Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet–Induced Obesity and Insulin Resistance by Inhibiting Lipolysis

Kuang, Jiangying; Zhang, Yuwei; Liu, Qinhui; Shen, Jing; Pu, Shiyun; Cheng, Shihai; Chen, Lei; Li, Hong; Wu, Tong; Li, Rui; Li, Yanping; Zou, Min; Zhang, Zhiyong; Jiang, Wei; Gao, Xu; Qu, Aijuan; Xie, Wen; He, Jinhan

doi:10.2337/db16-1225

Cited by 101 publications

(109 citation statements)

References 43 publications

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“…Sirt6 deficiency results in mice metabolic defects, and Sirt6 transgenic mice accumulate less fat, cholesterol, and triglycerides after HFD treatment . A previous study has demonstrated that Sirt6 expression is reduced in obese patients, and fat‐specific Sirt6 deficiency increased inflammation and insulin resistance in HFD‐treated mice . In this study, we demonstrated that USP10 interacts with Sirt6 and inhibits its ubiquitination and degradation.…”

Section: Discussionsupporting

confidence: 56%

“…(29) A previous study has demonstrated that Sirt6 expression is reduced in obese patients, and fat-specific Sirt6 deficiency increased inflammation and insulin resistance in HFD-treated mice. (30,31) In this study, we demonstrated that USP10 interacts with Sirt6 and inhibits its ubiquitination and degradation. Then, we established Sirt6-KO, Sirt6-TG, USP10-TG/Sirt6-KO, and USP10-KO/Sirt6-TG mice and performed HFD treatment.…”

Section: Discussionmentioning

confidence: 59%

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Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Luo

Qin²,

Zhu

et al. 2018

Hepatology

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Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 59%

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Luo

Qin²,

Zhu

et al. 2018

Hepatology

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“…Therefore, insulin resistance in skeletal muscle plays a vital role in the onset of diabetes [Ferrannini et al, 1985]. Numerous studies including clinical researches and animal experiments illustrated that adipocyte hypertrophy rather than its hyperplasia led to insulin resistance [Kuang et al, 2017]. As for adipose tissue, it plays an important role not only in glucose metabolism but also in endocrine.…”

Section: Discussionmentioning

confidence: 99%

“…As an endocrine organ, adipose tissue can secrete a type of cytokines related to inflammatory response, insulin resistance and cardiovascular diseases, such as leptin, adiponectin, resistin, TNFa, and visfatin [Antuna-Puente et al, 2008]. Numerous studies including clinical researches and animal experiments illustrated that adipocyte hypertrophy rather than its hyperplasia led to insulin resistance [Kuang et al, 2017]. In our study, with StAR overexpression, the surface area of adipocytes and intramuscular lipid accumulation were remarkably decreased, as well as the enhanced blood glucose and insulin levels by HFD were significantly reduced.…”

Section: Discussionmentioning

confidence: 99%

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

Qiu

Sui

Cao

et al. 2017

J of Cellular Biochemistry

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Steroidogenic acute regulatory protein (StAR), a mitochondrial cholesterol delivery protein, plays a beneficial role in hyperlipidemia, NAFLD, and endothelial inflammation. Elevated circulating fatty acids and low grade inflammation are known as key risk factors of insulin resistance and type 2 diabetes. In the present study, C57BL/6J mice were fed with HFD and infected with recombinant adenovirus expressing StAR by tail-vein injection. Intraperitoneal glucose/insulin tolerance test was performed to assess the insulin sensitivity. Morphological analysis and intramuscular lipid determination were used to illustrate the adipose hypertrophy and ectopic fat accumulation in skeletal muscle. The levels of inflammatory factor and nitric oxide were determined by ELISA and classic Griess reagent methods, respectively. The fatty acids composition was analysis using gas chromatography-mass spectrometry (GC-MS). The expression of genes associated with inflammation and insulin resistance were determined by Western blotting and qPCR to elucidate the underlying mechanism. We demonstrated that StAR overexpression ameliorated insulin resistance and systemic inflammatory response with the reduction of adipose hypertrophy and intramuscular lipid in HFD-fed mice. In addition, StAR overexpression increased serum unsaturated fatty acids (UFAs) and PPARγ expression in muscle and adipose tissue of obese mice. In conclusion, StAR may activate PPARγ by increasing UFAs, which leads to a protective role in systemic inflammation and insulin resistance in obese mice. J. Cell. Biochem. 118: 3932-3942, 2017. © 2017 Wiley Periodicals, Inc.

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“…Sirt6 controls metabolic homeostasis and is regulated by nutrient availability (26,27). To investigate whether Sirt6 plays a role in ketogenesis, we measured the hepatic Sirt6 expression in mouse models of ketogenesis.…”

Section: Sirt6 Is Regulated By Ketogenesismentioning

confidence: 99%

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

Chen

Liu

Tang

et al. 2019

Journal of Biological Chemistry

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Sirt6 is an NADH (NAD ؉ )-dependent deacetylase with a critical role in hepatic lipid metabolism. Ketogenesis is controlled by a signaling network of hepatic lipid metabolism. However, how Sirt6 functions in ketogenesis remains unclear. Here, we demonstrated that Sirt6 functions as a mediator of ketogenesis in response to a fasting and ketogenic diet (KD). The KD-fed hepatocyte-specific Sirt6 deficiency (HKO) mice exhibited impaired ketogenesis, which was due to enhanced Fsp27 (fatspecific induction of protein 27), a protein known to regulate lipid metabolism. In contrast, overexpression of Sirt6 in mouse primary hepatocytes promoted ketogenesis. Mechanistically, Sirt6 repressed Fsp27␤ expression by interacting with Crebh (cAMP response element-binding protein H) and preventing its recruitment to the Fsp27␤ gene promoter. The KD-fed HKO mice also showed exacerbated hepatic steatosis and inflammation. Finally, Fsp27 silencing rescued hypoketonemia and other metabolic phenotypes in KD-fed HKO mice. Our data suggest that the Sirt6 -Crebh-Fsp27 axis is pivotal for hepatic lipid metabolism and inflammation. Sirt6 may be a pharmacological target to remedy metabolic diseases. De novo lipogenesis analysis using stable isotopes tracerNewly isolated mouse primary hepatocytes were seeded in 10-cm culture dishes and cultured in low-glucose Dulbecco's Sirt6 regulates ketogenesis

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Fat-Specific Sirt6 Ablation Sensitizes Mice to High-Fat Diet–Induced Obesity and Insulin Resistance by Inhibiting Lipolysis

Cited by 101 publications

References 43 publications

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Ubiquitin‐Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6

Steroidogenic Acute Regulatory Protein (StAR) Overexpression Reduces Inflammation and Insulin Resistance in Obese Mice

Hepatocyte-specific Sirt6 deficiency impairs ketogenesis

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