Chlorogenic Acid Improves High Fat Diet-Induced Hepatic Steatosis and Insulin Resistance in Mice

Supplementation of black rice anthocyanins (BRAN) alleviated high fat diet-induced obesity, insulin resistance and hepatic steatosis by improvement of lipid metabolism and modification of the gut microbiota.

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Effect of the Hepatocyte-Specific Deletion of SND1 in Mice on the Liver Insulin Resistance and Acute Liver Failure

10.21203/rs.3.rs-48660/v1 ◽

2020 ◽

Author(s):

Chunyan Zhao ◽

Xiaoteng Cui ◽

Baoxin Qian ◽

Nan Zhang ◽

Lingbiao Xin ◽

...

Keyword(s):

Insulin Resistance ◽

Liver Failure ◽

Acute Liver Failure ◽

Cholesterol Level ◽

Hepatic Steatosis ◽

Glucose Homeostasis ◽

Hepatic Failure ◽

High Fat Diet ◽

High Fat ◽

Specific Deletion

Abstract Background: The multifunctional protein SND1 was reported to be involved in a variety of biological processes, such as cell cycle, proliferation or lipogenesis. We previously proposed that global-expressed SND1 in vivo is likely to be a key regulator for ameliorating HFD-induced hepatic steatosis and systemic insulin resistance. Herein, we are very interested in investigating further whether the hepatocyte-specific deletion of SND1 affects the insulin resistance or acute liver failure (ALF) of mice.Methods: By using Cre-loxP technique, we constructed conditional knockout (LKO) mice of SND1 driven by albumin in hepatocytes and analyze the changes of glucose homeostasis, cholesterol level, hepatic steatosis and hepatic failure under the treatment of high-fat diet (HFD) or upon the simulation of Lipopolysaccharide/galactosamine (LPS/GalN).Results: No difference for the body weight, liver weight, and cholesterol level was detected. Furthermore, we did not observe the alteration of glucose homeostasis in SND1 hepatic knockout mice on either chow diet or high-fat diet. Besides, hepatocyte-specific deletion of SND1 failed to influence the hepatic failure of mice induced by LPS/GalN.Conclusions: These findings suggest that hepatic SND1, independently, is insufficient for changing glucose homeostasis, hepatic lipid accumulation and inflammation. The synergistic action of multiple organs may contribute to the role of SND1 in insulin sensitivity or inflammatory response.

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WDR76 mediates obesity and hepatic steatosis via HRas destabilization

Scientific Reports ◽

10.1038/s41598-019-56211-6 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Jong-Chan Park ◽

Woo-Jeong Jeong ◽

Seol Hwa Seo ◽

Kang-Yell Choi

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Metabolic Regulation ◽

Adipocyte Differentiation ◽

High Fat ◽

Active Protein ◽

Wd40 Repeat ◽

Ras Protein ◽

Protein Kinase Signaling

AbstractRas/MAPK (mitogen active protein kinase) signaling plays contradictory roles in adipocyte differentiation and is tightly regulated during adipogenesis. However, mechanisms regulating adipocyte differentiation involving Ras protein stability regulation are unknown. Here, we show that WD40 repeat protein 76 (WDR76), a novel Ras regulating E3 linker protein, controls 3T3-L1 adipocyte differentiation through HRas stability regulation. The roles of WDR76 in obesity and metabolic regulation were characterized using a high-fat diet (HFD)-induced obesity model using Wdr76−/− mice and liver-specific Wdr76 transgenic mice (Wdr76Li−TG). Wdr76−/− mice are resistant to HFD-induced obesity, insulin resistance and hyperlipidemia with an increment of HRas levels. In contrast, Wdr76Li-TG mice showed increased HFD-induced obesity, insulin resistance with reduced HRas levels. Our findings suggest that WDR76 controls HFD-induced obesity and hepatic steatosis via HRas destabilization. These data provide insights into the links between WDR76, HRas, and obesity.

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Disrupting phosphatase SHP2 in macrophages protects mice from high-fat diet-induced hepatic steatosis and insulin resistance by elevating IL-18 levels

Journal of Biological Chemistry ◽

10.1074/jbc.ra119.011840 ◽

2020 ◽

Vol 295 (31) ◽

pp. 10842-10856 ◽

Cited By ~ 1

Author(s):

Wen Liu ◽

Ye Yin ◽

Meijing Wang ◽

Ting Fan ◽

Yuyu Zhu ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Metabolic Disorders ◽

Metabolic Diseases ◽

Low Grade ◽

High Fat ◽

Caspase 1

Chronic low-grade inflammation plays an important role in the pathogenesis of type 2 diabetes. Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) has been reported to play diverse roles in different tissues during the development of metabolic disorders. We previously reported that SHP2 inhibition in macrophages results in increased cytokine production. Here, we investigated the association between SHP2 inhibition in macrophages and the development of metabolic diseases. Unexpectedly, we found that mice with a conditional SHP2 knockout in macrophages (cSHP2-KO) have ameliorated metabolic disorders. cSHP2-KO mice fed a high-fat diet (HFD) gained less body weight and exhibited decreased hepatic steatosis, as well as improved glucose intolerance and insulin sensitivity, compared with HFD-fed WT littermates. Further experiments revealed that SHP2 deficiency leads to hyperactivation of caspase-1 and subsequent elevation of interleukin 18 (IL-18) levels, both in vivo and in vitro. Of note, IL-18 neutralization and caspase-1 knockout reversed the amelioration of hepatic steatosis and insulin resistance observed in the cSHP2-KO mice. Administration of two specific SHP2 inhibitors, SHP099 and Phps1, improved HFD-induced hepatic steatosis and insulin resistance. Our findings provide detailed insights into the role of macrophagic SHP2 in metabolic disorders. We conclude that pharmacological inhibition of SHP2 may represent a therapeutic strategy for the management of type 2 diabetes.

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Dehydroabietic acid alleviates high fat diet-induced insulin resistance and hepatic steatosis through dual activation of PPAR-γ and PPAR-α

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2020.110155 ◽

2020 ◽

Vol 127 ◽

pp. 110155 ◽

Cited By ~ 1

Author(s):

Zhishen Xie ◽

Gai Gao ◽

Hui Wang ◽

Erwen Li ◽

Yong Yuan ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Dehydroabietic Acid ◽

High Fat ◽

Ppar Γ ◽

Dual Activation

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GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice

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

10.1016/j.bbadis.2018.07.012 ◽

2018 ◽

Vol 1864 (10) ◽

pp. 3257-3267 ◽

Cited By ~ 8

Author(s):

Shasha Liu ◽

Juntao Yuan ◽

Wenhui Yue ◽

Yanwei Bi ◽

Xiyue Shen ◽

...

Keyword(s):

Insulin Resistance ◽

Hepatic Steatosis ◽

High Fat Diet ◽

High Fat

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Peripancreatic adipose tissue protects against high-fat-diet-induced hepatic steatosis and insulin resistance in mice

International Journal of Obesity ◽

10.1038/s41366-020-00657-6 ◽

2020 ◽

Vol 44 (11) ◽

pp. 2323-2334

Author(s):

Belén Chanclón ◽

Yanling Wu ◽

Milica Vujičić ◽

Marco Bauzá-Thorbrügge ◽

Elin Banke ◽

...

Keyword(s):

Gene Expression ◽

Insulin Resistance ◽

Adipose Tissue ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Obese Mice ◽

High Fat ◽

Insulin Levels ◽

Fat Depots ◽

Fat Depot

Abstract Background/objectives Visceral adiposity is associated with increased diabetes risk, while expansion of subcutaneous adipose tissue may be protective. However, the visceral compartment contains different fat depots. Peripancreatic adipose tissue (PAT) is an understudied visceral fat depot. Here, we aimed to define PAT functionality in lean and high-fat-diet (HFD)-induced obese mice. Subjects/methods Four adipose tissue depots (inguinal, mesenteric, gonadal, and peripancreatic adipose tissue) from chow- and HFD-fed male mice were compared with respect to adipocyte size (n = 4–5/group), cellular composition (FACS analysis, n = 5–6/group), lipogenesis and lipolysis (n = 3/group), and gene expression (n = 6–10/group). Radioactive tracers were used to compare lipid and glucose metabolism between these four fat depots in vivo (n = 5–11/group). To determine the role of PAT in obesity-associated metabolic disturbances, PAT was surgically removed prior to challenging the mice with HFD. PAT-ectomized mice were compared to sham controls with respect to glucose tolerance, basal and glucose-stimulated insulin levels, hepatic and pancreatic steatosis, and gene expression (n = 8–10/group). Results We found that PAT is a tiny fat depot (~0.2% of the total fat mass) containing relatively small adipocytes and many “non-adipocytes” such as leukocytes and fibroblasts. PAT was distinguished from the other fat depots by increased glucose uptake and increased fatty acid oxidation in both lean and obese mice. Moreover, PAT was the only fat depot where the tissue weight correlated positively with liver weight in obese mice (R = 0.65; p = 0.009). Surgical removal of PAT followed by 16-week HFD feeding was associated with aggravated hepatic steatosis (p = 0.008) and higher basal (p < 0.05) and glucose-stimulated insulin levels (p < 0.01). PAT removal also led to enlarged pancreatic islets and increased pancreatic expression of markers of glucose-stimulated insulin secretion and islet development (p < 0.05). Conclusions PAT is a small metabolically highly active fat depot that plays a previously unrecognized role in the pathogenesis of hepatic steatosis and insulin resistance in advanced obesity.

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