Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

In obesity, there are no effective therapies for parallel immune and metabolic abnormalities, including systemic/tissue insulin-resistance/inflammation, adiposity and hepatic steatosis. Caffeine has anti-inflammation, antihepatic steatosis, and anti-insulin resistance effects. In this study, we evaluated the effects and molecular mechanisms of 6 wk of caffeine treatment (HFD-caf) on immunological and metabolic abnormalities of high-fat diet (HFD)-induced obese rats. Compared with HFD vehicle (HFD-V) rats, in HFD-caf rats the suppressed circulating immune cell inflammatory [TNFα, MCP-1, IL-6, intercellular adhesion molecule 1 (ICAM-1), and nitrite] profiles were accompanied by decreased liver, white adipose tissue (WAT), and muscle macrophages and their intracellular cytokine levels. Metabolically, the increase in metabolic rates reduced lipid accumulation in various tissues, resulting in reduced adiposity, lower fat mass, decreased body weight, amelioration of hepatic steatosis, and improved systemic/muscle insulin resistance. Further mechanistic approaches revealed an upregulation of tissue lipogenic [(SREBP1c, fatty acid synthase, acetyl-CoA carboxylase)/insulin-sensitizing (GLUT4 and p-IRS1)] markers in HFD-caf rats. Significantly, ex vivo experiments revealed that the cytokine release by the cocultured peripheral blood mononuclear cell (monocyte) and WAT (adipocyte), which are known to stimulate macrophage migration and hepatocyte lipogenesis, were lower in HFD-V groups than HFD-caf groups. Caffeine treatment simultaneously ameliorates immune and metabolic pathogenic signals present in tissue to normalize immunolgical and metabolic abnormalities found in HFD-induced obese rats.

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FXR-dependent reduction of hepatic steatosis in a bile salt deficient mouse model

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease ◽

10.1016/j.bbadis.2014.02.004 ◽

2014 ◽

Vol 1842 (5) ◽

pp. 739-746 ◽

Cited By ~ 19

Author(s):

Cindy Kunne ◽

Alexandra Acco ◽

Suzanne Duijst ◽

Dirk R. de Waart ◽

Coen C. Paulusma ◽

...

Keyword(s):

Mouse Model ◽

Bile Salt ◽

Hepatic Steatosis ◽

Deficient Mouse

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Dietary Eriodictyol Alleviates Adiposity, Hepatic Steatosis, Insulin Resistance, and Inflammation in Diet-Induced Obese Mice

International Journal of Molecular Sciences ◽

10.3390/ijms20051227 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1227 ◽

Cited By ~ 10

Author(s):

Eun-Young Kwon ◽

Myung-Sook Choi

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Molecular Mechanisms ◽

Gastric Inhibitory Polypeptide ◽

Normal Diet ◽

Acid Oxidation ◽

Obese Mice ◽

Metabolic Disturbances ◽

Glucagon Like Peptide 1 ◽

Hepatic Fatty Acid Oxidation

The present study aimed to investigate the molecular mechanisms underlying the anti-obesity effect of flavonoid eriodictyol (ED) supplementation in mice fed with a high-fat diet (HFD). C57BL/6N mice were fed with normal diet (ND), HFD (40 kcal% fat), or HFD + 0.005% (w/w) ED for 16 weeks. In HFD-induced obese mice, dietary ED supplementation significantly alleviated dyslipidemia and adiposity by downregulating the expression of lipogenesis-related genes in white adipose tissue (WAT), while enhancing fecal lipid excretion. ED additionally improved hepatic steatosis and decreased the production of pro-inflammatory cytokines by downregulating the expression of hepatic enzymes and the genes involved in lipogenesis and upregulating the expression of hepatic fatty acid oxidation-related enzymes and genes. In addition, ED improved insulin resistance (IR) by suppressing hepatic gluconeogenesis, enhancing glucose utilization, and modulating the production and release of two incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Taken together, the current findings indicated that ED can protect against diet-induced obesity and related metabolic disturbances, including dyslipidemia, inflammation, fatty liver disease, and IR in diet-induced obese mice.

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Deepure Tea Improves High Fat Diet-Induced Insulin Resistance and Nonalcoholic Fatty Liver Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2015/980345 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Jing-Na Deng ◽

Juan Li ◽

Hong-Na Mu ◽

Yu-Ying Liu ◽

Ming-Xia Wang ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Hepatic Steatosis ◽

Fatty Acid Synthesis ◽

High Fat Diet ◽

Molecular Mechanisms ◽

Regulatory Element ◽

Acid Synthesis ◽

High Fat ◽

The Metabolic Syndrome

This study was to explore the protective effects of Deepure tea against insulin resistance and hepatic steatosis and elucidate the potential underlying molecular mechanisms. C57BL/6 mice were fed with a high fat diet (HFD) for 8 weeks to induce the metabolic syndrome. In the Deepure tea group, HFD mice were administrated with Deepure tea at 160 mg/kg/day by gavage for 14 days. The mice in HFD group received water in the same way over the same period. The age-matched C57BL/6 mice fed with standard chow were used as normal control. Compared to the mice in HFD group, mice that received Deepure tea showed significantly reduced plasma insulin and improved insulin sensitivity. Deepure tea increased the expression of insulin receptor substrate 2 (IRS-2), which plays an important role in hepatic insulin signaling pathway. Deepure tea also led to a decrease in hepatic fatty acid synthesis and lipid accumulation, which were mediated by the downregulation of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthesis (FAS), and acetyl-CoA carboxylase (ACC) proteins that are involved in liver lipogenesis. These results suggest that Deepure tea may be effective for protecting against insulin resistance and hepatic steatosis via modulating IRS-2 and downstream signaling SREBP-1c, FAS, and ACC.

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Molecular mechanisms involved in hepatic steatosis and insulin resistance

Journal of Diabetes Investigation ◽

10.1111/j.2040-1124.2011.00111.x ◽

2011 ◽

Vol 2 (3) ◽

pp. 170-175 ◽

Cited By ~ 34

Author(s):

Takashi Matsuzaka ◽

Hitoshi Shimano

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

Molecular Mechanisms

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Mitochondrial stress protein HSP60 regulates ER stress-induced hepatic lipogenesis

Journal of Molecular Endocrinology ◽

10.1530/jme-19-0207 ◽

2020 ◽

Vol 64 (2) ◽

pp. 67-75 ◽

Cited By ~ 4

Author(s):

Ting Xiao ◽

Xiuci Liang ◽

Hailan Liu ◽

Feng Zhang ◽

Wen Meng ◽

...

Keyword(s):

Insulin Resistance ◽

Er Stress ◽

Mitochondrial Dysfunction ◽

Hepatic Steatosis ◽

Molecular Mechanisms ◽

Stress Protein ◽

Hepatic Lipogenesis ◽

Mitochondrial Stress ◽

Hsp60 Expression ◽

Mouse Hepatocytes

Endoplasmic reticulum (ER) stress and mitochondrial dysfunction are associated with hepatic steatosis and insulin resistance. Molecular mechanisms underlying ER stress and/or mitochondrial dysfunction that cause metabolic disorders and hepatic steatosis remain to be fully understood. Here, we found that a high fat diet (HFD) or chemically induced ER stress can stimulate mitochondrial stress protein HSP60 expression, impair mitochondrial respiration, and decrease mitochondrial membrane potential in mouse hepatocytes. HSP60 overexpression promotes ER stress and hepatic lipogenic protein expression and impairs insulin signaling in mouse hepatocytes. Mechanistically, HSP60 regulates ER stress-induced hepatic lipogenesis via the mTORC1-SREBP1 signaling pathway. These results suggest that HSP60 is an important ER and mitochondrial stress cross-talking protein and may control ER stress-induced hepatic lipogenesis and insulin resistance.

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Abstract 12189: Molecular Mechanisms Underlying Fasting Modulated Liver Insulin Sensitivity and Metabolism in Male Lipodystrophic Bscl2/Seipin-Deficient Mice

Circulation ◽

10.1161/circ.130.suppl_2.12189 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Weiqin Chen ◽

Hongyi Zhou ◽

Pradip Saha ◽

Luge Li ◽

Lawrence Chan

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Insulin Signaling ◽

Molecular Mechanisms ◽

De Novo ◽

Liver Lipid ◽

De Novo Lipogenesis ◽

Hepatic Insulin Signaling ◽

A Cell

Bscl2–/– mice recapitulate many of the major metabolic manifestations in Berardinelli-Seip Congenital Lipodystrophy type 2 (BSCL2) individuals, including lipodystrophy, hepatomegly, hepatic steatosis and insulin resistance. The mechanisms that underlie hepatic steatosis and insulin resistance in Bscl2–/– mice are poorly understood. To address this issue, we performed hyperinsulinemic-euglycemic clamp on Bscl2–/– and wild-type mice after an overnight (16-h) fast, and found that Bscl2–/– actually displayed increased hepatic insulin sensitivity. Interestingly, liver in Bscl2–/– mice after a short term (4-h) fast had impaired acute insulin signaling, a defect that disappeared after a 16-h fast. Notably, fasting dependent hepatic insulin signaling in Bscl2–/– mice was not associated with liver diacylglyceride and ceramide contents, but could be attributable in part to the expression of hepatic insulin signaling receptor and substrates. Meanwhile, increased de novo lipogenesis and decreased β-oxidation led to severe hepatic steatosis in fed or short fasted Bscl2–/– mice while liver lipid accumulation and metabolism in Bscl2–/– mice was markedly impacted by prolonged fasting. Furthermore, mice with liver-specific inactivation of Bscl2 manifested no hepatic steatosis even under high fat diet, suggesting Bscl2 does not play a cell autonomous role in regulating liver lipid homeostasis. Overall, our results offered new insights into the metabolic adaptations of liver in response to fasting and uncovered a novel fasting-dependent regulation of hepatic insulin signaling in a mouse model of human BSCL2.

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