Hepatocyte growth factor alleviates hepatic insulin resistance and lipid accumulation in high-fat diet-fed mice

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance and metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism is not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed decreased blood glucose and serum insulin and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which are induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the addition of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate-induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element-binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes.

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Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance

Journal of Ethnopharmacology ◽

10.1016/j.jep.2020.113576 ◽

2020 ◽

pp. 113576

Author(s):

Prabhakar Yellanur Konda ◽

Vidyasagar Chennupati ◽

Sreenivasulu Dasari ◽

Nishesh Sharma ◽

Muthukumaran Muthulingam ◽

...

Keyword(s):

Insulin Resistance ◽

Aqueous Extract ◽

Insulin Signaling ◽

High Fat Diet ◽

Hepatic Insulin Resistance ◽

High Fat

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PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1804379115 ◽

2018 ◽

Vol 115 (38) ◽

pp. E8996-E9005 ◽

Cited By ~ 20

Author(s):

Brandon M. Gassaway ◽

Max C. Petersen ◽

Yulia V. Surovtseva ◽

Karl W. Barber ◽

Joshua B. Sheetz ◽

...

Keyword(s):

Insulin Resistance ◽

Protein Phosphorylation ◽

Cross Talk ◽

Insulin Signaling ◽

High Fat Diet ◽

Large Scale ◽

Kinase Assay ◽

Hepatic Insulin Resistance ◽

High Fat ◽

The Impact

Insulin resistance drives the development of type 2 diabetes (T2D). In liver, diacylglycerol (DAG) is a key mediator of lipid-induced insulin resistance. DAG activates protein kinase C ε (PKCε), which phosphorylates and inhibits the insulin receptor. In rats, a 3-day high-fat diet produces hepatic insulin resistance through this mechanism, and knockdown of hepatic PKCε protects against high-fat diet-induced hepatic insulin resistance. Here, we employed a systems-level approach to uncover additional signaling pathways involved in high-fat diet-induced hepatic insulin resistance. We used quantitative phosphoproteomics to map global in vivo changes in hepatic protein phosphorylation in chow-fed, high-fat–fed, and high-fat–fed with PKCε knockdown rats to distinguish the impact of lipid- and PKCε-induced protein phosphorylation. This was followed by a functional siRNA-based screen to determine which dynamically regulated phosphoproteins may be involved in canonical insulin signaling. Direct PKCε substrates were identified by motif analysis of phosphoproteomics data and validated using a large-scale in vitro kinase assay. These substrates included the p70S6K substrates RPS6 and IRS1, which suggested cross talk between PKCε and p70S6K in high-fat diet-induced hepatic insulin resistance. These results identify an expanded set of proteins through which PKCε may drive high-fat diet-induced hepatic insulin resistance that may direct new therapeutic approaches for T2D.

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SO023HEPATOCYTE GROWTH FACTOR (HGF) PRECLUDE HIGH-FAT DIET-INDUCED OBESITY AND IMPROVED INSULIN RESISTANCE IN MICE

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa139.so023 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Jun Muratsu ◽

Yoshiaki Taniyama ◽

Fumihiro Sanada ◽

Atsuyuki Morishima ◽

Katsuhiko Sakaguchi ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Growth Factor ◽

Inflammatory Mediators ◽

High Fat Diet ◽

Neutralizing Antibody ◽

Mrna Levels ◽

Wild Type ◽

High Fat

Abstract Background and Aims Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. Method In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4-5 times higher serum HGF levels than wild-type mice were used. We chose cardiac specific HGF overexpression, as other strain of HGF transgenic mice such as liver and kidney specific HGF overexpression mice develop cancer and cystic diseases, which are rare in the heart. In the present study, using HGF-Tg mice and anti-HGF neutralizing antibody (HGF-Ab), we explored the role of HGF in obese and insulin resistance induced by high fat diet (HFD) for 14 weeks (200 or 400ug/week). Results With normal chow diet (ND), there were no significant changes in body weight between WT and HGF-Tg mice. While body weight in wild-type mice fed with HFD for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. Insulin resistance in obesity arises from the combination of altered functions of insulin target cells (e.g., liver, skeletal muscle, and adipose tissue) and the accumulation of macrophages that secrete pro-inflammatory mediators in adipose tissue. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. In the gWAT, the mRNA levels of the mature macrophage marker F4/80, the chemoattractants, MCP-1 and CXCL2, and the inflammatory cytokines, such as TNF-α and iNOS, were significantly increased in WT mice fed with HFD. However, these levels were markedly reduced in HGF-Tg mice fed with HFD. Additionally, activation of Akt by insulin administration was significantly reduced in the gWAT SM, and liver by HFD; however, this activation was restored in HGF-Tg mice. Moreover, insulin-induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition. Importantly, HFD significantly increased the level of HGF mRNA by approximately 2 fold in gWAT, SM, and liver without changing cMet expression. All together, these data indicate that the HGF as one of the systemic gWAT, SM, and liver-derived growth factor plays a role in compensatory mechanism against insulin-resistance through the at least anti-inflammatory effect in adipose tissue. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. Conclusion HGF suppresses inflammation in adipose tissue induced by a high-fat diet, and as a result improves systemic insulin resistance. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

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Emodin ameliorates high-fat-diet induced insulin resistance in rats by reducing lipid accumulation in skeletal muscle

European Journal of Pharmacology ◽

10.1016/j.ejphar.2016.03.049 ◽

2016 ◽

Vol 780 ◽

pp. 194-201 ◽

Cited By ~ 7

Author(s):

Yanni Cao ◽

Shufang Chang ◽

Jie Dong ◽

Shenyin Zhu ◽

Xiaoying Zheng ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat

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Kupffer cell activation is a causal factor for hepatic insulin resistance

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00391.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. G107-G116 ◽

Cited By ~ 138

Author(s):

Nicolas Lanthier ◽

Olivier Molendi-Coste ◽

Yves Horsmans ◽

Nico van Rooijen ◽

Patrice D. Cani ◽

...

Keyword(s):

Insulin Resistance ◽

Kupffer Cell ◽

High Fat Diet ◽

Cell Activation ◽

Hepatic Insulin Resistance ◽

High Fat ◽

Short Term ◽

Adipose Tissue Macrophages ◽

Diet Model

Recruited adipose tissue macrophages contribute to chronic and low-grade inflammation causing insulin resistance in obesity. Similarly, we hypothesized here that Kupffer cells, the hepatic resident macrophages, play a pathogenic role in hepatic insulin resistance induced by a high-fat diet. Mice were fed a normal diet or high-fat diet for 3 days. Kupffer cell activation was evaluated by immunohistochemistry and quantitative RT-PCR. Insulin sensitivity was assessed in vivo by hyperinsulinemic-euglycemic clamp and insulin-activated signaling was investigated by Western blot. Liposome-encapsulated clodronate was injected intravenously to deplete macrophages prior to a short-term exposure to high-fat diet. Here, we characterized a short-term high-fat diet model in mice and demonstrated early hepatic insulin resistance and steatosis concurrent with Kupffer cell activation. We demonstrated that selective Kupffer cell depletion obtained by intravenous clodronate, without affecting adipose tissue macrophages, was sufficient to enhance insulin-dependent insulin signaling and significantly improve hepatic insulin sensitivity in vivo in this short-term high-fat diet model. Our study clearly shows that hepatic macrophage response participates to the onset of high-fat diet-induced hepatic insulin resistance and may therefore represent an attractive target for prevention and treatment of diet- and obesity-induced insulin resistance.

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Mitochondrial-Targeted Catalase Protects Against High-Fat Diet–Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation

Diabetes ◽

10.2337/db16-1334 ◽

2017 ◽

Vol 66 (8) ◽

pp. 2072-2081 ◽

Cited By ~ 22

Author(s):

Hui-Young Lee ◽

Jae Sung Lee ◽

Tiago Alves ◽

Warren Ladiges ◽

Peter S. Rabinovitch ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat ◽

Muscle Insulin Resistance ◽

Intramuscular Lipid

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Impaired Insulin Resistance in IF1-Deficient Mice Subjected to a High-Fat Diet with Reduced-Fat Mass and Skeletal Muscle Lipid Accumulation

Diabetes ◽

10.2337/db18-1748-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1748-P ◽

Cited By ~ 1

Author(s):

FENGYUAN HUANG ◽

KEVIN YANG ◽

KAMALAMMA SAJA ◽

YICHENG HUANG ◽

QINGQIANG LONG ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Lipid Accumulation ◽

High Fat Diet ◽

High Fat ◽

Muscle Lipid ◽

Reduced Fat ◽

Impaired Insulin ◽

Skeletal Muscle Lipid ◽

Deficient Mice

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Adipose Triglyceride Lipase-Null Mice Are Resistant to High-Fat Diet–Induced Insulin Resistance Despite Reduced Energy Expenditure and Ectopic Lipid Accumulation

Endocrinology ◽

10.1210/en.2010-0661 ◽

2011 ◽

Vol 152 (1) ◽

pp. 48-58 ◽

Cited By ~ 74

Author(s):

Andrew J. Hoy ◽

Clinton R. Bruce ◽

Sarah M. Turpin ◽

Alexander J. Morris ◽

Mark A. Febbraio ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acids ◽

Insulin Sensitivity ◽

Energy Expenditure ◽

Glucose Tolerance ◽

Lipid Accumulation ◽

High Fat Diet ◽

Adipose Triglyceride Lipase ◽

Wild Type ◽

High Fat

Abstract Adipose triglyceride lipase (ATGL) null (−/−) mice store vast amounts of triacylglycerol in key glucoregulatory tissues yet exhibit enhanced insulin sensitivity and glucose tolerance. The mechanisms underpinning these divergent observations are unknown but may relate to the reduced availability of circulating fatty acids. The aim of this study was to determine whether the enhancements in insulin stimulated glucose metabolism in ATGL−/− mice persist when challenged with a high-fat diet. ATGL−/− mice fed a low-fat diet exhibit improved whole-body insulin sensitivity and glucose tolerance compared with wild-type mice. Wild-type mice became hyperlipidemic and insulin-resistant when challenged with a high-fat diet (HFD, 60% fat) for 4 wk. ATGL−/− mice fed a HFD had elevated circulating fatty acids but had reduced fasting glycemia compared to pre–high-fat diet levels and were refractory to glucose intolerance and insulin resistance. This protection from high-fat diet–induced metabolic perturbations was associated with a preference for fatty acid utilization but reduced energy expenditure and no change in markers of mitochondrial capacity or density. The protection from high-fat diet–induced insulin resistance in ATGL−/− mice was due to increased cardiac and liver insulin-stimulated glucose clearance despite increased lipid content in these tissues. Additionally, there was no difference in skeletal muscle insulin-stimulated glucose disposal, but there was a reduction observed in brown adipose tissue. Overall, these results show that ATGL−/− mice are protected from HFD-induced insulin resistance and reveal a tissue specific disparity between lipid accumulation and insulin sensitivity.

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