Chongqing 400038, China
| | - Hao Liu
- Basic Medical College, Army Medical University, Chongqing 400038, China
| | - Li-Juan Tu
- Department of Endocrinology, Rare Disease Center, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
| | - Jiong-Yu Hu
- Department of Endocrinology, Rare Disease Center, The First Affiliated Hospital of Army Medical University, Chongqing 400038, China
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Aibara D, Sakaguchi A, Matsusue K. Transmembrane and coiled-coil domain family 3 gene is a novel target of hepatic peroxisome proliferator-activated receptor γ in fatty liver disease. Mol Cell Endocrinol 2024; 594:112379. [PMID: 39326649 DOI: 10.1016/j.mce.2024.112379] [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: 05/23/2024] [Revised: 09/19/2024] [Accepted: 09/24/2024] [Indexed: 09/28/2024]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor abundantly expressed in the nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the mechanism by which PPARγ regulates the transmembrane and coiled-coil domain family 3 (Tmcc3) gene in the liver. We found that TMCC3 is highly expressed in the fatty liver of humans and mice with NAFLD and alcoholic fatty liver disease. Three exon 1 variants (Tmcc3-1a, -1b, and -1c) of mouse Tmcc3 were identified. TMCC3-1B was highly expressed in the fatty liver of type 2 diabetic ob/ob mice; however, this increase in expression was ameliorated by liver-specific knockout of PPARγ. Reporter assays and electrophoretic mobility shift assays showed that PPARγ positively regulates Tmcc3-1b and -1c transcription through the same PPARγ-responsive element present in the 5'-region of each Tmcc3. Altogether, our results indicate that Tmcc3 is a novel PPARγ target in the fatty liver disease.
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Affiliation(s)
- Daisuke Aibara
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Ai Sakaguchi
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan.
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D P, Hani U, Haider N, Talath S, Shanmugarajan D, P P, P A, Prashantha Kumar BR. Novel PPAR-γ agonists as potential neuroprotective agents against Alzheimer's disease: rational design, synthesis , in silico evaluation, PPAR-γ binding assay and transactivation and expression studies. RSC Adv 2024; 14:33247-33266. [PMID: 39434987 PMCID: PMC11492828 DOI: 10.1039/d4ra06330a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 09/30/2024] [Indexed: 10/23/2024] Open
Abstract
Alzheimer's disease (AD) is a neurological disorder. It is caused by accumulation of amyloid beta (Aβ) plaques and tau tangles, which gradually leads to cognitive decline and memory loss. Peroxisome proliferator-activated receptor gamma (PPAR-γ), a nuclear receptor, plays a significant role in regulating genes responsible for metabolism and inflammation. Studies have shown that PPAR-γ activation has neuroprotective effects, can potentially reduce inflammation and oxidative stress, and stimulates mitochondrial biogenesis. Current study presents the design, synthesis and in vitro evaluation of PPAR-γ agonists for AD that are tailored to optimize binding with the PPAR-γ receptor. The compounds 4a, 4h and 4j exhibited notable binding affinities towards PPAR-γ LBD, with IC50 values of 8.607, 9.242, and 5.974 μM, respectively, in TR-FRET binding assay. These compounds were cell proliferative and non-cytotoxic in a neuroblastoma cell line (SH-SY5Y). They also demonstrated dose-dependent PPAR-γ activation in transactivation assay. Their neuroprotective effect was studied based on their anti-inflammatory and anti-oxidant potential by reducing the levels of proinflammatory markers (TNF-α, IL-6 and IL-1β) and ROS in Aβ-induced SH-SY5Y neuroblastoma cells using a flow cytometry method. The synthesized compounds also showed interactions in molecular docking study with the PPAR-γ receptor and demonstrated good stability in MD simulation. Our results highlight that through activation of PPAR-γ, the compounds 4a, 4h and 4j offer neuroprotective effects by reducing neuroinflammation and oxidative stress, and hence, they may be considered lead molecules for treating AD.
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Affiliation(s)
- Priya D
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Umme Hani
- Department of Pharmaceutics, College of Pharmacy, King Khalid University Abha 62529 Saudi Arabia
| | - Nazima Haider
- Department of Pathology, College of Medicine, King Khalid University Abha 62529 Saudi Arabia
| | - Sirajunisa Talath
- Department of Pharmaceutical Chemistry, RAK College of Pharmacy, RAK Medical and Health Sciences University Ras Al Khaimah 11172 United Arab Emirates
| | - Dhivya Shanmugarajan
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Prabitha P
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - Archana P
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
| | - B R Prashantha Kumar
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education and Research Sri Shivarathreeshwara Nagara Mysuru 570015 India +91-821-2548359 +91-821-2548353
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Zhang L, Xu L, Rong A, Cui Y, Wang L, Li L, Han X, Xiao X, Wu H. Effect of Rab18 on liver injury and lipid accumulation by regulating perilipin 2 and peroxisome proliferator-activated receptor gamma in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2024; 39:2219-2227. [PMID: 39030773 DOI: 10.1111/jgh.16676] [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: 03/20/2024] [Revised: 05/29/2024] [Accepted: 06/19/2024] [Indexed: 07/22/2024]
Abstract
BACKGROUND AND AIM Nonalcoholic fatty liver disease (NAFLD) is currently one of the most common chronic liver diseases worldwide, characterized by the presence of lipid droplets. Rab18 is an important lipid droplet protein; however, its effects and mechanisms of action on NAFLD remain unclear. METHODS Free fatty acid-stimulated AML-12 cells and high-fat diet (HFD)-fed mice were used as NAFLD models. Lentiviruses overexpressing Rab18 (Rab18-OE) or knockdown (Rab18-KD) were used to generate stable cell lines for genetic analysis. Blood serum levels of alanine aminotransferase, aspartate aminotransferase, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glucose, and leptin were measured using a biochemical autoanalyzer. Hematoxylin and eosin staining was performed to detect pathological damage to the liver. Lipid accumulation in the cells was assessed by Oil Red O staining. Target expression was measured using qPCR, western blotting, and immunocytochemistry. RESULTS Rab18 mRNA and protein expression levels increased in free fatty acid-stimulated AML-12 cells and the livers of HFD-fed mice. Rab18-OE increased lipid accumulation in vitro, which was attenuated by Rab18-KD. In vivo, Rab18-OE augmented liver pathological damage, serum alanine aminotransferase/aspartate aminotransferase activity, and triglyceride, total cholesterol, and low-density lipoprotein levels, whereas Rab18-KD decreased these indicators. Rab18-KD also downregulated blood glucose levels in HFD-fed mice. Mechanistically, Rab18-OE and Rab18-KD regulated the mRNA and protein expression levels of perilipin 2 (PLIN2) and peroxisome proliferator-activated receptor gamma (PPARγ) in vitro and in vivo, respectively. Immunocytochemistry revealed that Rab18 colocalized with PLIN2 and PPARγ in AML-12 cells. CONCLUSION Rab18 expression was elevated in vitro and in vivo in the NAFLD mouse model. Rab18 regulates PLIN2 and PPARγ expression to exaggerate liver injury and lipid accumulation in patients with NAFLD. Thus, Rab18 may be a crucial protein in this disease and a potential therapeutic target.
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Affiliation(s)
- Lei Zhang
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lidong Xu
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Aimei Rong
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Yuanbo Cui
- Department of Translational Medicine Center, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lin Wang
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Lu Li
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Xiaomeng Han
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Xingguo Xiao
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
| | - Huili Wu
- Department of Gastroenterology, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, China
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Flowers E, Stroebel B, Gong X, Lewis KA, Aouizerat BE, Gadgil M, Kanaya AM, Zhang L. Longitudinal associations between microRNAs and weight in the diabetes prevention program. Front Endocrinol (Lausanne) 2024; 15:1419812. [PMID: 39359416 PMCID: PMC11445047 DOI: 10.3389/fendo.2024.1419812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/26/2024] [Indexed: 10/04/2024] Open
Abstract
Objective Circulating microRNAs show cross-sectional associations with overweight and obesity. Few studies provided data to differentiate between a snapshot perspective on these associations versus how microRNAs characterize prodromal risk from disease pathology and complications. This study assessed longitudinal relationships between circulating microRNAs and weight at multiple time-points in the Diabetes Prevention Program trial. Research design and methods A subset of participants (n=150) from the Diabetes Prevention Program were included. MicroRNAs were measured from banked plasma using a Fireplex Assay. We used generalized linear mixed models to evaluate relationships between microRNAs and changes in weight at baseline, year-1, and year-2. Logistic regression was used to evaluate whether microRNAs at baseline were associated with weight change after 2 years. Results In fully adjusted models that included relevant covariates, seven miRs (i.e., miR-126, miR-15a, miR-192, miR-23a, and miR-27a) were statistically associated with weight over 2 years. MiR-197 and miR-320a remained significant after adjustment for multiple comparisons. Baseline levels of let-7f, miR-17, and miR-320c were significantly associated with 3% weight loss after 2 years in fully adjusted models. Discussion This study provided evidence for longitudinal relationships between circulating microRNAs and weight. Because microRNAs characterize the combined effects of genetic determinants and responses to behavioral determinants, they may provide insights about the etiology of overweight and obesity in the context or risk for common, complex diseases. Additional studies are needed to validate the potential genes and biological pathways that might be targeted by these microRNA biomarkers and have mechanistic implications for weight loss and disease prevention.
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Affiliation(s)
- Elena Flowers
- Department of Physiological Nursing, University of California, San Francisco, San Francisco, CA, United States
- Institute for Human Genetics, University of California, San Francisco, San Francisco, CA, United States
| | - Benjamin Stroebel
- Department of Physiological Nursing, University of California, San Francisco, San Francisco, CA, United States
| | - Xingyue Gong
- Department of Physiological Nursing, University of California, San Francisco, San Francisco, CA, United States
| | - Kimberly A. Lewis
- Department of Physiological Nursing, University of California, San Francisco, San Francisco, CA, United States
| | - Bradley E. Aouizerat
- Bluestone Center for Clinical Research, New York University, New York, NY, United States
- Department of Oral and Maxillofacial Surgery, New York University, New York, NY, United States
| | - Meghana Gadgil
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Alka M. Kanaya
- Division of General Internal Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
| | - Li Zhang
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, United States
- Division of Hematology and Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
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Steiner BM, Benvie AM, Lee D, Jiang Y, Berry DC. Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner. Nat Commun 2024; 15:6622. [PMID: 39103342 PMCID: PMC11300861 DOI: 10.1038/s41467-024-50985-8] [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: 08/10/2022] [Accepted: 07/26/2024] [Indexed: 08/07/2024] Open
Abstract
Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.
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Affiliation(s)
- Benjamin M Steiner
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Abigail M Benvie
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Derek Lee
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA
| | - Yuwei Jiang
- Department of Physiology and Biophysics, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Daniel C Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, 14853, USA.
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11
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Heintz MM, Klaren WD, East AW, Haws LC, McGreal SR, Campbell RR, Thompson CM. Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in mouse, rat, and pooled human hepatocytes. Toxicol Sci 2024; 200:165-182. [PMID: 38574381 PMCID: PMC11199992 DOI: 10.1093/toxsci/kfae044] [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: 04/06/2024] Open
Abstract
Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARα mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat, and pooled human hepatocytes treated for 12, 24, or 72 h with various concentrations of HFPO-DA, or agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxic agents (ie, acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated the greatest concordance between HFPO-DA and PPARα agonist GW7647-treated hepatocytes compared with the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARα or PPARγ, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARα/γ agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARα signaling mechanisms as part of the MOA for PPARα activator-induced rodent hepatocarcinogenesis. Thus, effects observed in mouse liver are not appropriate endpoints for toxicity value development for HFPO-DA in human health risk assessment.
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12
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Strnadová M, Thor D, Kaczmarek I. Protocol for changing gene expression in 3T3-L1 (pre)adipocytes using siRNA-mediated knockdown. STAR Protoc 2024; 5:103075. [PMID: 38805394 PMCID: PMC11153903 DOI: 10.1016/j.xpro.2024.103075] [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: 11/24/2023] [Revised: 03/21/2024] [Accepted: 04/26/2024] [Indexed: 05/30/2024] Open
Abstract
3T3-L1 is a model cell line which can be differentiated from preadipocytes into mature adipocytes. Here, we present a protocol for changing gene expression in 3T3-L1 (pre)adipocytes using small interfering RNA (siRNA)-mediated knockdown. We describe steps to perform the knockdown of a certain gene prior to differentiation (day 4) to analyze the impact on adipogenesis. We then detail procedures for knockdown on day 8 of differentiation to study the role of a certain gene in mature adipocyte function. For complete details on the use and execution of this protocol, please refer to Kaczmarek et al.1.
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Affiliation(s)
- Martina Strnadová
- Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Leipzig, 04103 Saxony, Germany
| | - Doreen Thor
- Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Leipzig, 04103 Saxony, Germany.
| | - Isabell Kaczmarek
- Rudolf Schönheimer Institute of Biochemistry, Medical Faculty, Leipzig University, Leipzig, 04103 Saxony, Germany.
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13
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Useini A, Schwerin IK, Künze G, Sträter N. Structural Studies on the Binding Mode of Bisphenols to PPARγ. Biomolecules 2024; 14:640. [PMID: 38927044 PMCID: PMC11202036 DOI: 10.3390/biom14060640] [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: 05/07/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Bisphenol A (BPA) and bisphenol B (BPB) are widely used in the production of plastics, and their potential adverse health effects, particularly on endocrine disruption and metabolic health, have raised concern. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in metabolic regulation and adipogenesis, making it a target of interest in understanding the development of obesity and associated health impacts. In this study, we employ X-ray crystallography and molecular dynamics (MD) simulations to study the interaction of PPARγ with BPA and BPB. Crystallographic structures reveal the binding of BPA and BPB to the ligand binding domain of PPARγ, next to C285, where binding of partial agonists as well as antagonists and inverse agonists of PPARγ signaling has been previously observed. However, no interaction of BPA and BPB with Y437 in the activation function 2 site is observed, showing that these ligands cannot stabilize the active conformation of helix 12 directly. Furthermore, free energy analyses of the MD simulations revealed that I341 has a large energetic contribution to the BPA and BPB binding modes characterized in this study.
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Affiliation(s)
- Abibe Useini
- Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany;
| | - Inken Kaja Schwerin
- Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany;
| | - Georg Künze
- Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany;
- Interdisciplinary Center for Bioinformatics, Leipzig University, 04107 Leipzig, Germany
- Center for Scalable Data Analytics and Artificial Intelligence (ScaDS.AI), Leipzig University, 04105 Leipzig, Germany
| | - Norbert Sträter
- Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany;
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14
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Zhang F, Pan X, Zhang X, Tong N. The effect of thiazolidinediones on body fat redistribution in adults: A systematic review and meta-analysis of randomized controlled trials. Obes Rev 2024; 25:e13675. [PMID: 38098209 DOI: 10.1111/obr.13675] [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: 08/29/2022] [Revised: 11/04/2023] [Accepted: 11/10/2023] [Indexed: 02/28/2024]
Abstract
Visceral adiposity is a strong predictor of cardiometabolic risk. Thiazolidinediones (TZDs) are associated with a shift in fat redistribution from visceral adipose tissue (VAT) to subcutaneous adipose tissue (SAT). We aimed to compare the effects of TZD and other interventions on fat remodeling in adults in randomized controlled trials. Among the 1331 retrieved studies, 39 trials with 1765 participants were included in the meta-analysis. The standardized mean difference in VAT change was not significantly different between TZD and comparators across the overall studies. Intriguingly, TZD treatment resulted in significant decreases in VAT compared with placebo and sulfonylureas (p < 0.05), although recombinant human growth hormone was superior to TZD regarding VAT reduction (p < 0.05). Data from 216 participants showed TZD leading to a greater reduction in liver fat percentage than comparators (p < 0.05). Compared with the controls, TZD significantly increased SAT, total body fat, weight, waist circumference, and body mass index (p < 0.05). However, TZD pronouncedly improved glucose control, insulin resistance, adiponectin, and lipid profile (p < 0.05). TZD provides a favorable effect on fat redistribution and benefits insulin sensitivity, suggesting a potentially valuable approach in cardiometabolic risk management.
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Affiliation(s)
- Fang Zhang
- Division of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xiaohui Pan
- Division of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Xinyue Zhang
- Division of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Nanwei Tong
- Division of Endocrinology and Metabolism, Center for Diabetes and Metabolism Research, West China Hospital of Sichuan University, Chengdu, Sichuan, China
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15
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Benvie AM, Lee D, Jiang Y, Berry DC. Platelet-derived growth factor receptor beta is required for embryonic specification and confinement of the adult white adipose lineage. iScience 2024; 27:108682. [PMID: 38235323 PMCID: PMC10792241 DOI: 10.1016/j.isci.2023.108682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Revised: 10/31/2023] [Accepted: 12/05/2023] [Indexed: 01/19/2024] Open
Abstract
White adipose tissue (WAT) development and adult homeostasis rely on distinct adipocyte progenitor cells (APCs). While adult APCs are defined early during embryogenesis and generate adipocytes after WAT organogenesis, the mechanisms underlying adult adipose lineage determination and preservation remain undefined. Here, we uncover a critical role for platelet-derived growth factor receptor beta (Pdgfrβ) in identifying the adult APC lineage. Without Pdgfrβ, APCs lose their adipogenic competency to incite fibrotic tissue replacement and inflammation. Through lineage tracing analysis, we reveal that the adult APC lineage is lost and develops into macrophages when Pdgfrβ is deleted embryonically. Moreover, to maintain the APC lineage, Pdgfrβ activation stimulates p38/MAPK phosphorylation to promote APC proliferation and maintains the APC state by phosphorylating peroxisome proliferator activated receptor gamma (Pparγ) at serine 112. Together, our findings identify a role for Pdgfrβ acting as a rheostat for adult adipose lineage confinement to prevent unintended lineage switches.
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Affiliation(s)
- Abigail M. Benvie
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Derek Lee
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
| | - Yuwei Jiang
- Department of Physiology and Biophysics, University of Illinois College of Medicine at Chicago, Chicago, IL 60612, USA
| | - Daniel C. Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY 14853, USA
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16
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Engin AB. Message Transmission Between Adipocyte and Macrophage in Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:273-295. [PMID: 39287855 DOI: 10.1007/978-3-031-63657-8_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
Obesity is characterized by the chronic low-grade activation of the innate immune system. In this respect, macrophage-elicited metabolic inflammation and adipocyte-macrophage interaction have primary importance in obesity. Large quantity of macrophages is accumulated by different mechanisms in obese adipose tissue. Hypertrophic adipocyte-derived chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) pathway promotes more macrophage accumulation into the obese adipose tissue. However, obesity-induced changes in adipose tissue macrophage density are mainly dependent on increases in the triple-positive cluster of differentiation (CD)11b+ F4/80+ CD11c+ adipose tissue macrophage subpopulation. As epigenetic regulators, microRNAs (miRNAs) are one of the most important mediators of obesity. miRNAs are expressed by adipocytes as well as macrophages and regulate inflammation with the expression of target genes. A paracrine loop involving free fatty acids and tumor necrosis factor-alpha (TNF-α) between adipocytes and macrophages establishes a vicious cycle that aggravates inflammatory changes in the adipose tissue. Adipocyte-specific caspase-1 and production of interleukin-1beta (IL-1β) by macrophages; both adipocyte and macrophage induction by toll-like receptor-4 (TLR4) through nuclear factor-kappaB (NF-κB) activation; free fatty acid-induced and TLR-mediated activation of c-Jun N-terminal kinase (JNK)-related pro-inflammatory pathways in CD11c+ immune cells; are effective in mutual message transmission between adipocyte and macrophage and in the development of adipose tissue inflammation. Thus, the metabolic status of adipocytes and their released exosomes are important determinants of macrophage inflammatory output. However, old adipocytes are removed by macrophages through trogocytosis or sending an "eat me" signal. As a single miRNA can be able to regulate a variety of target genes and signaling pathways, reciprocal transfer of miRNAs between adipocytes and macrophages via miRNA-loaded exosomes reorganizes the different stages of obesity. Changes in the expression of circulating miRNAs because of obesity progression or anti-obesity treatment indicate that miRNAs could be used as potential biomarkers. Therefore, it is believed that targeting macrophage-associated miRNAs with anti-obesity miRNA-loaded nano-carriers may be successful in the attenuation of both obesity and adipose tissue inflammation in clinical practice. Moreover, miRNA-containing exosomes and transferable mitochondria between the adipocyte and macrophage are investigated as new therapeutic targets for obesity-related metabolic disorders.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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17
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Kim G, Lee J, Ha J, Kang I, Choe W. Endoplasmic Reticulum Stress and Its Impact on Adipogenesis: Molecular Mechanisms Implicated. Nutrients 2023; 15:5082. [PMID: 38140341 PMCID: PMC10745682 DOI: 10.3390/nu15245082] [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: 10/28/2023] [Revised: 11/30/2023] [Accepted: 12/09/2023] [Indexed: 12/24/2023] Open
Abstract
Endoplasmic reticulum (ER) stress plays a pivotal role in adipogenesis, which encompasses the differentiation of adipocytes and lipid accumulation. Sustained ER stress has the potential to disrupt the signaling of the unfolded protein response (UPR), thereby influencing adipogenesis. This comprehensive review illuminates the molecular mechanisms that underpin the interplay between ER stress and adipogenesis. We delve into the dysregulation of UPR pathways, namely, IRE1-XBP1, PERK and ATF6 in relation to adipocyte differentiation, lipid metabolism, and tissue inflammation. Moreover, we scrutinize how ER stress impacts key adipogenic transcription factors such as proliferator-activated receptor γ (PPARγ) and CCAAT-enhancer-binding proteins (C/EBPs) along with their interaction with other signaling pathways. The cellular ramifications include alterations in lipid metabolism, dysregulation of adipokines, and aged adipose tissue inflammation. We also discuss the potential roles the molecular chaperones cyclophilin A and cyclophilin B play in adipogenesis. By shedding light on the intricate relationship between ER stress and adipogenesis, this review paves the way for devising innovative therapeutic interventions.
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Affiliation(s)
- Gyuhui Kim
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Jiyoon Lee
- Department of Biological Sciences, Franklin College of Arts and Sciences, University of Georgia, Athens, GA 30609, USA;
| | - Joohun Ha
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Insug Kang
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
| | - Wonchae Choe
- Department of Biomedical Science, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (G.K.); (J.H.); (I.K.)
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea
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18
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Shen X, Tang J, Huang Y, Lan X, Lei C, Chen H. CircRNF111 Contributes to Adipocyte Differentiation by Elevating PPARγ Expression via miR-27a-3p. Epigenetics 2023; 18:2145058. [PMID: 36377797 PMCID: PMC9980459 DOI: 10.1080/15592294.2022.2145058] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The content and distribution of adipocytes is an important factor that affects meat quality. Previous studies showed that circRNAs are involved in various physiological processes. Nevertheless, more research is needed to investigate the function of circRNAs in adipogenesis. The present study examines the effects of circRNF111 on adipogenesis of bovine preadipocyte and aims to elucidate the underlying molecular mechanisms. In our study, the sequence signature of circRNF111 was identified using bioinformatics, RNA-FISH, and sequencing. Mechanistically, knockdown or exogenous expression of circRNF111 in preadipocytes was done to prove the functional significance of circRNF111. Combined with bioinformatics, a dual fluorescein reporter system, and immunoprecipitation, the interaction between circRNF111, miR-27a-3p, and the target gene PPARγ was verified. The results reveal that circRNF111 is positively correlated with adipocyte differentiation. The newly identified bovine circRNF111 functions as a miR-27a-3p sponge to rescue the inhibitory effect of miR-27a-3p on the PPARγ gene, thereby promoting adipogenesis.
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Affiliation(s)
- Xuemei Shen
- Engineering Research Center of Sichuan Province Higher School of Local Chicken Breeds Industrialization in Southern Sichuan, College of Life Science, Leshan Normal University, Leshan, China,Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Jia Tang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Yongzhen Huang
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Xianyong Lan
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Chuzhao Lei
- Key Laboratory of Animal Genetics, Breeding and Reproduction of Shaanxi Province, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Hong Chen
- College of Animal Science, Xinjiang Agricultural University, Urumqi, China,CONTACT Hong Chen College of Animal Science, Xinjiang Agricultural University, Urumqi, China
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19
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Alami M, Boumezough K, Khalil A, Ramchoun M, Boulbaroud S, Fulop T, Morvaridzadeh M, Berrougui H. The Modulatory Bioeffects of Pomegranate ( Punica granatum L.) Polyphenols on Metabolic Disorders: Understanding Their Preventive Role against Metabolic Syndrome. Nutrients 2023; 15:4879. [PMID: 38068738 PMCID: PMC10707905 DOI: 10.3390/nu15234879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
Modern research achievements support the health-promoting effects of natural products and diets rich in polyphenols. Pomegranate (PG) (Punica granatum L.) contains a considerable number of bioactive compounds that exert a broad spectrum of beneficial biological activities, including antimicrobial, antidiabetic, antiobesity, and atheroprotective properties. In this context, the reviewed literature shows that PG intake might reduce insulin resistance, cytokine levels, redox gene expression, blood pressure elevation, vascular injuries, and lipoprotein oxidative modifications. The lipid parameter corrective capabilities of PG-ellagitannins have also been extensively reported to be significantly effective in reducing hyperlipidemia (TC, LDL-C, VLDL-C, and TAGs), while increasing plasma HDL-C concentrations and improving the TC/HDL-C and LDL-C/HDL-C ratios. The health benefits of pomegranate consumption seem to be acheived through the amelioration of adipose tissue endocrine function, fatty acid utilization, GLUT receptor expression, paraoxonase activity enhancement, and the modulation of PPAR and NF-κB. While the results from animal experiments are promising, human findings published in this field are inconsistent and are still limited in several aspects. The present review aims to discuss and provide a critical analysis of PG's bioeffects on the components of metabolic syndrome, type-2 diabetes, obesity, and dyslipidemia, as well as on certain cardiovascular-related diseases. Additionally, a brief overview of the pharmacokinetic properties, safety, and bioavailability of PG-ellagitannins is included.
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Affiliation(s)
- Mehdi Alami
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Kaoutar Boumezough
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Abdelouahed Khalil
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Mhamed Ramchoun
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Samira Boulbaroud
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Tamas Fulop
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Mojgan Morvaridzadeh
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Hicham Berrougui
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
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20
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Guo YC, Cao HD, Lian XF, Wu PX, Zhang F, Zhang H, Lu DH. Molecular mechanisms of noncoding RNA and epigenetic regulation in obesity with consequent diabetes mellitus development. World J Diabetes 2023; 14:1621-1631. [DOI: 10.4239/wjd.v14.i11.1621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/26/2023] [Accepted: 09/27/2023] [Indexed: 11/14/2023] Open
Abstract
Diabetes mellitus (DM) and obesity have become two of the most prevalent and challenging diseases worldwide, with increasing incidence and serious complications. Recent studies have shown that noncoding RNA (ncRNA) and epigenetic regulation play crucial roles in the pathogenesis of DM complicated by obesity. Identification of the involvement of ncRNA and epigenetic regulation in the pathogenesis of diabetes with obesity has opened new avenues of investigation. Targeting these mechanisms with small molecules or RNA-based therapies may provide a more precise and effective approach to diabetes treatment than traditional therapies. In this review, we discuss the molecular mechanisms of ncRNA and epigenetic regulation and their potential therapeutic targets, and the research prospects for DM complicated with obesity.
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Affiliation(s)
- Yi-Chen Guo
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Hao-Di Cao
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Xiao-Fen Lian
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Pei-Xian Wu
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Fan Zhang
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Hua Zhang
- Department of Endocrinology, Zhujiang Hospital of Southern Medical University, Guangzhou 510282, Guangdong Province, China
| | - Dong-Hui Lu
- Department of Endo-crinology, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
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21
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Zhao YK, Zhu XD, Liu R, Yang X, Liang YL, Wang Y. The Role of PPARγ Gene Polymorphisms, Gut Microbiota in Type 2 Diabetes: Current Progress and Future Prospects. Diabetes Metab Syndr Obes 2023; 16:3557-3566. [PMID: 37954888 PMCID: PMC10638901 DOI: 10.2147/dmso.s429825] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 10/18/2023] [Indexed: 11/14/2023] Open
Abstract
Over the past decade, there has been a significant increase in studies investigating the relationship between the polymorphisms of the Peroxisome Proliferator-Activated Receptor gamma (PPARγ) gene and Type 2 Diabetes (T2D). PPARγ, a critical transcription factor, plays a central role in lipid metabolism, insulin resistance, and inflammatory response. Concurrently, the influence of gut microbiota on the development of T2D has gained increasing attention, especially their role in affecting host metabolism, such as lipid metabolism and the PPARγ signaling pathway. This review provides a comprehensive analysis of recent studies on PPARγ gene polymorphisms and their association with T2D, with a specific emphasis on the implications of gut microbiota and their interaction with PPARγ pathways. We also discuss the potential of manipulating gut microbiota and targeting PPARγ gene polymorphisms in T2D management. By deepening our understanding of these relationships, we aim to pave the way for novel preventative and therapeutic strategies for T2D.
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Affiliation(s)
- Yi-Kun Zhao
- Department of Basic Medical College, Gansu University of Chinese Medicine, Lanzhou City, People’s Republic of China
| | - Xiang-Dong Zhu
- Department of Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan city, People’s Republic of China
| | - Rong Liu
- Department of Basic Medical College, Gansu University of Chinese Medicine, Lanzhou City, People’s Republic of China
| | - Xia Yang
- Department of Basic Medical College, Gansu University of Chinese Medicine, Lanzhou City, People’s Republic of China
| | - Yong-Lin Liang
- Department of Basic Medical College, Gansu University of Chinese Medicine, Lanzhou City, People’s Republic of China
| | - Yan Wang
- Department of Traditional Chinese Medicine College, Ningxia Medical University, Yinchuan city, People’s Republic of China
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22
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Wang J, Duan Z, Zeng R, Yang L, Liu W, Liu Y, Yao Q, Chen X, Zhang LJ, Li M. Antimicrobial peptide-producing dermal preadipocytes defend against Candida albicans skin infection via the FGFR-MEK-ERK pathway. PLoS Pathog 2023; 19:e1011754. [PMID: 38032898 PMCID: PMC10688742 DOI: 10.1371/journal.ppat.1011754] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 10/14/2023] [Indexed: 12/02/2023] Open
Abstract
Dermal fibroblasts (dFBs) defend against deep bacterial skin infections by differentiating into preadipocytes (pAds) that produce the antimicrobial peptide cathelicidin; this differentiation is known as the dermal reactive adipogenesis response. However, the role of dFBs in fungal infection remains unknown. Here, we found that cathelicidin-producing pAds were present in high numbers in skin lesions from patients with cutaneous Candida granulomas. Second, we showed that dermal Candida albicans (C. albicans) infection in mice robustly triggered the dermal reactive adipogenesis response and induced cathelicidin expression, and inhibition of adipogenesis with pharmacological inhibitors of peroxisome proliferator-activated receptor γ (PPARγ) impaired skin resistance to C. albicans. In vitro, C. albicans products induced cathelicidin expression in pAds, and differentiating pAds markedly suppressed the growth of C. albicans by producing cathelicidin. Finally, we showed that C. albicans induced an antimicrobial response in pAds through the FGFR-MEK-ERK pathway. Together, our data reveal a previously unknown role of dFBs in the defense against skin infection caused by C. albicans.
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Affiliation(s)
- Jianing Wang
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Zhimin Duan
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Rong Zeng
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Lu Yang
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
| | - Weizhao Liu
- School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yiman Liu
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Qian Yao
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Xu Chen
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- School of Public Health, Nanjing Medical University, Nanjing, China
| | - Ling-juan Zhang
- State Key Laboratory of Cellular Stress Biology, School of Pharmaceutical Sciences, Xiamen University, Xiamen, China
| | - Min Li
- Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and Sexually Transmitted Infections, Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China
- School of Public Health, Nanjing Medical University, Nanjing, China
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23
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Abd Rami AZ, Aminuddin A, Hamid AA, Mokhtar MH, Ugusman A. Nicotine Impairs the Anti-Contractile Function of Perivascular Adipose Tissue by Inhibiting the PPARγ-Adiponectin-AdipoR1 Axis. Int J Mol Sci 2023; 24:15100. [PMID: 37894791 PMCID: PMC10606313 DOI: 10.3390/ijms242015100] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 10/06/2023] [Accepted: 10/09/2023] [Indexed: 10/29/2023] Open
Abstract
Nicotine is an addictive compound found in cigarette smoke that leads to vascular dysfunction and cardiovascular diseases. Perivascular adipose tissue (PVAT) exerts an anti-contractile effect on the underlying vasculature through the production of adipokines, such as adiponectin, which acts on adiponectin receptors 1 (adipoR1) to cause vasorelaxation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that regulates adiponectin gene expression and PVAT development. This study aimed to determine the effect of nicotine on the anti-contractile function of PVAT via the PPARγ-adiponectin-adipoR1 axis. Male Sprague Dawley rats were divided into a control group (given normal saline), a nicotine group (given 0.8 mg/kg of nicotine), and a nicotine + PPARγ agonist group (given nicotine and 5 mg/kg of telmisartan). Thoracic aorta PVAT was harvested after 21 days of treatment. The results showed that nicotine reduced the anti-contractile effect of PVAT on the underlying thoracic aorta. Nicotine also decreased the gene and protein expression of PPARγ, adiponectin, and adipoR1 in PVAT. Treatment with telmisartan restored the anti-contractile effect of PVAT and increased the gene and protein expression of PPARγ, adiponectin, and adipoR1 in PVAT. In conclusion, nicotine attenuates the anti-contractile function of PVAT through inhibition of the PPARγ-adiponectin-adipoR1 axis.
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Affiliation(s)
| | - Amilia Aminuddin
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur 56000, Malaysia; (A.Z.A.R.); (A.A.H.); (M.H.M.)
| | | | | | - Azizah Ugusman
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras, Kuala Lumpur 56000, Malaysia; (A.Z.A.R.); (A.A.H.); (M.H.M.)
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24
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Yu L, Gao Y, Aaron N, Qiang L. A glimpse of the connection between PPARγ and macrophage. Front Pharmacol 2023; 14:1254317. [PMID: 37701041 PMCID: PMC10493289 DOI: 10.3389/fphar.2023.1254317] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 07/31/2023] [Indexed: 09/14/2023] Open
Abstract
Nuclear receptors are ligand-regulated transcription factors that regulate vast cellular activities and serve as an important class of drug targets. Among them, peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and have been extensively studied for their roles in metabolism, differentiation, development, and cancer, among others. Recently, there has been considerable interest in understanding and defining the function of PPARs and their agonists in regulating innate and adaptive immune responses and their pharmacological potential in combating chronic inflammatory diseases. In this review, we focus on emerging evidence for the potential role of PPARγ in macrophage biology, which is the prior innate immune executive in metabolic and tissue homeostasis. We also discuss the role of PPARγ as a regulator of macrophage function in inflammatory diseases. Lastly, we discuss the possible application of PPARγ antagonists in metabolic pathologies.
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Affiliation(s)
- Lexiang Yu
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
| | - Yuen Gao
- Department of Physiology, Michigan State University, East Lansing, MI, United States
| | - Nicole Aaron
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, NY, United States
| | - Li Qiang
- Naomi Berrie Diabetes Center, Columbia University, New York, NY, United States
- Department of Pathology and Cell Biology, Columbia University, New York, NY, United States
- Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
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25
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Sheng W, Wang Q, Qin H, Cao S, Wei Y, Weng J, Yu F, Zeng H. Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors. Int J Mol Sci 2023; 24:13137. [PMID: 37685944 PMCID: PMC10487662 DOI: 10.3390/ijms241713137] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/15/2023] [Indexed: 09/10/2023] Open
Abstract
Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes-PPARα, PPARβ/δ, and PPARγ-find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.
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Affiliation(s)
- Weibei Sheng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Qichang Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Haotian Qin
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Siyang Cao
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yihao Wei
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jian Weng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Fei Yu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
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26
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Yang S, Zhu T, Wakefield JS, Mauro TM, Elias PM, Man MQ. Link between obesity and atopic dermatitis: Does obesity predispose to atopic dermatitis, or vice versa? Exp Dermatol 2023; 32:975-985. [PMID: 37029451 PMCID: PMC10524376 DOI: 10.1111/exd.14801] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 03/11/2023] [Accepted: 03/24/2023] [Indexed: 04/09/2023]
Abstract
Two serious health conditions, obesity and atopic dermatitis (AD), share some pathological features such as insulin resistance, leptin resistance and inflammation, and a growing body of evidence suggests a link between obesity and AD. Obesity predisposes an individual to and/or worsens AD, whereas AD increases the risk of obesity. Obesity and AD's interactions are mediated by cytokines, chemokines and immune cells. Obese individuals with AD are more resistant to anti-inflammatory therapy, while weight loss can alleviate AD. In this review, we summarize the evidence linking AD and obesity. We also discuss the pathogenic role of obesity in AD, and vice versa. Because of the connection between these two conditions, mitigation of one could possibly prevent the development of or alleviate the other condition. Effective management of AD and weight loss can enhance the wellness of individuals with both of these conditions. However, proper clinical studies are warranted to validate this speculation.
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Affiliation(s)
- Shuyun Yang
- Department of Dermatology, The People’s Hospital of Baoshan, Yunnan, China
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
| | - Tingting Zhu
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
- Department of Dermatology, The First Affiliated Hospital of Soochow University, Jiangsu, China
| | - Joan S. Wakefield
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
| | - Theodora M. Mauro
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
| | - Peter M. Elias
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
| | - Mao-Qiang Man
- Dermatology Service, Veterans Affairs Medical Center San Francisco, and Department of Dermatology, University of California San Francisco, CA, USA
- Dermatology Hospital, Southern Medical University, Guangdong 510091, China
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27
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Kang T, Ree J, Park JW, Choe H, Park YI. Anti-Obesity Effects of SPY Fermented with Lactobacillus rhamnosus BST-L.601 via Suppression of Adipogenesis and Lipogenesis in High-Fat Diet-Induced Obese Mice. Foods 2023; 12:foods12112202. [PMID: 37297447 DOI: 10.3390/foods12112202] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/19/2023] [Accepted: 05/27/2023] [Indexed: 06/12/2023] Open
Abstract
In this research, the potential anti-obesity efficacy of Lactobacillus rhamnosus BST-L.601 and its fermented product (named SPY) with mashed sweet potato paste were investigated using 3T3-L1 preadipocytes and high-fat diet (HD)-induced obese mice. SPY (0-0.5 mg/mL) dose-dependently and significantly reduced lipid accumulation and TG content and the expression of adipogenic markers (C/EBPα, PPAR-γ, and aP2) and fatty acid synthetic pathway proteins (ACC and FAS) in 3T3-L1 adipocytes, demonstrating that SPY suppresses adipocyte differentiation and lipogenesis. Oral administration of SPY (4 × 107 CFU/kg body weight) to HD-induced obese mice for 12 weeks significantly reduced the body and liver weight, the size of adipocytes, and the weight of epididymal, visceral, and subcutaneous fat tissues. SPY was more effective in decreasing body weight gain in HD mice than in treatment with BST-L.601 alone. Administration of SPY or BST-L.601 also reduced the serum level of total cholesterol and LDL cholesterol and leptin secretion at a similar level. These results revealed that both SPY and BST-L.601 effectively suppress HD-induced adipogenesis and lipogenesis, suggesting that these materials would be useful in the functional foods industry to ameliorate and/or prevent obesity.
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Affiliation(s)
- Taewook Kang
- Department of Biotechnology, Graduate School, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Biostream Co., Ltd., Suwon 10442, Republic of Korea
| | - Jin Ree
- Department of Biotechnology, Graduate School, The Catholic University of Korea, Bucheon 14662, Republic of Korea
- Biostream Co., Ltd., Suwon 10442, Republic of Korea
| | | | - Hyewon Choe
- Biostream Co., Ltd., Suwon 10442, Republic of Korea
- Graduate School of Genetics and Biotechnology, Kyung Hee University, Yongin 17104, Republic of Korea
| | - Yong Il Park
- Department of Biotechnology, Graduate School, The Catholic University of Korea, Bucheon 14662, Republic of Korea
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28
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Zhang Y, Li Z, Liu X, Chen X, Zhang S, Chen Y, Chen J, Chen J, Wu F, Chen GQ. 3-Hydroxybutyrate ameliorates insulin resistance by inhibiting PPARγ Ser273 phosphorylation in type 2 diabetic mice. Signal Transduct Target Ther 2023; 8:190. [PMID: 37230992 DOI: 10.1038/s41392-023-01415-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 03/01/2023] [Accepted: 03/19/2023] [Indexed: 05/27/2023] Open
Abstract
3-Hydroxybutyrate (3HB) is a small ketone body molecule produced endogenously by the body in the liver. Previous studies have shown that 3HB can reduce blood glucose level in type 2 diabetic (T2D) patients. However, there is no systematic study and clear mechanism to evaluate and explain the hypoglycemic effect of 3HB. Here we demonstrate that 3HB reduces fasting blood glucose level, improves glucose tolerance, and ameliorates insulin resistance in type 2 diabetic mice through hydroxycarboxylic acid receptor 2 (HCAR2). Mechanistically, 3HB increases intracellular calcium ion (Ca2+) levels by activating HCAR2, thereby stimulating adenylate cyclase (AC) to increase cyclic adenosine monophosphate (cAMP) concentration, and then activating protein kinase A (PKA). Activated PKA inhibits Raf1 proto-oncogene serine/threonine-protein kinase (Raf1) activity, resulting in a decrease in extracellular signal-regulated kinases 1/2 (ERK1/2) activity and ultimately inhibiting peroxisome proliferator-activated receptor γ (PPARγ) Ser273 phosphorylation in adipocytes. Inhibition of PPARγ Ser273 phosphorylation by 3HB altered the expression of PPARγ regulated genes and reduced insulin resistance. Collectively, 3HB ameliorates insulin resistance in type 2 diabetic mice through a pathway of HCAR2/Ca2+/cAMP/PKA/Raf1/ERK1/2/PPARγ.
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Affiliation(s)
- Yudian Zhang
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Zihua Li
- Department of Medical Genetics and Cell Biology, School of Basic Medical Science of Ningxia Medical University, Yinchuan, Ningxia, 750004, P. R. China
| | - Xinyi Liu
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Xinyu Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Shujie Zhang
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Yuemeng Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Jiangnan Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Jin Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Fuqing Wu
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China
| | - Guo-Qiang Chen
- School of Life Sciences, Tsinghua University, Beijing, 100084, P. R. China.
- Center for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China.
- MOE Key Lab of Industrial Biocatalysis, Dept of Chemical Engineering, Tsinghua University, Beijing, 100084, P. R. China.
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29
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Zaiou M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Cells 2023; 12:cells12081205. [PMID: 37190114 DOI: 10.3390/cells12081205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean-Lamour, Université de Lorraine, UMR 7198 CNRS, 54505 Vandoeuvre-les-Nancy, France
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30
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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31
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Xue S, Lee D, Berry DC. Thermogenic adipose tissue in energy regulation and metabolic health. Front Endocrinol (Lausanne) 2023; 14:1150059. [PMID: 37020585 PMCID: PMC10067564 DOI: 10.3389/fendo.2023.1150059] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Accepted: 03/07/2023] [Indexed: 04/07/2023] Open
Abstract
The ability to generate thermogenic fat could be a targeted therapy to thwart obesity and improve metabolic health. Brown and beige adipocytes are two types of thermogenic fat cells that regulate energy balance. Both adipocytes share common morphological, biochemical, and thermogenic properties. Yet, recent evidence suggests unique features exist between brown and beige adipocytes, such as their cellular origin and thermogenic regulatory processes. Beige adipocytes also appear highly plastic, responding to environmental stimuli and interconverting between beige and white adipocyte states. Additionally, beige adipocytes appear to be metabolically heterogenic and have substrate specificity. Nevertheless, obese and aged individuals cannot develop beige adipocytes in response to thermogenic fat-inducers, creating a key clinical hurdle to their therapeutic promise. Thus, elucidating the underlying developmental, molecular, and functional mechanisms that govern thermogenic fat cells will improve our understanding of systemic energy regulation and strive for new targeted therapies to generate thermogenic fat. This review will examine the recent advances in thermogenic fat biogenesis, molecular regulation, and the potential mechanisms for their failure.
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Affiliation(s)
| | | | - Daniel C. Berry
- Division of Nutritional Sciences, Cornell University, Ithaca, NY, United States
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32
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Useini A, Engelberger F, Künze G, Sträter N. Structural basis of the activation of PPARγ by the plasticizer metabolites MEHP and MINCH. ENVIRONMENT INTERNATIONAL 2023; 173:107822. [PMID: 36841188 DOI: 10.1016/j.envint.2023.107822] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Revised: 01/20/2023] [Accepted: 02/11/2023] [Indexed: 06/18/2023]
Abstract
Di-2-ethylhexyl phthalate (DEHP) and its substitute 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) are widely used as plasticizers but may have adverse health effects. Via hydrolysis of one of the two ester bonds in the human body, DEHP and DINCH form the monoesters MEHP and MINCH, respectively. Previous studies demonstrated binding of these metabolites to PPARγ and the induction of adipogenesis via this pathway. Detailed structural understanding of how these metabolites interact with PPARγ and thereby affect human health is lacking until now. We therefore characterized the binding modes of MINCH and MEHP to the ligand binding domain of PPARγ by X-ray crystallography and molecular dynamics (MD) simulations. Both compounds bind to the activating function-2 (AF-2) binding site via an interaction of the free carboxylates with the histidines 323 and 449, tyrosine 473 and serine 289. The alkyl chains form hydrophobic interactions with the tunnel next to cysteine 285. These binding modes are generally stable as demonstrated by the MD simulations and they resemble the complexation of fatty acids and their metabolites to the AF-2 site of PPARγ. Similar to the situation for these natural PPARγ agonists, the interaction of the free carboxylate groups of MEHP and MINCH with tyrosine 473 and surrounding residues stabilizes the AF-2 helix in the upward conformation. This state promotes binding of coactivator proteins and thus formation of the active complex for transcription of the specific target genes. Moreover, a comparison of the residues involved in binding of the plasticizer metabolites in vertebrate PPARγ orthologs shows that these compounds likely have similar effects in other species.
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Affiliation(s)
- Abibe Useini
- Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany
| | - Felipe Engelberger
- Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany
| | - Georg Künze
- Institute for Drug Discovery, Leipzig University, Brüderstraße 34, 04103 Leipzig, Germany.
| | - Norbert Sträter
- Institute of Bioanalytical Chemistry, Centre for Biotechnology and Biomedicine, Leipzig University, Deutscher Platz 5, 04103 Leipzig, Germany.
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Cisplatin-induced changes in calcitonin gene-related peptide or TNF-α release in rat dorsal root ganglia in vitro model of neurotoxicity are not reverted by rosiglitazone. Neurotoxicology 2022; 93:211-221. [DOI: 10.1016/j.neuro.2022.10.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 09/24/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022]
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The Hippo pathway links adipocyte plasticity to adipose tissue fibrosis. Nat Commun 2022; 13:6030. [PMID: 36229481 PMCID: PMC9562301 DOI: 10.1038/s41467-022-33800-0] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Accepted: 09/29/2022] [Indexed: 11/29/2022] Open
Abstract
Fibrosis disrupts adipose tissue (AT) homeostasis and exacerbates metabolic dysfunction upon chronic caloric excess. The molecular mechanisms linking adipocyte plasticity to AT fibrosis are largely unknown. Here we show that the Hippo pathway is coupled with TGFβ signaling to orchestrate a cellular and/or functional shift of adipocytes from energy storage to extracellular matrix (ECM) remodeling in AT fibrosis. We found that Lats1/2-knockout adipocytes could dedifferentiate into DPP4+ progenitor cells and convert to DPP4− myofibroblasts upon TGFβ stimulation. On the other hand, Hippo pathway inhibition during obesity impaired adipocyte identity while promoted ECM remodeling activity of adipocytes. Macrophages recruited by CCL2 produced TGFβ to accelerate AT fibrosis. YAP and TAZ, the Hippo downstream effectors, enhanced SMAD2 stability to promote fibrotic responses. Importantly, inhibition of YAP/TAZ activity in obese mice markedly relieved AT fibrosis and improved metabolic homeostasis. Together, our findings identify the Hippo pathway as a molecular switch in the initiation and development of AT fibrosis, implying it as a therapeutic target. Adipose tissue fibrosis is connected to obesity-related metabolic dysfunction. Qiu and colleagues discover that the Hippo pathway acts as a molecular switch in the initiation and development of adipose tissue fibrosis upon TGFβ stimulation.
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The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells. Int J Mol Sci 2022; 23:ijms23179708. [PMID: 36077103 PMCID: PMC9456565 DOI: 10.3390/ijms23179708] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022] Open
Abstract
The peroxisome proliferator-activated receptor PPAR-γ is one of three PPAR nuclear receptors that act as ligand-activated transcription factors. In immune cells, the skin, and other organs, PPAR-γ regulates lipid, glucose, and amino acid metabolism. The receptor translates nutritional, pharmacological, and metabolic stimuli into the changes in gene expression. The activation of PPAR-γ promotes cell differentiation, reduces the proliferation rate, and modulates the immune response. In the skin, PPARs also contribute to the functioning of the skin barrier. Since we know that the route from identification to the registration of drugs is long and expensive, PPAR-γ agonists already approved for other diseases may also represent a high interest for psoriasis. In this review, we discuss the role of PPAR-γ in the activation, differentiation, and proliferation of skin and immune cells affected by psoriasis and in contributing to the pathogenesis of the disease. We also evaluate whether the agonists of PPAR-γ may become one of the therapeutic options to suppress the inflammatory response in lesional psoriatic skin and decrease the influence of comorbidities associated with psoriasis.
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36
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Farías MA, Diethelm-Varela B, Navarro AJ, Kalergis AM, González PA. Interplay between Lipid Metabolism, Lipid Droplets, and DNA Virus Infections. Cells 2022; 11:2224. [PMID: 35883666 PMCID: PMC9324743 DOI: 10.3390/cells11142224] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/05/2022] [Accepted: 07/09/2022] [Indexed: 12/10/2022] Open
Abstract
Lipid droplets (LDs) are cellular organelles rich in neutral lipids such as triglycerides and cholesterol esters that are coated by a phospholipid monolayer and associated proteins. LDs are known to play important roles in the storage and availability of lipids in the cell and to serve as a source of energy reserve for the cell. However, these structures have also been related to oxidative stress, reticular stress responses, and reduced antigen presentation to T cells. Importantly, LDs are also known to modulate viral infection by participating in virus replication and assembly. Here, we review and discuss the interplay between neutral lipid metabolism and LDs in the replication cycle of different DNA viruses, identifying potentially new molecular targets for the treatment of viral infections.
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Affiliation(s)
- Mónica A. Farías
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Benjamín Diethelm-Varela
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Areli J. Navarro
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
| | - Alexis M. Kalergis
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
- Departamento de Endocrinología, Facultad de Medicina, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile
| | - Pablo A. González
- Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8330025, Chile; (M.A.F.); (B.D.-V.); (A.J.N.); (A.M.K.)
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Heintz MM, Chappell GA, Thompson CM, Haws LC. Evaluation of Transcriptomic Responses in Livers of Mice Exposed to the Short-Chain PFAS Compound HFPO-DA. FRONTIERS IN TOXICOLOGY 2022; 4:937168. [PMID: 35832492 PMCID: PMC9271854 DOI: 10.3389/ftox.2022.937168] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/08/2022] [Indexed: 11/13/2022] Open
Abstract
HFPO-DA (ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate; CASRN 62037-80-3) is a component of the GenX technology platform used as a polymerization aid in the manufacture of some types of fluoropolymers. The liver is the primary target of toxicity for HFPO-DA in rodents and previous examination of hepatic transcriptomic responses in mice following oral exposure to HFPO-DA for 90 days showed induction of peroxisome proliferator-activated receptor signaling pathways, predominantly by PPARα, as well as increased gene expression of both peroxisomal and mitochondrial fatty acid metabolism. To further investigate the mechanism of liver toxicity, transcriptomic analysis was conducted on liver tissue from mice orally exposed to 0, 0.1, 0.5 or 5 mg/kg-bw/day HFPO-DA in a reproduction/developmental toxicity study. Hepatic gene expression changes demonstrated activation of the PPARα signaling pathway. Peroxisomal and mitochondrial fatty acid β-oxidation gene sets were enriched at lower HFPO-DA concentrations, and complement cascade, cell cycle and apoptosis related gene sets were enriched at higher HFPO-DA concentrations. These results support the reported histopathological findings in livers of mice from this study and indicate that the effects of HFPO-DA are mediated through rodent-specific PPARα signaling mechanisms regardless of reproductive status in mice.
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Affiliation(s)
- Melissa M. Heintz
- ToxStrategies, Inc, Asheville, NC, United States
- *Correspondence: Melissa M. Heintz,
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Nguyen HD, Kim MS. The protective effects of curcumin on metabolic syndrome and its components: In-silico analysis for genes, transcription factors, and microRNAs involved. Arch Biochem Biophys 2022; 727:109326. [PMID: 35728632 DOI: 10.1016/j.abb.2022.109326] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/04/2022] [Accepted: 06/16/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND We aimed to identify the molecular mechanisms behind curcumin's therapeutic benefits for metabolic syndrome (MetS) and its components. METHODS The Comparative Toxicogenomics Database, MIENTURNET, Metascape, GeneMania, and Cytoscape software were critical analytic tools. RESULTS Curcumin may have therapeutic effects on MetS and its components via the following genes: NOS3, IL6, INS, and ADIPOQ, particularly PPARG. Curcumin has higher docking scores than other genes with INS and PPARG (docking scores: -8.3 and -5.8, respectively). Physical interactions (56%) were found to be the most prevalent for dyslipidemia, co-expression for hypertension, obesity, T2DM, and MetS. "Galanin receptor pathway", "lipid particles composition", "IL-18 signaling pathway", "response to extracellular stimulus", and "insulin resistance" were listed in the first of the key pathways for MetS, dyslipidemia, hypertension, obesity, and diabetes, respectively. The protein-protein interaction enrichment analysis study also identified "vitamin B12 metabolism," "folate metabolism," and "selenium micronutrient network" as three major molecular pathways linked to MetS targeted by curcumin. PPARG was the key transcription factor that regulated practically all curcumin-targeted genes linked to MetS and its components. Curcumin targeted hsa-miR-155-5p, which has been linked to T2DM, hypertension, and MetS, as well as hsa-miR-130b-3p and hsa-miR-22-3p, which have been linked to dyslipidemia and obesity, respectively. In silico, sponges that regulated hsa-miR-155-5p were developed and evaluated. Curcumin, MetS, and its components have been found to target adipocytes, cardiac myocytes, smooth muscle, the liver, and pancreas. Curcumin's physicochemical properties and pharmacokinetics are closely connected with its therapeutic advantages in MetS and its components due to its high gastrointestinal absorption, drug-likeness, water solubility, and lipophilic nature. Curcumin is a CYP1A9 and CYP3A4 inhibitor. Although curcumin has a low bioavailability, it can be synthesized and administered to increase its pharmacokinetic features. CONCLUSIONS Curcumin needs to undergo therapeutic optimization and further study into its pharmacological structure before it can be used to treat MetS and its components.
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Affiliation(s)
- Hai Duc Nguyen
- Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.
| | - Min-Sun Kim
- Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.
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Inhibition of the 3-mercaptopyruvate sulfurtransferase-hydrogen sulfide system promotes cellular lipid accumulation. GeroScience 2022; 44:2271-2289. [PMID: 35680713 PMCID: PMC9616987 DOI: 10.1007/s11357-022-00600-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 05/31/2022] [Indexed: 12/30/2022] Open
Abstract
H2S is generated in the adipose tissue by cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase (3-MST). H2S plays multiple roles in the regulation of various metabolic processes, including insulin resistance. H2S biosynthesis also occurs in adipocytes. Aging is known to be associated with a decline in H2S. Therefore, the question arises whether endogenous H2S deficiency may affect the process of adipocyte maturation and lipid accumulation. Among the three H2S-generating enzymes, the role of 3-MST is the least understood in adipocytes. Here we tested the effect of the 3-MST inhibitor 2-[(4-hydroxy-6-methylpyrimidin-2-yl)sulfanyl]-1-(naphthalen-1-yl)ethan-1-one (HMPSNE) and the H2S donor (GYY4137) on the differentiation and adipogenesis of the adipocyte-like cells 3T3-L1 in vitro. 3T3-L1 cells were differentiated into mature adipocytes in the presence of GYY4137 or HMPSNE. HMPSNE significantly enhanced lipid accumulation into the maturing adipocytes. On the other hand, suppressed lipid accumulation was observed in cells treated with the H2S donor. 3-MST inhibition increased, while H2S donation suppressed the expression of various H2S-producing enzymes during adipocyte differentiation. 3-MST knockdown also facilitated adipocytic differentiation and lipid uptake. The underlying mechanisms may involve impairment of oxidative phosphorylation and fatty acid oxidation as well as the activation of various differentiation-associated transcription factors. Thus, the 3-MST/H2S system plays a tonic role in suppressing lipid accumulation and limiting the differentiation of adipocytes. Stimulation of 3-MST activity or supplementation of H2S—which has been recently linked to various experimental therapeutic approaches during aging—may be a potential experimental approach to counteract adipogenesis.
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40
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Velleman SG, Coy CS, Abasht B. Effect of expression of PPARG, DNM2L, RRAD, and LINGO1 on broiler chicken breast muscle satellite cell function. Comp Biochem Physiol A Mol Integr Physiol 2022; 268:111186. [PMID: 35278723 DOI: 10.1016/j.cbpa.2022.111186] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/07/2022] [Accepted: 03/07/2022] [Indexed: 12/20/2022]
Abstract
Disorders affecting the breast muscle of modern commercial broiler chickens have increased in recent years. Wooden Breast (WB) myopathy is characterized by a palpably hard breast muscle with increased fat deposition. WB is a metabolic disorder with lipid accumulation considered to be a primary causal factor. The adult myoblasts, satellite cells, are a partially differentiated stem cell population and primarily function in muscle growth and regeneration. The satellite cells also express adipogenic genes. The objective of this study was to determine the expression of the adipogenic genes PPARG, DNM2L, RRAD, and LINGO1 in commercial Ross 708 (708) and Randombred (RBch) satellite cells. RBch satellite cells are from commercial 1995 broilers before WB and 708 broilers are a modern commercial line. In general, expression of these genes was different between the 708 and RBch satellite cells during proliferation and differentiation. Expression of PPARG and RRAD were both significantly increased during both proliferation and differentiation in the 708 cells (P ≤ 0.05). Knocking down the expression of these genes with small interfering RNAs did not greatly affect either proliferation or differentiation. Lipid accumulation was affected by the knockdown of these genes with significant line effects from 48 h of proliferation through 72 h of differentiation. In general, 708 satellite cells had higher lipid levels. Knockdown treatment effect was specific to each gene. The results demonstrate that lipid biosynthesis has been affected in breast muscle satellite cells which may contribute to the increased lipid deposition in modern day commercial broiler chickens.
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Affiliation(s)
- Sandra G Velleman
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, United States of America.
| | - Cynthia S Coy
- Department of Animal Sciences, The Ohio State University, Wooster, OH 44691, United States of America
| | - Behnam Abasht
- University of Delaware, Newark, DE 19716, United States of America
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Ren Q, Xie X, Zhao C, Wen Q, Pan R, Du Y. 2,2',4,4'-Tetrabromodiphenyl Ether (PBDE 47) Selectively Stimulates Proatherogenic PPARγ Signatures in Human THP-1 Macrophages to Contribute to Foam Cell Formation. Chem Res Toxicol 2022; 35:1023-1035. [PMID: 35575305 DOI: 10.1021/acs.chemrestox.2c00043] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
2,2',4,4'-Tetrabromodiphenyl ether (PBDE 47) is one of the most prominent PBDE congeners detected in the human body, suggesting that the potential health risks of PBDE 47 should be thoroughly considered. However, the cardiovascular toxicity of PBDE 47 remains poorly understood. Here, toxic outcomes of PBDE 47 in human THP-1 macrophages concerning foam cell formation, which play crucial roles in the occurrence and development of atherosclerosis, were elucidated. First, our results indicated that PBDE 47 affected the PPARγ pathway most efficiently in THP-1 macrophages by transcriptomic analysis. Second, the PPARγ target genes CD36 and FABP4, responsible for lipid uptake and accumulation in macrophages, were consistently upregulated both at transcriptional and translational levels in THP-1 macrophages upon PBDE 47. Unexpectedly, PBDE 47 failed to activate the PPARγ target gene LXRα and PPARγ-LXRα-ABCA1/G1 cascade, which is activated by the PPARγ full agonist rosiglitazone and enables cholesterol efflux in macrophages. Thus, coincident with the selective upregulation of the PPARγ target genes CD36 and FABP4, PBDE 47, distinct from rosiglitazone, functionally resulted in more lipid accumulation and oxLDL uptake in THP-1 macrophages through high-content analysis (HCA). Moreover, these effects were markedly abrogated by the addition of the PPARγ antagonist T0070907. Mechanistically, the structural basis of selective activation of PPARγ by PBDE 47 was explored by molecular docking and dynamics simulation, which indicated that PBDE 47 interacted with the PPARγ ligand binding domain (PPARγ-LBD) distinctively from that of rosiglitazone. PBDE 47 was revealed to interact with helix 3 and helix 5 but not helix 12 in the PPARγ-LBD. Collectively, these results unraveled the potential cardiovascular toxicity of PBDE 47 by selective activation of PPARγ to facilitate foam cell formation for the first time.
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Affiliation(s)
- Qidong Ren
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.,College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xinni Xie
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Chuanfang Zhao
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
| | - Qing Wen
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.,College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruiying Pan
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.,College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuguo Du
- State Key Laboratory of Environmental Chemistry and Eco-Toxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.,College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100049, China
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Nartey MNN, Jisaka M, Syeda PK, Nishimura K, Shimizu H, Yokota K. Prostaglandin D2 and its analog, 11d-11m-PGD2, added during the differentiation phase contribute to adipogenic program inhibition in 3T3-L1 cells. Biosci Biotechnol Biochem 2022; 86:628-634. [DOI: 10.1093/bbb/zbac035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/04/2022] [Indexed: 12/15/2022]
Abstract
ABSTRACT
We previously reported that prostaglandin (PG)D2 and its isosteric analog, 11-deoxy-11-methylene-PGD2 (11d-11m-PGD2), promote adipogenesis in 3T3-L1 cells during the maturation phase. Focusing on the differentiation phase, although both PGs inhibited adipogenesis, this effect was canceled out by PGI2 and PGJ2 derivatives. Thus, PGD2 and 11d-11m-PGD2 play different roles during the phases, but do not affect PGI2- and PGJ2-derivative-induced adipogenesis.
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Affiliation(s)
- Michael N N Nartey
- The , 4-101 Koyama-Minami, Tottori , Japan
- United Graduate School of Agricultural Sciences, Tottori University , 4-101 Koyama-Minami, Tottori , Japan
- Council for Scientific and Industrial Research-Animal Research Institute , Achimota, Accra , Ghana
| | - Mitsuo Jisaka
- The , 4-101 Koyama-Minami, Tottori , Japan
- United Graduate School of Agricultural Sciences, Tottori University , 4-101 Koyama-Minami, Tottori , Japan
- Department of Life Science and Biotechnology, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Project Center for Fortification of Local Specialty Food Functions, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
| | - Pinky Karim Syeda
- Department of Life Science and Biotechnology, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
| | - Kohji Nishimura
- The , 4-101 Koyama-Minami, Tottori , Japan
- United Graduate School of Agricultural Sciences, Tottori University , 4-101 Koyama-Minami, Tottori , Japan
- Department of Life Science and Biotechnology, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Project Center for Fortification of Local Specialty Food Functions, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Interdisciplinary Center for Science Research, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Raman Project Center for Medical and Biological Applications, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
| | - Hidehisa Shimizu
- The , 4-101 Koyama-Minami, Tottori , Japan
- United Graduate School of Agricultural Sciences, Tottori University , 4-101 Koyama-Minami, Tottori , Japan
- Department of Life Science and Biotechnology, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Project Center for Fortification of Local Specialty Food Functions, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Interdisciplinary Center for Science Research, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Raman Project Center for Medical and Biological Applications, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Estuary Research Center, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
| | - Kazushige Yokota
- The , 4-101 Koyama-Minami, Tottori , Japan
- United Graduate School of Agricultural Sciences, Tottori University , 4-101 Koyama-Minami, Tottori , Japan
- Department of Life Science and Biotechnology, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Project Center for Fortification of Local Specialty Food Functions, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University , 1060 Nishikawatsu-Cho, Matsue, Shimane , Japan
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Lustig RH, Collier D, Kassotis C, Roepke TA, Ji Kim M, Blanc E, Barouki R, Bansal A, Cave MC, Chatterjee S, Choudhury M, Gilbertson M, Lagadic-Gossmann D, Howard S, Lind L, Tomlinson CR, Vondracek J, Heindel JJ. Obesity I: Overview and molecular and biochemical mechanisms. Biochem Pharmacol 2022; 199:115012. [PMID: 35393120 PMCID: PMC9050949 DOI: 10.1016/j.bcp.2022.115012] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 03/12/2022] [Accepted: 03/15/2022] [Indexed: 02/06/2023]
Abstract
Obesity is a chronic, relapsing condition characterized by excess body fat. Its prevalence has increased globally since the 1970s, and the number of obese and overweight people is now greater than those underweight. Obesity is a multifactorial condition, and as such, many components contribute to its development and pathogenesis. This is the first of three companion reviews that consider obesity. This review focuses on the genetics, viruses, insulin resistance, inflammation, gut microbiome, and circadian rhythms that promote obesity, along with hormones, growth factors, and organs and tissues that control its development. It shows that the regulation of energy balance (intake vs. expenditure) relies on the interplay of a variety of hormones from adipose tissue, gastrointestinal tract, pancreas, liver, and brain. It details how integrating central neurotransmitters and peripheral metabolic signals (e.g., leptin, insulin, ghrelin, peptide YY3-36) is essential for controlling energy homeostasis and feeding behavior. It describes the distinct types of adipocytes and how fat cell development is controlled by hormones and growth factors acting via a variety of receptors, including peroxisome proliferator-activated receptor-gamma, retinoid X, insulin, estrogen, androgen, glucocorticoid, thyroid hormone, liver X, constitutive androstane, pregnane X, farnesoid, and aryl hydrocarbon receptors. Finally, it demonstrates that obesity likely has origins in utero. Understanding these biochemical drivers of adiposity and metabolic dysfunction throughout the life cycle lends plausibility and credence to the "obesogen hypothesis" (i.e., the importance of environmental chemicals that disrupt these receptors to promote adiposity or alter metabolism), elucidated more fully in the two companion reviews.
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Affiliation(s)
- Robert H Lustig
- Division of Endocrinology, Department of Pediatrics, University of California, San Francisco, CA 94143, United States
| | - David Collier
- Brody School of Medicine, East Carolina University, Greenville, NC 27834, United States
| | - Christopher Kassotis
- Institute of Environmental Health Sciences and Department of Pharmacology, Wayne State University, Detroit, MI 48202, United States
| | - Troy A Roepke
- School of Environmental and Biological Sciences, Rutgers University, New Brunswick, NJ 08901, United States
| | - Min Ji Kim
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Etienne Blanc
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Robert Barouki
- Department of Biochemistry and Toxicology, University of Paris, INSERM U1224 (T3S), 75006 Paris, France
| | - Amita Bansal
- College of Health & Medicine, Australian National University, Canberra, Australia
| | - Matthew C Cave
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville, Louisville, KY 40402, United States
| | - Saurabh Chatterjee
- Environmental Health and Disease Laboratory, University of South Carolina, Columbia, SC 29208, United States
| | - Mahua Choudhury
- College of Pharmacy, Texas A&M University, College Station, TX 77843, United States
| | - Michael Gilbertson
- Occupational and Environmental Health Research Group, University of Stirling, Stirling, Scotland, United Kingdom
| | - Dominique Lagadic-Gossmann
- Research Institute for Environmental and Occupational Health, University of Rennes, INSERM, EHESP, Rennes, France
| | - Sarah Howard
- Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, United States
| | - Lars Lind
- Department of Medical Sciences, University of Uppsala, Uppsala, Sweden
| | - Craig R Tomlinson
- Norris Cotton Cancer Center, Department of Molecular and Systems Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, United States
| | - Jan Vondracek
- Department of Cytokinetics, Institute of Biophysics of the Czech Academy of Sciences, Brno, Czech Republic
| | - Jerrold J Heindel
- Healthy Environment and Endocrine Disruptor Strategies, Commonweal, Bolinas, CA 92924, United States.
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Lei Z, Wei D, Ma Y, Tang L, Wang S, Wang P, Pan C, Hu C, Wang X, Ma Y. miR-302b promotes bovine preadipocyte differentiation and inhibits proliferation by targeting CDK2. Anim Biotechnol 2022:1-8. [PMID: 35254208 DOI: 10.1080/10495398.2022.2029743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
MicroRNAs have been recently reported to act as key regulators of adipogenesis, a multifactorial complex process. One miRNA, miR-302b, is an important regulator of cell proliferation and differentiation and controls cancer development, but we speculate that miR-302b may also regulate bovine adipogenesis. Herein we have evaluated the role of this miRNA in bovine adipocyte differentiation using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR), Oil Red O staining, a dual-luciferase reporter. CDK2 was identified as the target gene of miR-302b, and miR-302b agomir promoted mRNA and protein expression levels of adipocyte-specific genes. In addition, a CCK-8 kit was used to show that miR-302b agomir, but not the negative control, inhibits preadipocyte proliferation. In conclusion, miR-302b promotes bovine preadipocyte differentiation and inhibits proliferation by targeting CDK2.
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Affiliation(s)
- Zhaoxiong Lei
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Dawei Wei
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Yanfen Ma
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Lin Tang
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Shuzhe Wang
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Pengfei Wang
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Cuili Pan
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Chunli Hu
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Xingping Wang
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China
| | - Yun Ma
- Key Laboratory of Ruminant Molecular Cell Breeding, School of Agriculture, Ningxia University, Yinchuan, China.,College of Life Science, Xinyang Normal University, Xinyang, China
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Kan S, Li R, Tan Y, Yang F, Xu S, Wang L, Zhang L, Sun X, Chen X, Yang Y, Shu W, Wan H, Chen ZF, Liang H, Chen M. Latexin deficiency attenuates adipocyte differentiation and protects mice against obesity and metabolic disorders induced by high-fat diet. Cell Death Dis 2022; 13:175. [PMID: 35210404 PMCID: PMC8873487 DOI: 10.1038/s41419-022-04636-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Revised: 01/14/2022] [Accepted: 02/10/2022] [Indexed: 12/12/2022]
Abstract
AbstractObesity is a risk factor for many chronic diseases, and is associated with increased incidence rate of type 2 diabetes, hypertension, dyslipidemia and cardiovascular diseases. Adipocyte differentiation play critical role during development of obesity. Latexin (LXN), a mammalian carboxypeptidase inhibitor, plays important role in the proliferation and differentiation of stem cells, and highlights as a differentiation-associated gene that was significantly downregulated in prostate stem cells and whose expression increases through differentiation. However, it is unclear whether LXN is involved in adipocyte differentiation. The aim of this study was to evaluate the role of LXN on adipocyte differentiation, as well as its effects on high fat-induced obesity and metabolic disorders. In this study, we determine the expression of LXN in adipose tissue of lean and fat mice by Western blot, qPCR and immunohistochemistry. We found that LXN in fat tissues was continuous increased during the development of diet-induced obesity. We fed wild-type (WT) and LXN−/−mice with high-fat diet (HFD) to study the effects of LXN on obesity and related metabolic functions. We found that mice deficient in LXN showed resistance against high-fat diet (HFD)-induced obesity, glucose tolerance, insulin tolerance and hepatic steatosis. In vitro studies indicated that LXN was highly induced during adipocyte differentiation, and positively regulated adipocyte differentiation and adipogenesis in 3T3-L1 cells and primary preadipocytes. Functional analysis revealed that the expression of LXN was positively regulated by mTOR/RXR/PPARɤ signaling pathway during the differentiation of adipocytes, while LXN deletion decreased the protein level of PPARɤ in adipocyte through enhancing FABP4 mediated ubiquitination, which led to impaired adipocyte differentiation and lipogenesis. Collectively, our data provide evidence that LXN is a key positive regulator of adipocyte differentiation, and therapeutics targeting LXN could be effective in preventing obesity and its associated disorders in clinical settings.
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Chae HS, Dale O, Mir TM, Avula B, Zhao J, Khan IA, Khan SI. A Multitarget Approach to Evaluate the Efficacy of Aquilaria sinensis Flower Extract against Metabolic Syndrome. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27030629. [PMID: 35163893 PMCID: PMC8838142 DOI: 10.3390/molecules27030629] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/07/2022] [Accepted: 01/15/2022] [Indexed: 11/16/2022]
Abstract
Aquilaria sinensis (Lour.) Spreng is known for its resinous secretion (agarwood), often secreted in defense against injuries. We investigated the effects of A. sinensis flower extract (AF) on peroxisome proliferator-activated receptors alpha and gamma (PPARα and PPARγ), liver X receptor (LXR), glucose uptake, and lipid accumulation (adipogenesis). Activation of PPARα, PPARγ and LXR was determined in hepatic (HepG2) cells by reporter gene assays. Glucose uptake was determined in differentiated muscle (C2C12) cells using 2-NBDG (2-deoxy-2-[(7-nitro-2,1,3-benzoxadiazol-4-yl)amino]-D-glucose). Adipogenesis was determined in adipocytes (3T3-L1 cells) by Oil red O staining. At a concentration of 50 µg/mL, AF caused 12.2-fold activation of PPARα and 5.7-fold activation of PPARγ, while the activation of LXR was only 1.7-fold. AF inhibited (28%) the adipogenic effect induced by rosiglitazone in adipocytes and increased glucose uptake (32.8%) in muscle cells at 50 μg/mL. It was concluded that AF acted as a PPARα/γ dual agonist without the undesired effect of adipogenesis and exhibited the property of enhancing glucose uptake. This is the first report to reveal the PPARα/γ dual agonistic action and glucose uptake enhancing property of AF along with its antiadipogenic effect, indicating its potential in ameliorating the symptoms of metabolic syndrome.
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Affiliation(s)
- Hee-Sung Chae
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
| | - Olivia Dale
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
| | - Tahir Maqbool Mir
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
| | - Bharathi Avula
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
| | - Jianping Zhao
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
| | - Ikhlas A. Khan
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
- Department of Biomolecular Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA
| | - Shabana I. Khan
- National Center for Natural Products Research, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA; (H.-S.C.); (O.D.); (T.M.M.); (B.A.); (J.Z.); (I.A.K.)
- Department of Biomolecular Sciences, School of Pharmacy, The University of Mississippi, Oxford, MS 38677, USA
- Correspondence: ; Tel.: +1-662-915-1041
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Modaresi SMS, Wei W, Emily M, DaSilva NA, Slitt AL. Per- and polyfluoroalkyl substances (PFAS) augment adipogenesis and shift the proteome in murine 3T3-L1 adipocytes. Toxicology 2022; 465:153044. [PMID: 34800597 PMCID: PMC8756374 DOI: 10.1016/j.tox.2021.153044] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 10/27/2021] [Accepted: 11/16/2021] [Indexed: 01/17/2023]
Abstract
The Per- and polyfluoroalkyl substances (PFAS) are a wide group of fluorinated compounds, which the health effects of many of them have not been investigated. Perfluorinated sulfonates, such as perfluorooctane sulfonate (PFOS) and perfluorinated carboxylates, such as perfluorooctanoic acid (PFOA) are members of this broad group of PFAS, and previous studies have shown a correlation between the body accumulation of PFOS and PFOA and increased adipogenesis. PFOA and PFOS have been withdrawn from the market and use is limited because of their persistence, toxicity, and bioaccumulative properties. Instead, short chain PFAS have been created to replace PFOA and PFOS, but the health effects of other short chain PFAS are largely unknown. Therefore, herein we aimed to comprehensively determined the potential adipogenesis of ten different PFAS (PFBS, PFHxS, PFOS, PFBA, PFHxA, PFHA, PFOA, PFNA, PFDA, and HFPO-DA) and investigated the differences in protein expression of 3T3-L1 cells upon exposure to each PFAS. 3T3-L1 cells were differentiated with or without each PFAS for 4-days, and cellular lipid was quantified using Nile Red staining. Analysis of the adipocyte proteome was performed to identify the pathways related to adipogenesis and quantify proteins significantly affected by each PFAS. The results showed that in general, every PFAS investigated in our study has the potential to induce the 3T3-L1 differentiation to adipocytes in the presence of rosiglitazone, with the concentrations that range between 0.25 and 25 μM. Proteomics analysis revealed specific markers regarding to adipogenesis upregulated upon exposure to each of the ten PFAS.
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Affiliation(s)
| | - Wei Wei
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA
| | - Marques Emily
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA
| | - Nicholas A DaSilva
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA
| | - Angela L Slitt
- Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI, 02881, USA.
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The Impact of Intermittent Hypobaric Hypoxia Exposures on Triacylglycerol Synthesis in Rat Liver. Rep Biochem Mol Biol 2022; 10:437-444. [PMID: 34981021 DOI: 10.52547/rbmb.10.3.437] [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: 04/19/2021] [Accepted: 05/23/2021] [Indexed: 11/18/2022]
Abstract
Background In a hypoxic state, fatty acid breakdown reaction may be inhibited due to a lack of oxygen. It is likely that the fatty acids will be stored as triacylglycerol. The aim of this study was to analyse triacylglycerol synthesis in the liver after intermittent hypobaric hypoxia (HH) exposures. Methods Samples are liver tissues from 25 male Wistar rats were divided into 5 groups: control group (normoxia), group I (once HH exposure), group II (twice HH exposures), group III (three-times HH exposures) and group IV (four-times HH exposures). The triacylglycerol level, mRNA expression of HIF-1α and PPAR-γ were measured in rat liver from each group. Results We demonstrated that triacylglycerol level, mRNA expression of HIF-1α and PPAR-γ is elevated in group I significantly compared to control group. In the intermittent HH groups (group II, III and IV), mRNA expression of HIF-1α and PPAR-γ tends to downregulate near to control group. However, the triacylglycerol level is still found increased in the intermittent HH exposures groups. Significant increasing of triacylglycerol level was found especially in group IV compared to control group. Conclusion We conclude that intermittent HH exposures will increase the triacylglycerol level in rat liver, supported by the increasing of HIF-1α and PPAR-γ mRNA expression that act as transcription factor to promote triacylglycerol synthesis.
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Zhang J, Yu H, Zhong H, Wang Q, Tang J, Shen F, Cai H, Liu T, Feng F, Zhao M. Dietary emulsifier glycerol monodecanoate affects gut microbiota contributing to regulating lipid metabolism, insulin sensitivity and inflammation. Food Funct 2022; 13:8804-8817. [DOI: 10.1039/d2fo01689c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Glycerol monodecanoate (GMD) is a medium-chain monoacylglycerol that possesses emulsifying and antibacterial properties. Common emulsifiers carboxymethylcellulose and polysorbate-80 have been reported to cause intestinal microbiota dysbiosis and metabolic disturbances. While...
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Nuclear Receptors in Energy Metabolism. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1390:61-82. [DOI: 10.1007/978-3-031-11836-4_4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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