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Den Hartogh DJ, MacPherson REK, Tsiani E. Muscle cell palmitate-induced insulin resistance, JNK, IKK/NF-κB, and STAT3 activation are attenuated by carnosic and rosmarinic acid. Appl Physiol Nutr Metab 2025; 50:1-14. [PMID: 39805098 DOI: 10.1139/apnm-2024-0302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
The worldwide epidemic of obesity has drastically worsened with the increase in more sedentary lifestyles and increased consumption of fatty foods. Increased blood free fatty acids, often observed in obesity, lead to impaired insulin action, and promote the development of insulin resistance and type 2 diabetes mellitus. c-Jun N-terminal kinase (JNK), inhibitor of kappa B (IκB) kinase (IKK)-nuclear factor-kappa B (NF-κB), and signal transducer and activator of transcription 3 (STAT3) are known to be involved in skeletal muscle insulin resistance. We reported previously that carnosic acid (CA) and rosmarinic acid (RA) attenuated the palmitate-induced skeletal muscle insulin resistance, an effect that was associated with increased AMPK activation and reduced mammalian target of rapamycin-p70S6K signaling. In the present study, we examined the effects of CA and RA on JNK, IKK-NF-κB, and STAT3. Exposure of cells to palmitate increased the phosphorylation/activation of JNK, IKKα/β, IκBα, NF-κBp65, and STAT3. Importantly, CA and RA attenuated the deleterious effects of palmitate. Our data indicate that CA and RA have the potential to counteract the palmitate-induced skeletal muscle cell insulin resistance by modulating JNK, IKK-NF-κB, and STAT3 signaling.
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Affiliation(s)
- Danja J Den Hartogh
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
| | - Rebecca E K MacPherson
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Neuroscience, Brock University, St. Catharines, ON L2S3A1, Canada
| | - Evangelia Tsiani
- Department of Health Sciences, Brock University, St. Catharines, ON L2S 3A1, Canada
- Centre for Bone and Muscle Health, Brock University, St. Catharines, ON L2S 3A1, Canada
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2
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Yuzbashian E, Berg E, de Campos Zani SC, Chan CB. Cow's Milk Bioactive Molecules in the Regulation of Glucose Homeostasis in Human and Animal Studies. Foods 2024; 13:2837. [PMID: 39272602 PMCID: PMC11395457 DOI: 10.3390/foods13172837] [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: 07/03/2024] [Revised: 08/26/2024] [Accepted: 08/31/2024] [Indexed: 09/15/2024] Open
Abstract
Obesity disrupts glucose metabolism, leading to insulin resistance (IR) and cardiometabolic diseases. Consumption of cow's milk and other dairy products may influence glucose metabolism. Within the complex matrix of cow's milk, various carbohydrates, lipids, and peptides act as bioactive molecules to alter human metabolism. Here, we summarize data from human studies and rodent experiments illustrating how these bioactive molecules regulate insulin and glucose homeostasis, supplemented with in vitro studies of the mechanisms behind their effects. Bioactive carbohydrates, including lactose, galactose, and oligosaccharides, generally reduce hyperglycemia, possibly by preventing gut microbiota dysbiosis. Milk-derived lipids of the milk fat globular membrane improve activation of insulin signaling pathways in animal trials but seem to have little impact on glycemia in human studies. However, other lipids produced by ruminants, including polar lipids, odd-chain, trans-, and branched-chain fatty acids, produce neutral or contradictory effects on glucose metabolism. Bioactive peptides derived from whey and casein may exert their effects both directly through their insulinotropic effects or renin-angiotensin-aldosterone system inhibition and indirectly by the regulation of incretin hormones. Overall, the results bolster many observational studies in humans and suggest that cow's milk intake reduces the risk of, and can perhaps be used in treating, metabolic disorders. However, the mechanisms of action for most bioactive compounds in milk are still largely undiscovered.
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Affiliation(s)
- Emad Yuzbashian
- Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
| | - Emily Berg
- Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | | | - Catherine B Chan
- Department of Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, AB T6G 2P5, Canada
- Department of Physiology, University of Alberta, Edmonton, AB T6G 2H7, Canada
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3
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Gan J, Shi Y, Zhao R, Li D, Jin H, Wu M, Liu Z, Li X, Xu A, Li Y, Lin Z, Wu F. Adipose c-Jun NH2-terminal kinase promotes angiotensin II-induced and deoxycorticosterone acetate salt-induced hypertension and vascular dysfunction by inhibition of adiponectin production and activation of SGK1 in mice. J Hypertens 2024; 42:856-872. [PMID: 38164960 DOI: 10.1097/hjh.0000000000003649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2024]
Abstract
BACKGROUND Adipose c-Jun NH2-terminal kinase 1/2 (JNK1/2) is a central mediator involved in the development of obesity and its complications. However, the roles of adipose JNK1/2 in hypertension remain elusive. Here we explored the role of adipose JNK1/2 in hypertension. METHODS AND RESULTS The roles of adipose JNK1/2 in hypertension were investigated by evaluating the impact of adipose JNK1/2 inactivation in both angiotensin II (Ang II)-induced and deoxycorticosterone acetate (DOCA) salt-induced hypertensive mice. Specific inactivation of JNK1/2 in adipocytes significantly alleviates Ang II-induced and DOCA salt-induced hypertension and target organ damage in mice. Interestingly, such beneficial effects are also observed in hypertensive mice after oral administration of JNK1/2 inhibitor SP600125. Mechanistically, adipose JNK1/2 acts on adipocytes to reduce the production of adiponectin (APN), then leads to promote serum and glucocorticoid-regulated kinase 1 (SGK1) phosphorylation and increases epithelial Na + channel α-subunit (ENaCα) expression in both renal cells and adipocytes, respectively, finally exacerbates Na + retention. In addition, chronic treatment of recombinant mouse APN significantly augments the beneficial effects of adipose JNK1/2 inactivation in DOCA salt-induced hypertension. By contrast, the blood pressure-lowering effects of adipose JNK1/2 inactivation are abrogated by adenovirus-mediated SGK1 overexpression in Ang II -treated adipose JNK1/2 inactivation mice. CONCLUSION Adipose JNK1/2 promotes hypertension and targets organ impairment via fine-tuning the multiorgan crosstalk among adipose tissue, kidney, and blood vessels.
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Affiliation(s)
- Jing Gan
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University
| | - Yaru Shi
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
- Department of Pharmacy, the Sixth Affiliated Hospital of Wenzhou Medical University, Lishui
| | - Ruyi Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Dan Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
- Department of clinical pharmacy, the Forth People's Hospital of Liaocheng, Liaocheng
| | - Hua Jin
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Maolan Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Zhen Liu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Xiaokun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
| | - Aimin Xu
- State Key Laboratory of Pharmaceutical Biotechnology, the University of Hong Kong, Hong Kong
| | - Yulin Li
- Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Anzhen Hospital of Capital Medical University, Beijing
| | - Zhuofeng Lin
- Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University
- The laboratory of Animal Center, Wenzhou Medical University, Wenzhou, China
| | - Fan Wu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou
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4
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Han B, Luo J, Xu B. Revealing Molecular Mechanisms of the Bioactive Saponins from Edible Root of Platycodon grandiflorum in Combating Obesity. PLANTS (BASEL, SWITZERLAND) 2024; 13:1123. [PMID: 38674532 PMCID: PMC11053671 DOI: 10.3390/plants13081123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 04/12/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024]
Abstract
Obesity has emerged as a significant health concern, as it is a disease linked to metabolic disorders in the body and is characterized by the excessive accumulation of lipids. As a plant-derived food, Platycodon grandiflorum (PG) was reported by many studies, indicating that the saponins from PG can improve obesity effectively. However, the anti-obesity saponins from PG and its anti-obesity mechanisms have not been fully identified. This study identified the active saponins and their molecular targets for treating obesity. The TCMSP database was used to obtain information on 18 saponins in PG. The anti-obesity target of the PG saponins was 115 targets and 44 core targets. GO and KEGG analyses using 44 core anti-obesity genes and targets of PG-active saponins screened from GeneCards, OMIM, Drugbank, and DisGeNet showed that the PI3K-Akt pathway, the JAK-STAT pathway, and the MAPK pathway were the major pathways involved in the anti-obesity effects of PG saponins. BIOVIA Discovery Studio Visualizer and AutoDock Vina were used to perform molecular docking and process the molecular docking results. The molecular docking results showed that the active saponins of PG could bind to the major therapeutic obesity targets to play an obesity-inhibitory role. The results of this study laid the foundation for further research on the anti-obesity saponins in PG and their anti-obesity mechanism and provided a new direction for the development of functional plant-derived food. This research studied the molecular mechanism of PG saponins combating obesity through various signaling pathways, and prosapogenin D can be used to develop as a new potential anti-obesity drug.
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Affiliation(s)
| | | | - Baojun Xu
- Guangdong Provincial Key Laboratory IRADS and Department of Life Sciences, BNU-HKBU United International College, Zhuhai 519087, China; (B.H.); (J.L.)
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5
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Cao R, Tian H, Zhang Y, Liu G, Xu H, Rao G, Tian Y, Fu X. Signaling pathways and intervention for therapy of type 2 diabetes mellitus. MedComm (Beijing) 2023; 4:e283. [PMID: 37303813 PMCID: PMC10248034 DOI: 10.1002/mco2.283] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 06/13/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID-19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.
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Affiliation(s)
- Rong Cao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Huimin Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yu Zhang
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Geng Liu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Haixia Xu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Guocheng Rao
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
| | - Yan Tian
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
| | - Xianghui Fu
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengduSichuanChina
- Department of Endocrinology and MetabolismState Key Laboratory of Biotherapy and Cancer CenterWest China Medical School, West China HospitalSichuan UniversityChengduSichuanChina
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Yao Y, Luo ZP, Li HW, Wang SX, Wu YC, Hu Y, Hu S, Yang CC, Yang JF, Wang JP, Peng L, Chen F, Pan LX, Xu T. P38γ modulates the lipid metabolism in non-alcoholic fatty liver disease by regulating the JAK-STAT signaling pathway. FASEB J 2023; 37:e22716. [PMID: 36527390 DOI: 10.1096/fj.202200939rr] [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: 06/18/2022] [Revised: 11/08/2022] [Accepted: 12/05/2022] [Indexed: 12/23/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem in Western countries and has become the most common cause of chronic liver disease. Although NAFLD is closely associated with obesity, inflammation, and insulin resistance, its pathogenesis remains unclear. The disease begins with excessive accumulation of triglycerides in the liver, which in turn leads to liver cell damage, steatosis, inflammation, and so on. P38γ is one of the four isoforms of P38 mitogen-activated protein kinases (P38 MAPKs) that contributes to inflammation in different diseases. In this research, we investigated the role of P38γ in NAFLD. In vivo, a NAFLD model was established by feeding C57BL/6J mice with a methionine- and choline-deficient (MCD) diet and adeno-associated virus (AAV9-shRNA-P38γ) was injected into C57BL/6J mice by tail vein for knockdown P38γ. The results indicated that the expression level of P38γ was upregulated in MCD-fed mice. Furthermore, the downregulation of P38γ significantly attenuated liver injury and lipid accumulation in mice. In vitro, mouse hepatocytes AML-12 were treated with free fatty acid (FFA). We found that P38γ was obviously increased in FFA-treated AML-12 cells, whereas knockdown of P38γ significantly suppressed lipid accumulation in FFA-treated AML-12 cells. Furthermore, P38γ regulated the Janus Kinase-Signal transducers and activators of transcription (JAK-STAT) signaling pathway. Inhibition of P38γ can inhibit the JAK-STAT signaling pathway, thereby inhibiting lipid accumulation in FFA-treated AML-12 cells. In conclusion, our results suggest that targeting P38γ contributes to the suppression of lipid accumulation in fatty liver disease.
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Affiliation(s)
- Yan Yao
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Zhi-Pan Luo
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hai-Wen Li
- Department of Gastroenterology, The Third Affiliated Hospital of Anhui Medical University, Hefei, China.,Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shu-Xian Wang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Yin-Cui Wu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Shuang Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Chen-Chen Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jun-Fa Yang
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Jian-Peng Wang
- First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Li Peng
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Fei Chen
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
| | - Lin-Xin Pan
- School of Life Sciences, Anhui Medical University, Hefei, China
| | - Tao Xu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China.,Institute for Liver Diseases of Anhui Medical University, Hefei, China
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Metabolic Impact of MKP-2 Upregulation in Obesity Promotes Insulin Resistance and Fatty Liver Disease. Nutrients 2022; 14:nu14122475. [PMID: 35745205 PMCID: PMC9228271 DOI: 10.3390/nu14122475] [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: 04/13/2022] [Revised: 06/08/2022] [Accepted: 06/13/2022] [Indexed: 11/23/2022] Open
Abstract
The mechanisms connecting obesity with type 2 diabetes, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular diseases remain incompletely understood. The function of MAPK phosphatase-2 (MKP-2), a type 1 dual-specific phosphatase (DUSP) in whole-body metabolism, and how this contributes to the development of diet-induced obesity, type 2 diabetes (T2D), and insulin resistance is largely unknown. We investigated the physiological contribution of MKP-2 in whole-body metabolism and whether MKP-2 is altered in obesity and human fatty liver disease using MKP-2 knockout mice models and human liver tissue derived from fatty liver disease patients. We demonstrate that, for the first time, MKP-2 expression was upregulated in liver tissue in humans with obesity and fatty liver disease and in insulin-responsive tissues in mice with obesity. MKP-2-deficient mice have enhanced p38 MAPK, JNK, and ERK activities in insulin-responsive tissues compared with wild-type mice. MKP-2 deficiency in mice protects against diet-induced obesity and hepatic steatosis and was accompanied by improved glucose homeostasis and insulin sensitivity. Mkp-2−/− mice are resistant to diet-induced obesity owing to reduced food intake and associated lower respiratory exchange ratio. This was associated with enhanced circulating insulin-like growth factor-1 (IGF-1) and stromal cell-derived factor 1 (SDF-1) levels in Mkp-2−/− mice. PTEN, a negative regulator of Akt, was downregulated in livers of Mkp-2−/− mice, resulting in enhanced Akt activity consistent with increased insulin sensitivity. These studies identify a novel role for MKP-2 in the regulation of systemic metabolism and pathophysiology of obesity-induced insulin resistance and fatty liver disease.
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Busquets O, Espinosa-Jiménez T, Ettcheto M, Olloquequi J, Bulló M, Carro E, Cantero JL, Casadesús G, Folch J, Verdaguer E, Auladell C, Camins A. JNK1 and JNK3: divergent functions in hippocampal metabolic-cognitive function. Mol Med 2022; 28:48. [PMID: 35508978 PMCID: PMC9066854 DOI: 10.1186/s10020-022-00471-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2021] [Accepted: 04/08/2022] [Indexed: 11/21/2022] Open
Abstract
Background and aim The appearance of alterations in normal metabolic activity has been increasingly considered a risk factor for the development of sporadic and late-onset neurodegenerative diseases. In this report, we induced chronic metabolic stress by feeding of a high-fat diet (HFD) in order to study its consequences in cognition. We also studied the effects of a loss of function of isoforms 1 and 3 of the c-Jun N-terminal Kinases (JNK), stress and cell death response elements. Methods Animals were fed either with conventional chow or with HFD, from their weaning until their sacrifice at 9 months. Before sacrifice, body weight, intraperitoneal glucose and insulin tolerance test (IP-GTT and IP‑ITT) were performed to evaluate peripheral biometrics. Additionally, cognitive behavioral tests and analysis of spine density were performed to assess cognitive function. Molecular studies were carried out to confirm the effects of metabolic stressors in the hippocampus relative to cognitive loss. Results Our studies demonstrated that HFD in Jnk3−/− lead to synergetic responses. Loss of function of JNK3 led to increased body weight, especially when exposed to an HFD and they had significantly decreased response to insulin. These mice also showed increased stress in the endoplasmic reticulum and diminished cognitive capacity. However, loss of function of JNK1 promoted normal or heightened energetic metabolism and preserved cognitive function even when chronically metabolically stressed. Conclusions Downregulation of JNK3 does not seem to be a suitable target for the modulation of energetic-cognitive dysregulations while loss of function of JNK1 seems to promote a good metabolic-cognitive profile, just like resistance to the negative effects of chronic feeding with HFD. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-022-00471-y.
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Affiliation(s)
- Oriol Busquets
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Dominick P. Purpura Department of Neurosciences, Albert Einstein College of Medicine, New York City, 10461, USA
| | - Triana Espinosa-Jiménez
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain
| | - Miren Ettcheto
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain.,Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain
| | - Jordi Olloquequi
- Laboratory of Cellular and Molecular Pathology, Facultad de Ciencias de La Salud, Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Talca, Chile
| | - Mònica Bulló
- Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Institut d'Investigació Sanitària Pere Virgili (IISPV), Hospital Universitari de Sant Joan de Reus, 43204, Reus, Spain.,CIBER de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Eva Carro
- Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Madrid, Spain.,Group of Neurodegenerative Diseases, Hospital Universitario 12 de Octubre Research Institute (imas12), Madrid, Spain
| | - José Luis Cantero
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Laboratory of Functional Neuroscience, Pablo de Olavide University, 41013, Seville, Spain
| | - Gemma Casadesús
- Department of Pharmacology & Therapeutics, College of Medicine, University of Florida, Gainesville, FL, 32610, USA
| | - Jaume Folch
- Department of Biochemistry and Biotechnology, Medicine and Health Sciences Faculty, University Rovira i Virgili, 43201, Reus, Spain.,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ester Verdaguer
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Biology Faculty, University of Barcelona, 08028, Barcelona, Spain
| | - Carme Auladell
- Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain.,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.,Department of Cell Biology, Physiology and Immunology, Biology Faculty, University of Barcelona, 08028, Barcelona, Spain
| | - Antoni Camins
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Pharmacy and Food Sciences Faculty, University of Barcelona, 08028, Barcelona, Spain. .,Centre for Biomedical Research of Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, 28029, Madrid, Spain. .,Institut de Neurociències, University of Barcelona, 08035, Barcelona, Spain.
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9
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Abstract
The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.
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10
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Liu D, Wu L, Gao Q, Long X, Hou X, Qian L, Ni J, Fang Q, Li H, Jia W. FGF21/adiponectin ratio predicts deterioration in glycemia: a 4.6-year prospective study in China. Cardiovasc Diabetol 2021; 20:157. [PMID: 34321008 PMCID: PMC8320224 DOI: 10.1186/s12933-021-01351-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 07/21/2021] [Indexed: 12/29/2022] Open
Abstract
Background The fibroblast growth factor (FGF) 21-adiponectin pathway is involved in the regulation of insulin resistance. However, the relationship between the FGF21-adiponectin pathway and type 2 diabetes in humans is unclear. Here, we investigated the association of FGF21/adiponectin ratio with deterioration in glycemia in a prospective cohort study. Methods We studied 6361 subjects recruited from the prospective Shanghai Nicheng Cohort Study in China. The association between baseline FGF21/adiponectin ratio and new-onset diabetes and incident prediabetes was evaluated using multiple logistic regression analysis. Results At baseline, FGF21/adiponectin ratio levels increased progressively with the deterioration in glycemic control from normal glucose tolerance to prediabetes and diabetes (p for trend < 0.001). Over a median follow-up of 4.6 years, 195 subjects developed new-onset diabetes and 351 subjects developed incident prediabetes. Elevated baseline FGF21/adiponectin ratio was a significant predictor of new-onset diabetes independent of traditional risk factors, especially in subjects with prediabetes (odds ratio, 1.367; p = 0.001). Moreover, FGF21/adiponectin ratio predicted incident prediabetes (odds ratio, 1.185; p = 0.021) while neither FGF21 nor adiponectin were independent predictors of incident prediabetes (both p > 0.05). Furthermore, net reclassification improvement and integrated discrimination improvement analyses showed that FGF21/adiponectin ratio provided a better performance in diabetes risk prediction than the use of FGF21 or adiponectin alone. Conclusions FGF21/adiponectin ratio independently predicted the onset of prediabetes and diabetes, with the potential to be a useful biomarker of deterioration in glycemia. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-021-01351-1.
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Affiliation(s)
- Dan Liu
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.,Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liang Wu
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Qiongmei Gao
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Xiaoxue Long
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.,Department of Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuhong Hou
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Lingling Qian
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Jiacheng Ni
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Qichen Fang
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Huating Li
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
| | - Weiping Jia
- Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
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11
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Garg R, Kumariya S, Katekar R, Verma S, Goand UK, Gayen JR. JNK signaling pathway in metabolic disorders: An emerging therapeutic target. Eur J Pharmacol 2021; 901:174079. [PMID: 33812885 DOI: 10.1016/j.ejphar.2021.174079] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/18/2021] [Accepted: 03/25/2021] [Indexed: 02/08/2023]
Abstract
Metabolic Syndrome is a multifactorial disease associated with increased risk of cardiovascular disorders, type 2 diabetes mellitus, fatty liver disease, etc. Various stress stimuli such as reactive oxygen species, endoplasmic reticulum stress, mitochondrial dysfunction, increased cytokines, or free fatty acids are known to aggravate progressive development of hyperglycemia and hyperlipidemia. Although the exact mechanism contributing to altered metabolism is unclear. Evidence suggests stress kinase role to be a crucial one in metabolic syndrome. Stress kinase, c-jun N-terminal kinase activation (JNK) is involved in various metabolic manifestations including obesity, insulin resistance, fatty liver disease as well as cardiometabolic disorders. It emerged as a foremost mediator in regulating metabolism in the liver, skeletal muscle, adipose tissue as well as pancreatic β cells. It has three isoforms each having a unique and tissue-specific role in altered metabolism. Current findings based on genetic manipulation or chemical inhibition studies identified JNK isoforms to play a central role in the regulation of whole-body metabolism, suggesting it to be a novel therapeutic target. Hence, it is imperative to elucidate its role in metabolic syndrome onset and progression. The purpose of this review is to elucidate in vitro and in vivo implications of JNK signaling along with the therapeutic strategy to inhibit specific isoform. Since metabolic syndrome is an array of diseases and complex pathway, carefully examining each tissue will be important for specific treatment strategies.
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Affiliation(s)
- Richa Garg
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Sanjana Kumariya
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India
| | - Roshan Katekar
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Saurabh Verma
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Umesh K Goand
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Jiaur R Gayen
- Pharmaceutics & Pharmacokinetics, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Pharmacology Division, CSIR-Central Drug Research Institute, Jankipuram Extension, Lucknow, 226031, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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12
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Jorquera G, Russell J, Monsalves-Álvarez M, Cruz G, Valladares-Ide D, Basualto-Alarcón C, Barrientos G, Estrada M, Llanos P. NLRP3 Inflammasome: Potential Role in Obesity Related Low-Grade Inflammation and Insulin Resistance in Skeletal Muscle. Int J Mol Sci 2021; 22:ijms22063254. [PMID: 33806797 PMCID: PMC8005007 DOI: 10.3390/ijms22063254] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 03/07/2021] [Accepted: 03/10/2021] [Indexed: 02/07/2023] Open
Abstract
Among multiple mechanisms, low-grade inflammation is critical for the development of insulin resistance as a feature of type 2 diabetes. The nucleotide-binding oligomerization domain-like receptor family (NOD-like) pyrin domain containing 3 (NLRP3) inflammasome has been linked to the development of insulin resistance in various tissues; however, its role in the development of insulin resistance in the skeletal muscle has not been explored in depth. Currently, there is limited evidence that supports the pathological role of NLRP3 inflammasome activation in glucose handling in the skeletal muscle of obese individuals. Here, we have centered our focus on insulin signaling in skeletal muscle, which is the main site of postprandial glucose disposal in humans. We discuss the current evidence showing that the NLRP3 inflammasome disturbs glucose homeostasis. We also review how NLRP3-associated interleukin and its gasdermin D-mediated efflux could affect insulin-dependent intracellular pathways. Finally, we address pharmacological NLRP3 inhibitors that may have a therapeutical use in obesity-related metabolic alterations.
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Affiliation(s)
- Gonzalo Jorquera
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile; (G.J.); (G.C.)
| | - Javier Russell
- Escuela de Pedagogía en Educación Física, Facultad de Educación, Universidad Autónoma de Chile, Santiago 8900000, Chile;
| | - Matías Monsalves-Álvarez
- Instituto de Ciencias de la Salud, Universidad de O’Higgins, Rancagua 2820000, Chile; (M.M.-Á.); (D.V.-I.)
| | - Gonzalo Cruz
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile; (G.J.); (G.C.)
| | - Denisse Valladares-Ide
- Instituto de Ciencias de la Salud, Universidad de O’Higgins, Rancagua 2820000, Chile; (M.M.-Á.); (D.V.-I.)
| | - Carla Basualto-Alarcón
- Departamento de Ciencias de la Salud, Universidad de Aysén, Coyhaique 5951537, Chile;
- Departamento de Anatomía y Medicina Legal, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Genaro Barrientos
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (G.B.); (M.E.)
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
| | - Manuel Estrada
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (G.B.); (M.E.)
| | - Paola Llanos
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
- Facultad de Odontología, Instituto de Investigación en Ciencias Odontológicas, Universidad de Chile, Santiago 8380544, Chile
- Correspondence: ; Tel.: +56-229-781-727
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13
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JNK signaling as a target for anticancer therapy. Pharmacol Rep 2021; 73:405-434. [PMID: 33710509 DOI: 10.1007/s43440-021-00238-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/30/2021] [Accepted: 02/15/2021] [Indexed: 12/15/2022]
Abstract
The JNKs are members of mitogen-activated protein kinases (MAPK) which regulate many physiological processes including inflammatory responses, macrophages, cell proliferation, differentiation, survival, and death. It is increasingly clear that the continuous activation of JNKs has a role in cancer development and progression. Therefore, JNKs represent attractive oncogenic targets for cancer therapy using small molecule kinase inhibitors. Studies showed that the two major JNK proteins JNK1 and JNK2 have opposite functions in different types of cancers, which need more specification in the design of JNK inhibitors. Some of ATP- competitive and ATP non-competitive inhibitors have been developed and widely used in vitro, but this type of inhibitors lack selectivity and inhibits phosphorylation of all JNK substrates and may lead to cellular toxicity. In this review, we summarized and discussed the strategies of JNK binding inhibitors and the role of JNK signaling in the pathogenesis of different solid and hematological malignancies.
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14
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Mazzoli A, Sardi C, Breasson L, Theilig F, Becattini B, Solinas G. JNK1 ablation improves pancreatic β-cell mass and function in db/db diabetic mice without affecting insulin sensitivity and adipose tissue inflammation. FASEB Bioadv 2021; 3:94-107. [PMID: 33615154 PMCID: PMC7876705 DOI: 10.1096/fba.2020-00081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 12/12/2020] [Accepted: 12/16/2020] [Indexed: 12/15/2022] Open
Abstract
The cJun N‐terminal Kinases (JNK) emerged as a major link between obesity and insulin resistance, but their role in the loss of pancreatic β‐cell mass and function driving the progression from insulin resistance to type‐2 diabetes and in the complications of diabetes was not investigated to the same extent. Furthermore, it was shown that pan‐JNK inhibition exacerbates kidney damage in the db/db model of obesity‐driven diabetes. Here we investigate the role of JNK1 in the db/db model of obesity‐driven type‐2 diabetes. Mice with systemic ablation of JNK1 (JNK1−/−) were backcrossed for more than 10 generations in db/+ C57BL/KS mice to generate db/db‐JNK1−/− mice and db/db control mice. To define the role of JNK1 in the loss of β‐cell mass and function occurring during obesity‐driven diabetes we performed comprehensive metabolic phenotyping, evaluated steatosis and metabolic inflammation, performed morphometric and cellular composition analysis of pancreatic islets, and evaluated kidney function in db/db‐JNK1−/− mice and db/db controls. db/db‐JNK1−/− mice and db/db control mice developed insulin resistance, fatty liver, and metabolic inflammation to a similar extent. However, db/db‐JNK1−/− mice displayed better glucose tolerance and improved insulin levels during glucose tolerance test, higher pancreatic insulin content, and larger pancreatic islets with more β‐cells than db/db mice. Finally, albuminuria, kidney histopathology, kidney inflammation and oxidative stress in db/db‐JNK1−/− mice and in db/db mice were similar. Our data indicate that selective JNK1 ablation improves glucose tolerance in db/db mice by reducing the loss of functional β‐cells occurring in the db/db mouse model of obesity‐driven diabetes, without significantly affecting metabolic inflammation, steatosis, and insulin sensitivity. Furthermore, we have found that, differently from what previously reported for pan‐JNK inhibitors, selective JNK1 ablation does not exacerbate kidney dysfunction in db/db mice. We conclude that selective JNK1 inactivation may have a superior therapeutic index than pan‐JNK inhibition in obesity‐driven diabetes.
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Affiliation(s)
- Arianna Mazzoli
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Claudia Sardi
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Ludovic Breasson
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Franziska Theilig
- Institute of Anatomy Christian Albrechts-University Kiel Kiel Germany
| | - Barbara Becattini
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
| | - Giovanni Solinas
- The Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research Department of Molecular and Clinical Medicine Institute of Medicine University of Gothenburg Gothenburg Sweden
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15
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Abstract
Obesity, which has long since reached epidemic proportions worldwide, is associated with long-term stress to a variety of organs and results in diseases including type 2 diabetes. In the brain, overnutrition induces hypothalamic stress associated with the activation of several signalling pathways, together with central insulin and leptin resistance. This central action of nutrient overload appears very rapidly, suggesting that nutrition-induced hypothalamic stress is a major upstream initiator of obesity and associated diseases. The cellular response to nutrient overload includes the activation of the stress-activated c-Jun N-terminal kinases (JNKs) JNK1, JNK2 and JNK3, which are widely expressed in the brain. Here, we review recent findings on the regulation and effects of these kinases, with particular focus on the hypothalamus, a key brain region in the control of energy and glucose homeostasis. JNK1 blocks the hypothalamic-pituitary-thyroid axis, reducing energy expenditure and promoting obesity. Recently, opposing roles have been identified for JNK1 and JNK3 in hypothalamic agouti gene-related protein (AgRP) neurons: while JNK1 activation in AgRP neurons induces feeding and weight gain and impairs insulin and leptin signalling, JNK3 (also known as MAPK10) deletion in the same neuronal population produces very similar effects. The opposing roles of these kinases, and the unknown role of hypothalamic JNK2, reflect the complexity of JNK biology. Future studies should address the specific function of each kinase, not only in different neuronal subsets, but also in non-neuronal cells in the central nervous system. Decoding the puzzle of brain stress kinases will help to define the central stimuli and mechanisms implicated in the control of energy balance. Graphical abstract.
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Affiliation(s)
- Rubén Nogueiras
- Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
- Galician Agency of Innovation (GAIN), Xunta de Galicia, Santiago de Compostela, Spain
| | - Guadalupe Sabio
- Department of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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Lemmer IL, Willemsen N, Hilal N, Bartelt A. A guide to understanding endoplasmic reticulum stress in metabolic disorders. Mol Metab 2021; 47:101169. [PMID: 33484951 PMCID: PMC7887651 DOI: 10.1016/j.molmet.2021.101169] [Citation(s) in RCA: 182] [Impact Index Per Article: 45.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Revised: 01/08/2021] [Accepted: 01/18/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The global rise of metabolic disorders, such as obesity, type 2 diabetes, and cardiovascular disease, demands a thorough molecular understanding of the cellular mechanisms that govern health or disease. The endoplasmic reticulum (ER) is a key organelle for cellular function and metabolic adaptation and, therefore disturbed ER function, known as "ER stress," is a key feature of metabolic disorders. SCOPE OF REVIEW As ER stress remains a poorly defined phenomenon, this review provides a general guide to understanding the nature, etiology, and consequences of ER stress in metabolic disorders. We define ER stress by its type of stressor, which is driven by proteotoxicity, lipotoxicity, and/or glucotoxicity. We discuss the implications of ER stress in metabolic disorders by reviewing evidence implicating ER phenotypes and organelle communication, protein quality control, calcium homeostasis, lipid and carbohydrate metabolism, and inflammation as key mechanisms in the development of ER stress and metabolic dysfunction. MAJOR CONCLUSIONS In mammalian biology, ER is a phenotypically and functionally diverse platform for nutrient sensing, which is critical for cell type-specific metabolic control by hepatocytes, adipocytes, muscle cells, and neurons. In these cells, ER stress is a distinct, transient state of functional imbalance, which is usually resolved by the activation of adaptive programs such as the unfolded protein response (UPR), ER-associated protein degradation (ERAD), or autophagy. However, challenges to proteostasis also impact lipid and glucose metabolism and vice versa. In the ER, sensing and adaptive measures are integrated and failure of the ER to adapt leads to aberrant metabolism, organelle dysfunction, insulin resistance, and inflammation. In conclusion, the ER is intricately linked to a wide spectrum of cellular functions and is a critical component in maintaining and restoring metabolic health.
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Affiliation(s)
- Imke L Lemmer
- Institute for Cardiovascular Prevention (IPEK), Pettenkoferstr. 9, Ludwig-Maximilians-University, 80336 Munich, Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany
| | - Nienke Willemsen
- Institute for Cardiovascular Prevention (IPEK), Pettenkoferstr. 9, Ludwig-Maximilians-University, 80336 Munich, Germany
| | - Nazia Hilal
- Institute for Cardiovascular Prevention (IPEK), Pettenkoferstr. 9, Ludwig-Maximilians-University, 80336 Munich, Germany
| | - Alexander Bartelt
- Institute for Cardiovascular Prevention (IPEK), Pettenkoferstr. 9, Ludwig-Maximilians-University, 80336 Munich, Germany; Institute for Diabetes and Cancer (IDC), Helmholtz Center Munich, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Technische Universität München, Biedersteiner Str. 29, 80802 München, Germany; Department of Molecular Metabolism, 665 Huntington Avenue, Harvard T.H. Chan School of Public Health, 02115 Boston, MA, USA.
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17
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Pinto PR, Yoshinaga MY, Del Bianco V, Bochi AP, Ferreira GS, Pinto IFD, Rodrigues LG, Nakandakare ER, Okamoto MM, Machado UF, Miyamoto S, Catanozi S, Passarelli M. Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice. J Biol Chem 2021; 296:100344. [PMID: 33524391 PMCID: PMC7949138 DOI: 10.1016/j.jbc.2021.100344] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 12/15/2022] Open
Abstract
A low-sodium (LS) diet has been shown to reduce blood pressure (BP) and the incidence of cardiovascular diseases. However, severe dietary sodium restriction promotes insulin resistance (IR) and dyslipidemia in animal models and humans. Thus, further clarification of the long-term consequences of LS is needed. Here, we investigated the effects of chronic LS on gastrocnemius gene and protein expression and lipidomics and its association with IR and plasma lipids in LDL receptor knockout mice. Three-month-old male mice were fed a normal sodium diet (NS; 0.5% Na; n = 12-19) or LS (0.06% Na; n = 14-20) over 90 days. Body mass (BM), BP, plasma total cholesterol, triacylglycerol (TG), glucose, hematocrit, and IR were evaluated. LS increased BM (9%), plasma TG (51%), blood glucose (19%), and IR (46%) when compared with the NS. RT-qPCR analysis revealed that genes involved in lipid uptake and oxidation were increased by the LS: Fabp3 (106%), Prkaa1 (46%), and Cpt1 (74%). Genes and proteins (assessed by Western blotting) involved in insulin signaling were not changed by the LS. Similarly, lipid species classically involved in muscle IR, such as diacylglycerols and ceramides detected by ultra-high-performance liquid chromatography coupled to mass spectrometry, were also unchanged by LS. Species of phosphatidylcholines (68%), phosphatidylinositol (90%), and free fatty acids (59%) increased while cardiolipins (41%) and acylcarnitines (9%) decreased in gastrocnemius in response to LS and were associated with glucose disposal rate. Together these results suggest that chronic LS alters glycerophospholipid and fatty acids species in gastrocnemius that may contribute to glucose and lipid homeostasis derangements in mice.
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Affiliation(s)
- Paula Ramos Pinto
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marcos Y Yoshinaga
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Vanessa Del Bianco
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Ana Paula Bochi
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Guilherme S Ferreira
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Isabella F D Pinto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Letícia G Rodrigues
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Edna R Nakandakare
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Maristela M Okamoto
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Ubiratan F Machado
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - Sayuri Miyamoto
- Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, Brazil
| | - Sergio Catanozi
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Marisa Passarelli
- Laboratório de Lípides (LIM-10), Hospital das Clínicas (HCFMUSP) da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil; Programa de Pós-Graduação em Medicina, Universidade Nove de Julho, São Paulo, Brazil.
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18
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Hepp Rehfeldt SC, Majolo F, Goettert MI, Laufer S. c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer's Diseases. Int J Mol Sci 2020; 21:E9677. [PMID: 33352989 PMCID: PMC7765872 DOI: 10.3390/ijms21249677] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/11/2020] [Accepted: 12/12/2020] [Indexed: 02/07/2023] Open
Abstract
Alzheimer's Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review.
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Affiliation(s)
- Stephanie Cristine Hepp Rehfeldt
- Graduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado CEP 95914-014, Rio Grande do Sul, Brazil; (S.C.H.R.); (F.M.)
| | - Fernanda Majolo
- Graduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado CEP 95914-014, Rio Grande do Sul, Brazil; (S.C.H.R.); (F.M.)
- Brain Institute of Rio Grande do Sul (BraIns), Pontifical Catholic University of Rio Grande do Sul (PUCRS), Porto Alegre CEP 90619-900, Rio Grande do Sul, Brazil
| | - Márcia Inês Goettert
- Graduate Program in Biotechnology, University of Vale do Taquari (Univates), Lajeado CEP 95914-014, Rio Grande do Sul, Brazil; (S.C.H.R.); (F.M.)
| | - Stefan Laufer
- Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmaceutical Sciences, Faculty of Sciences, University of Tuebingen, D-72076 Tuebingen, Germany
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Han MS, Perry RJ, Camporez JP, Scherer PE, Shulman GI, Gao G, Davis RJ. A feed-forward regulatory loop in adipose tissue promotes signaling by the hepatokine FGF21. Genes Dev 2020; 35:133-146. [PMID: 33334822 PMCID: PMC7778269 DOI: 10.1101/gad.344556.120] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Accepted: 11/02/2020] [Indexed: 12/13/2022]
Abstract
In this study, Han et al. demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues. The cJun NH2-terminal kinase (JNK) signaling pathway is activated by metabolic stress and promotes the development of metabolic syndrome, including hyperglycemia, hyperlipidemia, and insulin resistance. This integrated physiological response involves cross-talk between different organs. Here we demonstrate that JNK signaling in adipocytes causes an increased circulating concentration of the hepatokine fibroblast growth factor 21 (FGF21) that regulates systemic metabolism. The mechanism of organ crosstalk is mediated by a feed-forward regulatory loop caused by JNK-regulated FGF21 autocrine signaling in adipocytes that promotes increased expression of the adipokine adiponectin and subsequent hepatic expression of the hormone FGF21. The mechanism of organ cross-talk places circulating adiponectin downstream of autocrine FGF21 expressed by adipocytes and upstream of endocrine FGF21 expressed by hepatocytes. This regulatory loop represents a novel signaling paradigm that connects autocrine and endocrine signaling modes of the same hormone in different tissues.
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Affiliation(s)
- Myoung Sook Han
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
| | - Rachel J Perry
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA.,Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06520, USA
| | - João-Paulo Camporez
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.,Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
| | - Gerald I Shulman
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06520, USA.,Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, Connecticut 06520, USA
| | - Guangping Gao
- Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA
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Abstract
Obesity is a health condition that has reached pandemic levels and is implicated in the development and progression of type 2 diabetes mellitus, cancer and heart failure. A key characteristic of obesity is the activation of stress-activated protein kinases (SAPKs), such as the p38 and JNK stress kinases, in several organs, including adipose tissue, liver, skeletal muscle, immune organs and the central nervous system. The correct timing, intensity and duration of SAPK activation contributes to cellular metabolic adaptation. By contrast, uncontrolled SAPK activation has been proposed to contribute to the complications of obesity. The stress kinase signalling pathways have therefore been identified as potential targets for the development of novel therapeutic approaches for metabolic syndrome. The past few decades have seen intense research efforts to determine how these kinases are regulated in a cell-specific manner and to define their contribution to the development of obesity and insulin resistance. Several studies have uncovered new and unexpected functions of the non-classical members of both pathways. Here, we provide an overview of the role of SAPKs in metabolic control and highlight important discoveries in the field.
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Affiliation(s)
- Ivana Nikolic
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Magdalena Leiva
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Guadalupe Sabio
- Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
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A Review on Oxidative Stress, Diabetic Complications, and the Roles of Honey Polyphenols. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2020; 2020:8878172. [PMID: 33299532 PMCID: PMC7704201 DOI: 10.1155/2020/8878172] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/18/2020] [Accepted: 10/23/2020] [Indexed: 02/06/2023]
Abstract
Despite the availability of various antidiabetic drugs, diabetes mellitus (DM) remains one of the world's most prevalent chronic diseases and is a global burden. Hyperglycaemia, a characteristic of type 2 diabetes mellitus (T2DM), substantially leads to the generation of reactive oxygen species (ROS), triggering oxidative stress as well as numerous cellular and molecular modifications such as mitochondrial dysfunction affecting normal physiological functions in the body. In mitochondrial-mediated processes, oxidative pathways play an important role, although the responsible molecular mechanisms remain unclear. The impaired mitochondrial function is evidenced by insulin insensitivity in various cell types. In addition, the roles of master antioxidant pathway nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)/antioxidant response elements (ARE) are being deciphered to explain various molecular pathways involved in diabetes. Dietary factors are known to influence diabetes, and many natural dietary factors have been studied to improve diabetes. Honey is primarily rich in carbohydrates and is also abundant in flavonoids and phenolic acids; thus, it is a promising therapeutic antioxidant for various disorders. Various research has indicated that honey has strong wound-healing properties and has antibacterial, anti-inflammatory, antifungal, and antiviral effects; thus, it is a promising antidiabetic agent. The potential antidiabetic mechanisms of honey were proposed based on its major constituents. This review focuses on the various prospects of using honey as an antidiabetic agent and the potential insights.
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Kassouf T, Sumara G. Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases. Biomolecules 2020; 10:biom10091256. [PMID: 32872540 PMCID: PMC7563211 DOI: 10.3390/biom10091256] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/25/2020] [Accepted: 08/26/2020] [Indexed: 02/06/2023] Open
Abstract
The family of mitogen-activated protein kinases (MAPKs) consists of fourteen members and has been implicated in regulation of virtually all cellular processes. MAPKs are divided into two groups, conventional and atypical MAPKs. Conventional MAPKs are further classified into four sub-families: extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK1, 2 and 3), p38 (α, β, γ, δ), and extracellular signal-regulated kinase 5 (ERK5). Four kinases, extracellular signal-regulated kinase 3, 4, and 7 (ERK3, 4 and 7) as well as Nemo-like kinase (NLK) build a group of atypical MAPKs, which are activated by different upstream mechanisms than conventional MAPKs. Early studies identified JNK1/2 and ERK1/2 as well as p38α as a central mediators of inflammation-evoked insulin resistance. These kinases have been also implicated in the development of obesity and diabetes. Recently, other members of conventional MAPKs emerged as important mediators of liver, skeletal muscle, adipose tissue, and pancreatic β-cell metabolism. Moreover, latest studies indicate that atypical members of MAPK family play a central role in the regulation of adipose tissue function. In this review, we summarize early studies on conventional MAPKs as well as recent findings implicating previously ignored members of the MAPK family. Finally, we discuss the therapeutic potential of drugs targeting specific members of the MAPK family.
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Hodges JK, Sasaki GY, Bruno RS. Anti-inflammatory activities of green tea catechins along the gut-liver axis in nonalcoholic fatty liver disease: lessons learned from preclinical and human studies. J Nutr Biochem 2020; 85:108478. [PMID: 32801031 DOI: 10.1016/j.jnutbio.2020.108478] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/02/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is the most prevalent hepatic disorder worldwide, affecting 25% of the general population, describes a spectrum of progressive liver conditions ranging from relatively benign liver steatosis and advancing to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Hallmark features of NASH are fatty hepatocytes and inflammatory cell infiltrates in association with increased activation of hepatic nuclear factor kappa-B (NFκB) that exacerbates liver injury. Because no pharmacological treatments exist for NAFLD, emphasis has been placed on dietary approaches to manage NASH risk. Anti-inflammatory bioactivities of catechin-rich green tea extract (GTE) have been well-studied, especially in preclinical models that have detailed its effects on inflammatory responses downstream of NFκB activation. This review will therefore discuss the experimental evidence that has advanced an understanding of the mechanisms by which GTE, either directly through its catechins or potentially indirectly through microbiota-derived metabolites, limits NFκB activation and NASH-associated liver injury. Specifically, it will describe the hepatic-level benefits of GTE that attenuate intracellular redox distress and pro-inflammatory signaling from extracellular receptors that otherwise activate NFκB. In addition, it will discuss the anti-inflammatory activities of GTE on gut barrier function as well as prebiotic and antimicrobial effects on gut microbial ecology that help to limit the translocation of gut-derived endotoxins (e.g. lipopolysaccharides) to the liver where they otherwise upregulate NFκB activation by Toll-like receptor-4 signaling. This summary is therefore expected to advance research translation of the hepatic- and intestinal-level benefits of GTE and its catechins to help manage NAFLD-associated morbidity.
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Affiliation(s)
- Joanna K Hodges
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210
| | - Geoffrey Y Sasaki
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210
| | - Richard S Bruno
- Human Nutrition Program, The Ohio State University, Columbus, OH 43210.
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Role of c-Jun N-terminal Kinase (JNK) in Obesity and Type 2 Diabetes. Cells 2020; 9:cells9030706. [PMID: 32183037 PMCID: PMC7140703 DOI: 10.3390/cells9030706] [Citation(s) in RCA: 145] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/16/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Obesity has been described as a global epidemic and is a low-grade chronic inflammatory disease that arises as a consequence of energy imbalance. Obesity increases the risk of type 2 diabetes (T2D), by mechanisms that are not entirely clarified. Elevated circulating pro-inflammatory cytokines and free fatty acids (FFA) during obesity cause insulin resistance and ß-cell dysfunction, the two main features of T2D, which are both aggravated with the progressive development of hyperglycemia. The inflammatory kinase c-jun N-terminal kinase (JNK) responds to various cellular stress signals activated by cytokines, free fatty acids and hyperglycemia, and is a key mediator in the transition between obesity and T2D. Specifically, JNK mediates both insulin resistance and ß-cell dysfunction, and is therefore a potential target for T2D therapy.
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Qi Y, Zhang X, Seyoum B, Msallaty Z, Mallisho A, Caruso M, Damacharla D, Ma D, Al-janabi W, Tagett R, Alharbi M, Calme G, Mestareehi A, Draghici S, Abou-Samra A, Kowluru A, Yi Z. Kinome Profiling Reveals Abnormal Activity of Kinases in Skeletal Muscle From Adults With Obesity and Insulin Resistance. J Clin Endocrinol Metab 2020; 105:5607358. [PMID: 31652310 PMCID: PMC6991621 DOI: 10.1210/clinem/dgz115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 10/08/2019] [Indexed: 12/25/2022]
Abstract
CONTEXT Obesity-related insulin resistance (OIR) is one of the main contributors to type 2 diabetes and other metabolic diseases. Protein kinases are implicated in insulin signaling and glucose metabolism. Molecular mechanisms underlying OIR involving global kinase activities remain incompletely understood. OBJECTIVE To investigate abnormal kinase activity associated with OIR in human skeletal muscle. DESIGN Utilization of stable isotopic labeling-based quantitative proteomics combined with affinity-based active enzyme probes to profile in vivo kinase activity in skeletal muscle from lean control (Lean) and OIR participants. PARTICIPANTS A total of 16 nondiabetic adults, 8 Lean and 8 with OIR, underwent hyperinsulinemic-euglycemic clamp with muscle biopsy. RESULTS We identified the first active kinome, comprising 54 active protein kinases, in human skeletal muscle. The activities of 23 kinases were different in OIR muscle compared with Lean muscle (11 hyper- and 12 hypo-active), while their protein abundance was the same between the 2 groups. The activities of multiple kinases involved in adenosine monophosphate-activated protein kinase (AMPK) and p38 signaling were lower in OIR compared with Lean. On the contrary, multiple kinases in the c-Jun N-terminal kinase (JNK) signaling pathway exhibited higher activity in OIR vs Lean. The kinase-substrate-prediction based on experimental data further confirmed a potential downregulation of insulin signaling (eg, inhibited phosphorylation of insulin receptor substrate-1 and AKT1/2). CONCLUSIONS These findings provide a global view of the kinome activity in OIR and Lean muscle, pinpoint novel specific impairment in kinase activities in signaling pathways important for skeletal muscle insulin resistance, and may provide potential drug targets (ie, abnormal kinase activities) to prevent and/or reverse skeletal muscle insulin resistance in humans.
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Affiliation(s)
- Yue Qi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Xiangmin Zhang
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Berhane Seyoum
- Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI
| | - Zaher Msallaty
- Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI
| | - Abdullah Mallisho
- Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI
| | - Michael Caruso
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Divyasri Damacharla
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Danjun Ma
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Wissam Al-janabi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Rebecca Tagett
- Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI
| | - Majed Alharbi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Griffin Calme
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Aktham Mestareehi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
| | - Sorin Draghici
- Department of Computer Science, College of Engineering, Wayne State University, Detroit, MI
| | - Abdul Abou-Samra
- Division of Endocrinology, Wayne State University School of Medicine, Wayne State University, Detroit, MI
- Department of Medicine, Qatar Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Anjaneyulu Kowluru
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
- β-Cell Biochemistry Laboratory, John D. Dingell VA Medical Center, Detroit, MI
| | - Zhengping Yi
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI
- Correspondence: Zhengping Yi, PhD, Department of Pharmaceutical Sciences – Room 3146, Eugene Applebaum College of Pharmacy/Health Sciences, Wayne State University, 6135 Woodward Ave., Detroit, MI 48202. E-mail:
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26
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Pinheiro-Machado E, Gurgul-Convey E, Marzec MT. Immunometabolism in type 2 diabetes mellitus: tissue-specific interactions. Arch Med Sci 2020; 19:895-911. [PMID: 37560741 PMCID: PMC10408029 DOI: 10.5114/aoms.2020.92674] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 10/23/2019] [Indexed: 08/11/2023] Open
Abstract
The immune system is frequently described in the context of its protective function against infections and its role in the development of autoimmunity. For more than a decade, the interactions between the immune system and metabolic processes have been reported, in effect creating a new research field, termed immunometabolism. Accumulating evidence supports the hypothesis that the development of metabolic diseases may be linked to inflammation, and reflects, in some cases, the activation of immune responses. As such, immunometabolism is defined by 1) inflammation as a driver of disease development and/or 2) metabolic processes stimulating cellular differentiation of the immune components. In this review, the main factors capable of altering the immuno-metabolic communication leading to the development and establishment of obesity and diabetes are comprehensively presented. Tissue-specific immune responses suggested to impair metabolic processes are described, with an emphasis on the adipose tissue, gut, muscle, liver, and pancreas.
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Affiliation(s)
- Erika Pinheiro-Machado
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, Netherlands
| | - Ewa Gurgul-Convey
- Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany
| | - Michal T. Marzec
- Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark
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Bennett AM, Lawan A. Improving Obesity and Insulin Resistance by Targeting Skeletal Muscle MKP-1. JOURNAL OF CELLULAR SIGNALING 2020; 1:160-168. [PMID: 33179019 PMCID: PMC7654974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Obesity has reached a global epidemic and it predisposes to the development of insulin resistance, type 2 diabetes and related metabolic diseases. Current interventions against obesity and/or type 2 diabetes such as calorie restriction, exercise, genetic manipulations or established pharmacological treatments have not been successful for many patients with obesity and/or type 2 diabetes. There is an urgent need for new strategies to treat insulin resistance, T2D and obesity. Increased activity of stress-responsive pathways has been linked to the pathogenesis of insulin resistance in obesity. In this commentary, we argue that chronic upregulation of MKP-1 in skeletal muscle is part of a stress response that contributes to the development of insulin resistance, T2D and obesity. Therefore, inhibition of MKP-1 in skeletal muscle is a potential strategy for the treatment of T2D and obesity. We highlight therapeutic strategies for potential targeting of MKP-1 in skeletal muscle for the treatment of metabolic diseases as well as other diseases of skeletal muscle.
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Affiliation(s)
- Anton M. Bennett
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520, USA,Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA,Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520, USA
| | - Ahmed Lawan
- Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, Alabama 35899, USA,Correspondence should be addressed to Ahmed Lawan;
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Busquets O, Ettcheto M, Eritja À, Espinosa-Jiménez T, Verdaguer E, Olloquequi J, Beas-Zarate C, Castro-Torres RD, Casadesús G, Auladell C, Bulló M, Folch J, Camins A. c-Jun N-terminal Kinase 1 ablation protects against metabolic-induced hippocampal cognitive impairments. J Mol Med (Berl) 2019; 97:1723-1733. [DOI: 10.1007/s00109-019-01856-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/06/2019] [Accepted: 11/14/2019] [Indexed: 01/09/2023]
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JNK and cardiometabolic dysfunction. Biosci Rep 2019; 39:BSR20190267. [PMID: 31270248 PMCID: PMC6639461 DOI: 10.1042/bsr20190267] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/28/2019] [Accepted: 07/02/2019] [Indexed: 02/06/2023] Open
Abstract
Cardiometabolic syndrome (CMS) describes the cluster of metabolic and cardiovascular diseases that are generally characterized by impaired glucose tolerance, intra-abdominal adiposity, dyslipidemia, and hypertension. CMS currently affects more than 25% of the world’s population and the rates of diseases are rapidly rising. These CMS conditions represent critical risk factors for cardiovascular diseases including atherosclerosis, heart failure, myocardial infarction, and peripheral artery disease (PAD). Therefore, it is imperative to elucidate the underlying signaling involved in disease onset and progression. The c-Jun N-terminal Kinases (JNKs) are a family of stress signaling kinases that have been recently indicated in CMS. The purpose of this review is to examine the in vivo implications of JNK as a potential therapeutic target for CMS. As the constellation of diseases associated with CMS are complex and involve multiple tissues and environmental triggers, carefully examining what is known about the JNK pathway will be important for specificity in treatment strategies.
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Rivers SL, Klip A, Giacca A. NOD1: An Interface Between Innate Immunity and Insulin Resistance. Endocrinology 2019; 160:1021-1030. [PMID: 30807635 PMCID: PMC6477778 DOI: 10.1210/en.2018-01061] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 02/19/2019] [Indexed: 12/17/2022]
Abstract
Insulin resistance is driven, in part, by activation of the innate immune system. We have discussed the evidence linking nucleotide-binding oligomerization domain (NOD)1, an intracellular pattern recognition receptor, to the onset and progression of obesity-induced insulin resistance. On a molecular level, crosstalk between downstream NOD1 effectors and the insulin receptor pathway inhibits insulin signaling, potentially through reduced insulin receptor substrate action. In vivo studies have demonstrated that NOD1 activation induces peripheral, hepatic, and whole-body insulin resistance. Also, NOD1-deficient models are protected from high-fat diet (HFD)-induced insulin resistance. Moreover, hematopoietic NOD1 deficiency prevented HFD-induced changes in proinflammatory macrophage polarization status, thus protecting against the development of metabolic inflammation and insulin resistance. Serum from HFD-fed mice activated NOD1 signaling ex vivo; however, the molecular identity of the activating factors remains unclear. Many have proposed that an HFD changes the gut permeability, resulting in increased translocation of bacterial fragments and increased circulating NOD1 ligands. In contrast, others have suggested that NOD1 ligands are endogenous and potentially lipid-derived metabolites produced during states of nutrient overload. Nevertheless, that NOD1 contributes to the development of insulin resistance, and that NOD1-based therapy might provide benefit, is an exciting advancement in metabolic research.
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Affiliation(s)
- Sydney L Rivers
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Amira Klip
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Adria Giacca
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Correspondence: Adria Giacca, MD, Department of Physiology, Faculty of Medicine, University of Toronto, Medical Sciences Building, 1 King’s College Circle, No. 3336, Toronto, Ontario M5S 1A8, Canada. E-mail:
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Thoudam T, Ha CM, Leem J, Chanda D, Park JS, Kim HJ, Jeon JH, Choi YK, Liangpunsakul S, Huh YH, Kwon TH, Park KG, Harris RA, Park KS, Rhee HW, Lee IK. PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity. Diabetes 2019; 68:571-586. [PMID: 30523025 PMCID: PMC6385748 DOI: 10.2337/db18-0363] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Accepted: 11/20/2018] [Indexed: 12/17/2022]
Abstract
Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex-dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4-/- mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER-mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.
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Affiliation(s)
- Themis Thoudam
- Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Chae-Myeong Ha
- Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Jaechan Leem
- Department of Immunology, School of Medicine, Catholic University of Daegu, Daegu, Republic of Korea
| | - Dipanjan Chanda
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Jong-Seok Park
- Department of Chemistry, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Hyo-Jeong Kim
- Electron Microscopy Research Center, Korea Basic Science Institute, Ochang, Chungbuk, Republic of Korea
| | - Jae-Han Jeon
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Yeon-Kyung Choi
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Richard L. Roudebush VA Medical Center, Indianapolis, IN
| | - Yang Hoon Huh
- Electron Microscopy Research Center, Korea Basic Science Institute, Ochang, Chungbuk, Republic of Korea
| | - Tae-Hwan Kwon
- Department of Biomedical Science, The Graduate School, Kyungpook National University, Daegu, Republic of Korea
- BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea
| | - Keun-Gyu Park
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Robert A Harris
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
| | - Kyu-Sang Park
- Department of Physiology, Institute of Lifestyle Medicine, Yonsei University Wonju College of Medicine, Gangwon-Do, Republic of Korea
| | - Hyun-Woo Rhee
- Department of Chemistry, Seoul National University, Seoul, Republic of Korea
| | - In-Kyu Lee
- Leading-Edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, Republic of Korea
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
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Burhans MS, Hagman DK, Kuzma JN, Schmidt KA, Kratz M. Contribution of Adipose Tissue Inflammation to the Development of Type 2 Diabetes Mellitus. Compr Physiol 2018; 9:1-58. [PMID: 30549014 DOI: 10.1002/cphy.c170040] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The objective of this comprehensive review is to summarize and discuss the available evidence of how adipose tissue inflammation affects insulin sensitivity and glucose tolerance. Low-grade, chronic adipose tissue inflammation is characterized by infiltration of macrophages and other immune cell populations into adipose tissue, and a shift toward more proinflammatory subtypes of leukocytes. The infiltration of proinflammatory cells in adipose tissue is associated with an increased production of key chemokines such as C-C motif chemokine ligand 2, proinflammatory cytokines including tumor necrosis factor α and interleukins 1β and 6 as well as reduced expression of the key insulin-sensitizing adipokine, adiponectin. In both rodent models and humans, adipose tissue inflammation is consistently associated with excess fat mass and insulin resistance. In humans, associations with insulin resistance are stronger and more consistent for inflammation in visceral as opposed to subcutaneous fat. Further, genetic alterations in mouse models of obesity that reduce adipose tissue inflammation are-almost without exception-associated with improved insulin sensitivity. However, a dissociation between adipose tissue inflammation and insulin resistance can be observed in very few rodent models of obesity as well as in humans following bariatric surgery- or low-calorie-diet-induced weight loss, illustrating that the etiology of insulin resistance is multifactorial. Taken together, adipose tissue inflammation is a key factor in the development of insulin resistance and type 2 diabetes in obesity, along with other factors that likely include inflammation and fat accumulation in other metabolically active tissues. © 2019 American Physiological Society. Compr Physiol 9:1-58, 2019.
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Affiliation(s)
- Maggie S Burhans
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Derek K Hagman
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Jessica N Kuzma
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Kelsey A Schmidt
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA
| | - Mario Kratz
- Cancer Prevention Program, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.,Department of Epidemiology, University of Washington, Seattle, Washington, USA.,Department of Medicine, University of Washington, Seattle, Washington, USA
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Petersen MC, Shulman GI. Mechanisms of Insulin Action and Insulin Resistance. Physiol Rev 2018; 98:2133-2223. [PMID: 30067154 PMCID: PMC6170977 DOI: 10.1152/physrev.00063.2017] [Citation(s) in RCA: 1682] [Impact Index Per Article: 240.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Revised: 03/22/2018] [Accepted: 03/24/2018] [Indexed: 12/15/2022] Open
Abstract
The 1921 discovery of insulin was a Big Bang from which a vast and expanding universe of research into insulin action and resistance has issued. In the intervening century, some discoveries have matured, coalescing into solid and fertile ground for clinical application; others remain incompletely investigated and scientifically controversial. Here, we attempt to synthesize this work to guide further mechanistic investigation and to inform the development of novel therapies for type 2 diabetes (T2D). The rational development of such therapies necessitates detailed knowledge of one of the key pathophysiological processes involved in T2D: insulin resistance. Understanding insulin resistance, in turn, requires knowledge of normal insulin action. In this review, both the physiology of insulin action and the pathophysiology of insulin resistance are described, focusing on three key insulin target tissues: skeletal muscle, liver, and white adipose tissue. We aim to develop an integrated physiological perspective, placing the intricate signaling effectors that carry out the cell-autonomous response to insulin in the context of the tissue-specific functions that generate the coordinated organismal response. First, in section II, the effectors and effects of direct, cell-autonomous insulin action in muscle, liver, and white adipose tissue are reviewed, beginning at the insulin receptor and working downstream. Section III considers the critical and underappreciated role of tissue crosstalk in whole body insulin action, especially the essential interaction between adipose lipolysis and hepatic gluconeogenesis. The pathophysiology of insulin resistance is then described in section IV. Special attention is given to which signaling pathways and functions become insulin resistant in the setting of chronic overnutrition, and an alternative explanation for the phenomenon of ‟selective hepatic insulin resistanceˮ is presented. Sections V, VI, and VII critically examine the evidence for and against several putative mediators of insulin resistance. Section V reviews work linking the bioactive lipids diacylglycerol, ceramide, and acylcarnitine to insulin resistance; section VI considers the impact of nutrient stresses in the endoplasmic reticulum and mitochondria on insulin resistance; and section VII discusses non-cell autonomous factors proposed to induce insulin resistance, including inflammatory mediators, branched-chain amino acids, adipokines, and hepatokines. Finally, in section VIII, we propose an integrated model of insulin resistance that links these mediators to final common pathways of metabolite-driven gluconeogenesis and ectopic lipid accumulation.
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Affiliation(s)
- Max C Petersen
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Howard Hughes Medical Institute, Yale University School of Medicine , New Haven, Connecticut
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Kawamoto E, Tamakoshi K, Ra SG, Masuda H, Kawanaka K. Immobilization rapidly induces thioredoxin-interacting protein gene expression together with insulin resistance in rat skeletal muscle. J Appl Physiol (1985) 2018; 125:596-604. [DOI: 10.1152/japplphysiol.00951.2017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Acute short duration of disuse induces the development of insulin resistance for glucose uptake in rodent skeletal muscle. Because thioredoxin-interacting protein (TXNIP) has been implicated in the downregulation of insulin signaling and glucose uptake, we examined the possibility that muscle disuse rapidly induces insulin resistance via increased TXNIP mRNA and protein expression. Male Wistar rats were subjected to unilateral 6-h hindlimb immobilization by plaster cast. At the end of this period, the soleus muscles from both immobilized and contralateral nonimmobilized hindlimbs were excised and examined. The 6-h immobilization resulted in an increase in TXNIP mRNA and protein expressions together with a decrease in insulin-stimulated 2-deoxyglucose uptake in the rat soleus muscle. Additionally, in the rats euthanized 6 h after the plaster cast removal, TXNIP protein expression and insulin-stimulated glucose uptake in the immobilized muscle had both been restored to a normal level. Various interventions (pretreatment with transcription inhibitor actinomycin D or AMP-dependent protein kinase activator 5-aminoimidazole-4-carboxamide ribonucleotide) also suppressed the increase in TXNIP protein expression in 6-h-immobilized muscle together with partial prevention of insulin resistance for glucose uptake. These results suggested the possibility that increased TXNIP protein expression in immobilized rat soleus muscles was associated with the rapid induction of insulin resistance for glucose uptake in that tissue. NEW & NOTEWORTHY The cellular mechanism by which disuse rapidly induces muscle insulin resistance for glucose uptake remains to be identified. Using a rat hindlimb immobilization model, our findings suggest the possibility that transcriptional upregulation of thioredoxin-interacting protein is associated with the immobilization-induced rapid development of insulin resistance in skeletal muscle.
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Affiliation(s)
- Emi Kawamoto
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
- Department of Materials Engineering, Nagaoka National College of Technology, Nagaoka, Japan
| | - Keigo Tamakoshi
- Department of Physical Therapy, Niigata University of Health and Welfare, Niigata, Japan
| | - Song-Gyu Ra
- Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
| | - Hiroyuki Masuda
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
| | - Kentaro Kawanaka
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
- Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
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Jung TW, Chung YH, Kim HC, Abd El-Aty AM, Jeong JH. Hyperlipidemia-induced hepassocin in the liver contributes to insulin resistance in skeletal muscle. Mol Cell Endocrinol 2018; 470:26-33. [PMID: 29111387 DOI: 10.1016/j.mce.2017.10.014] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2017] [Revised: 10/24/2017] [Accepted: 10/26/2017] [Indexed: 12/30/2022]
Abstract
Hepassocin (HPS) has recently been identified as a novel hepatokine that causes hepatic steatosis. However, the role of HPS in the development of insulin resistance in skeletal muscle under obesity remains unclear. The effect of hyperlipidemia on hepatic HPS expression was evaluated in primary hepatocytes and liver of mice. HPS-mediated signal pathways were explored using small interfering (si) RNAs of specific genes or inhibitors. We found that treatment of primary hepatocytes with palmitate could induce HPS expression through C/EBPβ-mediated transcriptional activation. Furthermore, increased HPS expression was observed in the liver of high fat diet (HFD)-fed or tunicamycin-treated mice. Pretreatment with 4-phenylbutyrate (4-BPA) (an endoplasmic reticulum (ER) stress inhibitor) and suppression of p38 by siRNA abrogated the effect of palmitate on HPS expression in primary hepatocytes. Treatment of differentiated C2C12 cells with recombinant HPS caused c-Jun N-terminal kinase (JNK) phosphorylation and impairment of insulin sensitivity in a dose-dependent manner. siRNA-mediated suppression of JNK reduced the effect of HPS on insulin signaling. Furthermore, the suppression of epidermal growth factor receptor (EGFR) by siRNA mitigated both HPS-induced JNK phosphorylation and insulin resistance. In addition, HPS did not affect inflammation and ER stress in differentiated C2C12 cells. In conclusion, we elucidated that ER stress induced by palmitate could increase the expression of HPS in hepatocytes and further contribute to the development of insulin resistance in skeletal muscle via EGFR/JNK-mediated pathway. Taken together, we suggest that HPS could be a therapeutic target for obesity-linked insulin resistance.
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Affiliation(s)
- Tae Woo Jung
- Research Administration Team, Seoul National University Bundang Hospital, Gyeonggi, Republic of Korea
| | - Yoon Hee Chung
- Department of Anatomy, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyoung-Chun Kim
- Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211 Giza, Egypt; Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea; Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum 25240, Turkey.
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Cruz VH, Arner EN, Wynne KW, Scherer PE, Brekken RA. Loss of Tbk1 kinase activity protects mice from diet-induced metabolic dysfunction. Mol Metab 2018; 16:139-149. [PMID: 29935921 PMCID: PMC6157474 DOI: 10.1016/j.molmet.2018.06.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2018] [Revised: 05/30/2018] [Accepted: 06/07/2018] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVE TANK Binding Kinase 1 (TBK1) has been implicated in the regulation of metabolism through studies with the drug amlexanox, an inhibitor of the IκB kinase (IKK)-related kinases. Amlexanox induced weight loss, reduced fatty liver and insulin resistance in high fat diet (HFD) fed mice and has now progressed into clinical testing for the treatment and prevention of obesity and type 2 diabetes. However, since amlexanox is a dual IKKε/TBK1 inhibitor, the specific metabolic contribution of TBK1 is not clear. METHODS To distinguish metabolic functions unique to TBK1, we examined the metabolic profile of global Tbk1 mutant mice challenged with an obesogenic diet and investigated potential mechanisms for the improved metabolic phenotype. RESULTS AND CONCLUSION We report that systemic loss of TBK1 kinase function has an overall protective effect on metabolic readouts in mice on an obesogenic diet, which is mediated by loss of an inhibitory interaction between TBK1 and the insulin receptor.
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Affiliation(s)
- Victoria H Cruz
- Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA
| | - Emily N Arner
- Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA
| | - Katherine W Wynne
- Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA
| | | | - Rolf A Brekken
- Division of Surgical Oncology, Department of Surgery and the Hamon Center for Therapeutic Oncology Research, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
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37
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Lawan A, Min K, Zhang L, Canfran-Duque A, Jurczak MJ, Camporez JPG, Nie Y, Gavin TP, Shulman GI, Fernandez-Hernando C, Bennett AM. Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance. Diabetes 2018; 67:624-635. [PMID: 29317435 PMCID: PMC5860856 DOI: 10.2337/db17-0826] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2017] [Accepted: 01/03/2018] [Indexed: 12/16/2022]
Abstract
Stress responses promote obesity and insulin resistance, in part, by activating the stress-responsive mitogen-activated protein kinases (MAPKs), p38 MAPK, and c-Jun NH2-terminal kinase (JNK). Stress also induces expression of MAPK phosphatase-1 (MKP-1), which inactivates both JNK and p38 MAPK. However, the equilibrium between JNK/p38 MAPK and MKP-1 signaling in the development of obesity and insulin resistance is unclear. Skeletal muscle is a major tissue involved in energy expenditure and glucose metabolism. In skeletal muscle, MKP-1 is upregulated in high-fat diet-fed mice and in skeletal muscle of obese humans. Mice lacking skeletal muscle expression of MKP-1 (MKP1-MKO) showed increased skeletal muscle p38 MAPK and JNK activities and were resistant to the development of diet-induced obesity. MKP1-MKO mice exhibited increased whole-body energy expenditure that was associated with elevated levels of myofiber-associated mitochondrial oxygen consumption. miR-21, a negative regulator of PTEN expression, was upregulated in skeletal muscle of MKP1-MKO mice, resulting in increased Akt activity consistent with enhanced insulin sensitivity. Our results demonstrate that skeletal muscle MKP-1 represents a critical signaling node through which inactivation of the p38 MAPK/JNK module promotes obesity and insulin resistance.
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Affiliation(s)
- Ahmed Lawan
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT
| | - Kisuk Min
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT
| | - Lei Zhang
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT
| | - Alberto Canfran-Duque
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT
| | - Michael J Jurczak
- Cellular & Molecular Physiology and Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT
| | - Joao Paulo G Camporez
- Cellular & Molecular Physiology and Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT
| | - Yaohui Nie
- Department of Health and Kinesiology, Purdue University, West Lafayette, IN
| | - Timothy P Gavin
- Department of Health and Kinesiology, Purdue University, West Lafayette, IN
| | - Gerald I Shulman
- Cellular & Molecular Physiology and Department of Internal Medicine, Section of Endocrinology and Metabolism, Yale University School of Medicine, New Haven, CT
| | - Carlos Fernandez-Hernando
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT
| | - Anton M Bennett
- Department of Pharmacology, Yale University School of Medicine, New Haven, CT
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT
- Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT
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Lawan A, Bennett AM. Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab 2017; 28:868-878. [PMID: 29128158 PMCID: PMC5774993 DOI: 10.1016/j.tem.2017.10.007] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 10/20/2017] [Accepted: 10/20/2017] [Indexed: 01/11/2023]
Abstract
The mitogen-activated protein kinases (MAPKs) participate in a multitude of processes that control hepatic metabolism. The liver regulates glucose and lipid metabolism, and under pathophysiological conditions such as obesity, type 2 diabetes mellitus (T2DM), and non-alcoholic fatty liver disease (NAFLD) these processes become dysfunctional. Stress responses activate the hepatic MAPKs, and this is thought to impair insulin action and lipid metabolism. The MAPKs also activate the MAPK phosphatases (MKPs) which oppose their actions. How the MAPK/MKP balance is controlled in liver metabolism and how perturbations in these activities contribute to metabolic disease remains unclear. Discussion of recent insights into the MAPK/MKP signaling role in hepatic metabolic function and disease will be the focus of this review.
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Affiliation(s)
- Ahmed Lawan
- Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
| | - Anton M Bennett
- Department of Pharmacology, Yale University, New Haven, CT 06520, USA; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University, New Haven, CT 06520, USA
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Awazawa M, Gabel P, Tsaousidou E, Nolte H, Krüger M, Schmitz J, Ackermann PJ, Brandt C, Altmüller J, Motameny S, Wunderlich FT, Kornfeld JW, Blüher M, Brüning JC. A microRNA screen reveals that elevated hepatic ectodysplasin A expression contributes to obesity-induced insulin resistance in skeletal muscle. Nat Med 2017; 23:1466-1473. [DOI: 10.1038/nm.4420] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2016] [Accepted: 09/11/2017] [Indexed: 01/21/2023]
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Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol 2017; 23:6549-6570. [PMID: 29085205 PMCID: PMC5643281 DOI: 10.3748/wjg.v23.i36.6549] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/25/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
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Affiliation(s)
- Sukhpreet Singh
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
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41
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Kawamoto E, Koshinaka K, Yoshimura T, Masuda H, Kawanaka K. Immobilization rapidly induces muscle insulin resistance together with the activation of MAPKs (JNK and p38) and impairment of AS160 phosphorylation. Physiol Rep 2017; 4:4/15/e12876. [PMID: 27482072 PMCID: PMC4985544 DOI: 10.14814/phy2.12876] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Accepted: 07/06/2016] [Indexed: 11/24/2022] Open
Abstract
Acute short‐duration physical inactivity induces the development of insulin resistance for glucose uptake in skeletal muscle. We examined the possibility that inactivity rapidly induces muscle insulin resistance via the excessive activation of proinflammatory/stress pathways including those of IKK/IκB/NF‐κB, JNK, and p38 MAPK. We also examined the other possibility that inactivity‐induced rapid development of insulin resistance is associated with reduced phosphorylation of AS160, the most distal insulin‐signaling protein that have been linked to the regulation of glucose uptake. Male Wistar rats were subjected to unilateral hindlimb immobilization for 6 h. At the end of the immobilization, the soleus muscles from both immobilized and contralateral non‐immobilized hindlimbs were dissected out. Immobilization decreased insulin‐stimulated 2‐deoxyglucose uptake in rat soleus muscle within 6 h. This rapid development of insulin resistance was accompanied by elevated phosphorylation of both JNK and p38 (commonly used indicator of JNK and p38 pathway activity, respectively). In addition, the abundance of SPT2, a rate‐limiting enzyme regulating ceramide biosynthesis, was increased in immobilized muscle. Immobilization did not alter the abundance of IκBα (commonly used indicator of IKK/IκB/NF‐κB pathway activity). The basal phosphorylation of AS160 at Thr642 and Ser588 was decreased together with the development of insulin resistance. These results suggest the possibility that inactivity‐induced rapid development of insulin resistance in immobilized muscle is related to enhanced activation of JNK and/or p38. Elevated ceramide biosynthesis pathway may contribute to this activation. Our results also indicate that decreased basal phosphorylation of AS160 may be involved in inactivity‐induced insulin resistance.
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Affiliation(s)
- Emi Kawamoto
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan Department of Materials Engineering, Nagaoka National College of Technology, Nagaoka, Japan
| | - Keiichi Koshinaka
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
| | - Tatsuhiko Yoshimura
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
| | - Hiroyuki Masuda
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan
| | - Kentaro Kawanaka
- Department of Health and Nutrition, Niigata University of Health and Welfare, Niigata, Japan Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan
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Wei HK, Deng Z, Jiang SZ, Song TX, Zhou YF, Peng J, Tao YX. Eicosapentaenoic acid abolishes inhibition of insulin-induced mTOR phosphorylation by LPS via PTP1B downregulation in skeletal muscle. Mol Cell Endocrinol 2017; 439:116-125. [PMID: 27984084 DOI: 10.1016/j.mce.2016.10.029] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 10/01/2016] [Accepted: 10/26/2016] [Indexed: 12/21/2022]
Abstract
Dietary n-3 polyunsaturated fatty acids (n-3 PUFAs) increase insulin signaling in skeletal muscle. In the current study, we investigated the effect of eicosapentaenoic acid (EPA) on insulin-induced mammalian target of rapamycin (mTOR) phosphorylation in myotubes. We showed that EPA did not affect basal and insulin-induced mTOR phosphorylation in myotubes. However, EPA abolished lipopolysaccharide (LPS) -induced deficiency in insulin signaling (P < 0.05). Pre-incubation of nuclear factor κB (NF-κΒ) and c-Jun N-terminal kinases (JNK) inhibitors prevented the decreased insulin-induced mTOR phosphorylation elicited by LPS (P < 0.05). In addition, in protein tyrosine phosphatase-1B (PTP1B) knockdown myotubes, LPS failed to decrease insulin-induced mammalian target of rapamycin (mTOR) phosphorylation in myotubes (P > 0.05). In myotubes, LPS stimulated PTP1B expression via NF-κB and activation protein-1 (AP1). Pre-incubation of 50 μM EPA prevented the LPS-induced activation of AP1 and NF-κΒ as well as PTP1B expression (P < 0.05). Interestingly, incubation of peroxisome proliferator-activated receptor γ (PPARγ) antagonist (GW9662) prior to EPA treatment, the effect of EPA on insulin-induced mTOR phosphorylation was blocked. Accordingly, EPA did not inhibit the LPS-induced activation of AP1 or NF-κΒ as well as PTP1B expression when incubation of GW9662 prior to EPA treatment. The in vivo study showed that EPA prevented LPS-induced PTPT1B expression and a decrease in insulin-induced mTOR phosphorylation in muscle of mice. In summary, EPA abolished LPS inhibition of insulin-induced mTOR phosphorylation in myotubes, and one of the key mechanisms was to inhibit AP1 and NF-κB activation and PTP1B transcription.
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Affiliation(s)
- Hong-Kui Wei
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China
| | - Zhao Deng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China
| | - Shu-Zhong Jiang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China
| | - Tong-Xing Song
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China
| | - Yuan-Fei Zhou
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China
| | - Jian Peng
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, 430070, Wuhan, PR China.
| | - Ya-Xiong Tao
- Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, AL 36849, USA.
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43
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Wu H, Ballantyne CM. Skeletal muscle inflammation and insulin resistance in obesity. J Clin Invest 2017; 127:43-54. [PMID: 28045398 DOI: 10.1172/jci88880] [Citation(s) in RCA: 453] [Impact Index Per Article: 56.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Obesity is associated with chronic inflammation, which contributes to insulin resistance and type 2 diabetes mellitus. Under normal conditions, skeletal muscle is responsible for the majority of insulin-stimulated whole-body glucose disposal; thus, dysregulation of skeletal muscle metabolism can strongly influence whole-body glucose homeostasis and insulin sensitivity. Increasing evidence suggests that inflammation occurs in skeletal muscle in obesity and is mainly manifested by increased immune cell infiltration and proinflammatory activation in intermyocellular and perimuscular adipose tissue. By secreting proinflammatory molecules, immune cells may induce myocyte inflammation, adversely regulate myocyte metabolism, and contribute to insulin resistance via paracrine effects. Increased influx of fatty acids and inflammatory molecules from other tissues, particularly visceral adipose tissue, can also induce muscle inflammation and negatively regulate myocyte metabolism, leading to insulin resistance.
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Solinas G, Becattini B. JNK at the crossroad of obesity, insulin resistance, and cell stress response. Mol Metab 2016; 6:174-184. [PMID: 28180059 PMCID: PMC5279903 DOI: 10.1016/j.molmet.2016.12.001] [Citation(s) in RCA: 280] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 11/28/2016] [Accepted: 12/02/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The cJun-N-terminal-kinase (JNK) plays a central role in the cell stress response, with outcomes ranging from cell death to cell proliferation and survival, depending on the specific context. JNK is also one of the most investigated signal transducers in obesity and insulin resistance, and studies have identified new molecular mechanisms linking obesity and insulin resistance. Emerging evidence indicates that whereas JNK1 and JNK2 isoforms promote the development of obesity and insulin resistance, JNK3 activity protects from excessive adiposity. Furthermore, current evidence indicates that JNK activity within specific cell types may, in specific stages of disease progression, promote cell tolerance to the stress associated with obesity and type-2 diabetes. SCOPE OF REVIEW This review provides an overview of the current literature on the role of JNK in the progression from obesity to insulin resistance, NAFLD, type-2 diabetes, and diabetes complications. MAJOR CONCLUSION Whereas current evidence indicates that JNK1/2 inhibition may improve insulin sensitivity in obesity, the role of JNK in the progression from insulin resistance to diabetes, and its complications is largely unresolved. A better understanding of the role of JNK in the stress response to obesity and type-2 diabetes, and the development of isoform-specific inhibitors with specific tissue distribution will be necessary to exploit JNK as possible drug target for the treatment of type-2 diabetes.
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Affiliation(s)
- Giovanni Solinas
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden.
| | - Barbara Becattini
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
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Roy B, Curtis ME, Fears LS, Nahashon SN, Fentress HM. Molecular Mechanisms of Obesity-Induced Osteoporosis and Muscle Atrophy. Front Physiol 2016; 7:439. [PMID: 27746742 PMCID: PMC5040721 DOI: 10.3389/fphys.2016.00439] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Accepted: 09/15/2016] [Indexed: 12/19/2022] Open
Abstract
Obesity and osteoporosis are two alarming health disorders prominent among middle and old age populations, and the numbers of those affected by these two disorders are increasing. It is estimated that more than 600 million adults are obese and over 200 million people have osteoporosis worldwide. Interestingly, both of these abnormalities share some common features including a genetic predisposition, and a common origin: bone marrow mesenchymal stromal cells. Obesity is characterized by the expression of leptin, adiponectin, interleukin 6 (IL-6), interleukin 10 (IL-10), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), macrophage colony stimulating factor (M-CSF), growth hormone (GH), parathyroid hormone (PTH), angiotensin II (Ang II), 5-hydroxy-tryptamine (5-HT), Advance glycation end products (AGE), and myostatin, which exert their effects by modulating the signaling pathways within bone and muscle. Chemical messengers (e.g., TNF-α, IL-6, AGE, leptins) that are upregulated or downregulated as a result of obesity have been shown to act as negative regulators of osteoblasts, osteocytes and muscles, as well as positive regulators of osteoclasts. These additive effects of obesity ultimately increase the risk for osteoporosis and muscle atrophy. The aim of this review is to identify the potential cellular mechanisms through which obesity may facilitate osteoporosis, muscle atrophy and bone fractures.
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Affiliation(s)
- Bipradas Roy
- Department of Biological Sciences, Tennessee State University Nashville, TN, USA
| | - Mary E Curtis
- Department of Biological Sciences, Tennessee State University Nashville, TN, USA
| | - Letimicia S Fears
- Department of Biological Sciences, Tennessee State University Nashville, TN, USA
| | - Samuel N Nahashon
- Department of Agricultural and Environmental Sciences, Tennessee State University Nashville, TN, USA
| | - Hugh M Fentress
- Department of Biological Sciences, Tennessee State University Nashville, TN, USA
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JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol Biol Rev 2016; 80:793-835. [PMID: 27466283 DOI: 10.1128/mmbr.00043-14] [Citation(s) in RCA: 370] [Impact Index Per Article: 41.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The c-Jun N-terminal kinases (JNKs), as members of the mitogen-activated protein kinase (MAPK) family, mediate eukaryotic cell responses to a wide range of abiotic and biotic stress insults. JNKs also regulate important physiological processes, including neuronal functions, immunological actions, and embryonic development, via their impact on gene expression, cytoskeletal protein dynamics, and cell death/survival pathways. Although the JNK pathway has been under study for >20 years, its complexity is still perplexing, with multiple protein partners of JNKs underlying the diversity of actions. Here we review the current knowledge of JNK structure and isoforms as well as the partnerships of JNKs with a range of intracellular proteins. Many of these proteins are direct substrates of the JNKs. We analyzed almost 100 of these target proteins in detail within a framework of their classification based on their regulation by JNKs. Examples of these JNK substrates include a diverse assortment of nuclear transcription factors (Jun, ATF2, Myc, Elk1), cytoplasmic proteins involved in cytoskeleton regulation (DCX, Tau, WDR62) or vesicular transport (JIP1, JIP3), cell membrane receptors (BMPR2), and mitochondrial proteins (Mcl1, Bim). In addition, because upstream signaling components impact JNK activity, we critically assessed the involvement of signaling scaffolds and the roles of feedback mechanisms in the JNK pathway. Despite a clarification of many regulatory events in JNK-dependent signaling during the past decade, many other structural and mechanistic insights are just beginning to be revealed. These advances open new opportunities to understand the role of JNK signaling in diverse physiological and pathophysiological states.
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Khoshnood B, Dacklin I, Grabbe C. Urm1: an essential regulator of JNK signaling and oxidative stress in Drosophila melanogaster. Cell Mol Life Sci 2016; 73:1939-54. [PMID: 26715182 PMCID: PMC11108535 DOI: 10.1007/s00018-015-2121-x] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2015] [Revised: 11/28/2015] [Accepted: 12/15/2015] [Indexed: 12/29/2022]
Abstract
Ubiquitin-related modifier 1 (Urm1) is a ubiquitin-like molecule (UBL) with the dual capacity to act both as a sulphur carrier and posttranslational protein modifier. Here we characterize the Drosophila melanogaster homologues of Urm1 (CG33276) and its E1 activating enzyme Uba4 (CG13090), and show that they function together to induce protein urmylation in vivo. Urm1 conjugation to target proteins in general, and to the evolutionary conserved substrate Peroxiredoxin 5 (Prx5) specifically, is dependent on Uba4. A complete loss of Urm1 is lethal in flies, although a small number of adult zygotic Urm1 (n123) mutant escapers can be recovered. These escapers display a decreased general fitness and shortened lifespan, but in contrast to their S. cerevisiae counterparts, they are resistant to oxidative stress. Providing a molecular explanation, we demonstrate that cytoprotective JNK signaling is increased in Urm1 deficient animals. In agreement, molecular and genetic evidence suggest that elevated activity of the JNK downstream target genes Jafrac1 and gstD1 strongly contributes to the tolerance against oxidative stress displayed by Urm1 (n123) null mutants. In conclusion, Urm1 is a UBL that is involved in the regulation of JNK signaling and the response against oxidative stress in the fruit fly.
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Affiliation(s)
- B Khoshnood
- Department of Molecular Biology, Umeå University, Building 6L, 901 87, Umeå, Sweden
| | - I Dacklin
- Department of Molecular Biology, Umeå University, Building 6L, 901 87, Umeå, Sweden
| | - C Grabbe
- Department of Molecular Biology, Umeå University, Building 6L, 901 87, Umeå, Sweden.
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Vernia S, Cavanagh-Kyros J, Barrett T, Tournier C, Davis RJ. Fibroblast Growth Factor 21 Mediates Glycemic Regulation by Hepatic JNK. Cell Rep 2016; 14:2273-80. [PMID: 26947074 PMCID: PMC4794343 DOI: 10.1016/j.celrep.2016.02.026] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 12/16/2015] [Accepted: 02/01/2016] [Indexed: 12/15/2022] Open
Abstract
The cJun NH2-terminal kinase (JNK)-signaling pathway is implicated in metabolic syndrome, including dysregulated blood glucose concentration and insulin resistance. Fibroblast growth factor 21 (FGF21) is a target of the hepatic JNK-signaling pathway and may contribute to the regulation of glycemia. To test the role of FGF21, we established mice with selective ablation of the Fgf21 gene in hepatocytes. FGF21 deficiency in the liver caused marked loss of FGF21 protein circulating in the blood. Moreover, the protective effects of hepatic JNK deficiency to suppress metabolic syndrome in high-fat diet-fed mice were not observed in mice with hepatocyte-specific FGF21 deficiency, including reduced blood glucose concentration and reduced intolerance to glucose and insulin. Furthermore, we show that JNK contributes to the regulation of hepatic FGF21 expression during fasting/feeding cycles. These data demonstrate that the hepatokine FGF21 is a key mediator of JNK-regulated metabolic syndrome.
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Affiliation(s)
- Santiago Vernia
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Julie Cavanagh-Kyros
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA
| | - Tamera Barrett
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA
| | - Cathy Tournier
- Faculty of Life Sciences, Manchester University, Manchester M13 9PL, UK
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Howard Hughes Medical Institute, Worcester, MA 01605, USA.
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Vernia S, Morel C, Madara JC, Cavanagh-Kyros J, Barrett T, Chase K, Kennedy NJ, Jung DY, Kim JK, Aronin N, Flavell RA, Lowell BB, Davis RJ. Excitatory transmission onto AgRP neurons is regulated by cJun NH2-terminal kinase 3 in response to metabolic stress. eLife 2016; 5:e10031. [PMID: 26910012 PMCID: PMC4798947 DOI: 10.7554/elife.10031] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Accepted: 02/22/2016] [Indexed: 11/13/2022] Open
Abstract
The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the response to metabolic stress. Indeed, it is established that the ubiquitously expressed JNK1 and JNK2 isoforms regulate energy expenditure and insulin resistance. However, the role of the neuron-specific isoform JNK3 is unclear. Here we demonstrate that JNK3 deficiency causes hyperphagia selectively in high fat diet (HFD)-fed mice. JNK3 deficiency in neurons that express the leptin receptor LEPRb was sufficient to cause HFD-dependent hyperphagia. Studies of sub-groups of leptin-responsive neurons demonstrated that JNK3 deficiency in AgRP neurons, but not POMC neurons, was sufficient to cause the hyperphagic response. These effects of JNK3 deficiency were associated with enhanced excitatory signaling by AgRP neurons in HFD-fed mice. JNK3 therefore provides a mechanism that contributes to homeostatic regulation of energy balance in response to metabolic stress.
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Affiliation(s)
- Santiago Vernia
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
| | - Caroline Morel
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
| | - Joseph C Madara
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
- Harvard Medical School, Boston, United States
| | - Julie Cavanagh-Kyros
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
- Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
| | - Tamera Barrett
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
- Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
| | - Kathryn Chase
- Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
| | - Norman J Kennedy
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
| | - Dae Young Jung
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
| | - Jason K Kim
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
- Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
| | - Neil Aronin
- Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School, Worcester, United States
| | - Richard A Flavell
- Department of Immunobiology, Yale University School of Medicine, New Haven, United States
- Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
| | - Bradford B Lowell
- Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, United States
- Harvard Medical School, Boston, United States
| | - Roger J Davis
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
- Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, United States
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50
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González-Terán B, Matesanz N, Nikolic I, Verdugo MA, Sreeramkumar V, Hernández-Cosido L, Mora A, Crainiciuc G, Sáiz ML, Bernardo E, Leiva-Vega L, Rodríguez E, Bondía V, Torres JL, Perez-Sieira S, Ortega L, Cuenda A, Sanchez-Madrid F, Nogueiras R, Hidalgo A, Marcos M, Sabio G. p38γ and p38δ reprogram liver metabolism by modulating neutrophil infiltration. EMBO J 2016; 35:536-52. [PMID: 26843485 DOI: 10.15252/embj.201591857] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Accepted: 12/22/2015] [Indexed: 12/29/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major health problem and the main cause of liver disease in Western countries. Although NAFLD is strongly associated with obesity and insulin resistance, its pathogenesis remains poorly understood. The disease begins with an excessive accumulation of triglycerides in the liver, which stimulates an inflammatory response. Alternative p38 mitogen-activated kinases (p38γ and p38δ) have been shown to contribute to inflammation in different diseases. Here we demonstrate that p38δ is elevated in livers of obese patients with NAFLD and that mice lacking p38γ/δ in myeloid cells are resistant to diet-induced fatty liver, hepatic triglyceride accumulation and glucose intolerance. This protective effect is due to defective migration of p38γ/δ-deficient neutrophils to the damaged liver. We further show that neutrophil infiltration in wild-type mice contributes to steatosis development by means of inflammation and liver metabolic changes. Therefore, p38γ and p38δ in myeloid cells provide a potential target for NAFLD therapy.
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Affiliation(s)
| | - Nuria Matesanz
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Ivana Nikolic
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - María Angeles Verdugo
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | - Vinatha Sreeramkumar
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Lourdes Hernández-Cosido
- Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain Department of Surgery, University of Salamanca, Salamanca, Spain
| | - Alfonso Mora
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Georgiana Crainiciuc
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - María Laura Sáiz
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Edgar Bernardo
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Luis Leiva-Vega
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Elena Rodríguez
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Victor Bondía
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Jorge L Torres
- Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Salamanca, Spain Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Sonia Perez-Sieira
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Luis Ortega
- Bariatric Surgery Unit, Department of General Surgery, University Hospital of Salamanca, Salamanca, Spain Department of Surgery, University of Salamanca, Salamanca, Spain
| | - Ana Cuenda
- Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain
| | | | - Rubén Nogueiras
- Department of Physiology, CIMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, Spain CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, Spain
| | - Andrés Hidalgo
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
| | - Miguel Marcos
- Department of Internal Medicine, University Hospital of Salamanca-IBSAL, Salamanca, Spain Department of Medicine, University of Salamanca, Salamanca, Spain
| | - Guadalupe Sabio
- Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain
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