Role of Hepatic Glucocorticoid Receptor in Metabolism in Models of 5αR1 Deficiency in Male Mice

Abstract Inhibition of 5α-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed using a liver-selective glucocorticoid receptor (GR) antagonist, A-348441. Mice lacking 5α-reductase 1 (5αR1-KO) and their littermate controls were studied during consumption of a high-fat diet, with or without A-348441(120 mg/kg/d). Male C57BL/6 mice (age, 12 weeks) receiving dutasteride (1.8 mg/kg/d)) or vehicle with consumption of a high-fat diet, with or without A-348441, were also studied. In the 5αR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance but not more than that of the controls. Liver steatosis was not affected by hepatic GR antagonism in either 5αR1KO mice or littermate controls. In a second model of 5α-reductase inhibition using dutasteride and hepatic GR antagonism with A-348441 attenuated the excess weight gain resulting from dutasteride (mean ± SEM, 7.03 ± 0.5 vs 2.13 ± 0.4 g; dutasteride vs dutasteride plus A-348441; P < 0.05) and normalized the associated hyperinsulinemia after glucose challenge (area under the curve, 235.9 ± 17 vs 329.3 ± 16 vs 198.4 ± 25 ng/mL/min; high fat vs high fat plus dutasteride vs high fat plus dutasteride plus A-348441, respectively; P < 0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis. Thus, overall hepatic GR antagonism improved the insulin resistance but not the steatosis induced by a high-fat diet. Moreover, it attenuated the excessive insulin resistance caused by pharmacological inhibition of 5α-reductases but not genetic disruption of 5αR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial.

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4-Hydroxyisoleucine Alleviates Macrophage-Related Chronic Inflammation and Metabolic Syndrome in Mice Fed a High-Fat Diet

Frontiers in Pharmacology ◽

10.3389/fphar.2020.606514 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jiali Yang ◽

Yunhui Ran ◽

Yonghui Yang ◽

Shuyi Song ◽

Yahong Wu ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Chronic Inflammation ◽

Immune Cells ◽

High Fat Diet ◽

Liver Steatosis ◽

High Fat ◽

Protein Amino Acid

In obesity, macrophages and other immune cells accumulate in organs affected by insulin, leading to chronic inflammation and insulin resistance. 4-Hydroxyisoleucine (4-HIL) is a non-protein amino acid found in fenugreek seeds. 4-HIL enhances insulin sensitivity, but its mechanism is still unclear. In this study, 4-HIL intervention reduced weight gain, liver steatosis, and dyslipidemia; moreover, it increased systemic insulin sensitivity and improved insulin resistance in mice. Importantly, after administration, the accumulation of M1 like CD11c+ macrophages and inflammation in the liver and adipose tissue were reduced in the mice. 4-HIL also reduced the proportion of CD11c+ macrophages among bone marrow-derived macrophages, which were induced in vitro. These observations demonstrate a new role of 4-HIL in insulin resistance in hepatocytes and adipocytes. 4-HIL inhibits obesity-related insulin resistance by reducing inflammation and regulating the state of M1/M2 macrophages.

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Altered bone metabolism after high fat diet and exercise: role of Wnt signaling and insulin resistance

Bone Abstracts ◽

10.1530/boneabs.5.ni5 ◽

2016 ◽

Author(s):

Ann-Kristin Picke ◽

Lykke Sylow ◽

Lisbeth L V Moller ◽

Rasmus Kjobsted ◽

Erik Richter ◽

...

Keyword(s):

Insulin Resistance ◽

Wnt Signaling ◽

Bone Metabolism ◽

High Fat Diet ◽

High Fat ◽

Diet And Exercise

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Black rice anthocyanins alleviate hyperlipidemia, liver steatosis and insulin resistance by regulating lipid metabolism and gut microbiota in obese mice

Food & Function ◽

10.1039/d1fo01394g ◽

2021 ◽

Author(s):

Haizhao Song ◽

Xinchun Shen ◽

Yang Zhou ◽

Xiaodong Zheng

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Gut Microbiota ◽

Hepatic Steatosis ◽

High Fat Diet ◽

Liver Steatosis ◽

Obese Mice ◽

Black Rice ◽

High Fat ◽

Diet Induced Obesity

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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CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00215.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. E973-E983 ◽

Cited By ~ 3

Author(s):

Annie Hasib ◽

Chandani K. Hennayake ◽

Deanna P. Bracy ◽

Aimée R. Bugler-Lamb ◽

Louise Lantier ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

High Fat Diet ◽

Critical Role ◽

Chow Diet ◽

Wild Type ◽

High Fat ◽

Insulin Resistant ◽

Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

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Angiopoietin-like protein 4 improves glucose tolerance and insulin resistance but induces liver steatosis in high-fat-diet mice

Molecular Medicine Reports ◽

10.3892/mmr.2016.5637 ◽

2016 ◽

Vol 14 (4) ◽

pp. 3293-3300 ◽

Cited By ~ 20

Author(s):

Yi Wang ◽

Li-Ming Liu ◽

Li Wei ◽

Wei-Wei Ye ◽

Xiang-Ying Meng ◽

...

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

High Fat Diet ◽

Liver Steatosis ◽

High Fat

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Role of Supplementary Selenium on the Induction of Insulin Resistance and Oxidative Stress in NSY Mice Fed a High Fat Diet

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b17-00622 ◽

2018 ◽

Vol 41 (1) ◽

pp. 92-98 ◽

Cited By ~ 4

Author(s):

Koichi Murano ◽

Hirofumi Ogino ◽

Tomofumi Okuno ◽

Tomohiro Arakawa ◽

Hitoshi Ueno

Keyword(s):

Oxidative Stress ◽

Insulin Resistance ◽

High Fat Diet ◽

High Fat ◽

And Oxidative Stress

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Tu1921 THE INTERPLAY BETWEEN GUT MICROBIOTA AND HIGH-FAT-DIET-INDUCED INSULIN RESISTANCE AND SUBSEQUENT DEVELOPMENT OF OBESITY: POTENTIAL ROLE OF FKBP5.

Gastroenterology ◽

10.1016/s0016-5085(20)33708-2 ◽

2020 ◽

Vol 158 (6) ◽

pp. S-1220

Author(s):

Yu-Jen Liao ◽

Luen-Kui Chen ◽

Chi-Chang Juan ◽

Li-Ling Wu

Keyword(s):

Insulin Resistance ◽

Gut Microbiota ◽

High Fat Diet ◽

Potential Role ◽

Subsequent Development ◽

High Fat

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The Effects of Gymnema sylvestre in High-Fat Diet-Induced Metabolic Disorders

The American Journal of Chinese Medicine ◽

10.1142/s0192415x17500434 ◽

2017 ◽

Vol 45 (04) ◽

pp. 813-832 ◽

Cited By ~ 5

Author(s):

Hyeon-Jeong Kim ◽

Sanghwa Kim ◽

Ah Young Lee ◽

Yoonjeong Jang ◽

Orkhonselenge Davaadamdin ◽

...

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Adipose Tissue ◽

Dietary Supplement ◽

High Fat Diet ◽

Liver Steatosis ◽

Integrated Approach ◽

Serum Levels ◽

Gymnema Sylvestre ◽

High Fat

This study used an integrated approach to investigate the effects of Gymnema sylvestre (GS) extract as a functional dietary supplement with a high-fat diet. This approach examined insulin resistance, the dysfunction of adipose tissue, and liver steatosis. Male C57BL/6J mice were fed a normal chow or high-fat diet (HFD) for the acute and chronic study, in addition to GS in different doses (100, 250 and 500[Formula: see text]mg/kg body weight). Their body composition changes, serum lipid and glucose parameters, adipose and liver tissue histology, and gene expression were measured. It was found that GS significantly suppressed the increase of body weight, serum levels of lipid, insulin and leptin, and adipose tissue, and liver inflammation. GS also demonstrated hypoglycemic effects due to the amylase inhibition activity. Our results support the existence of a relationship between the HFD induced insulin resistance, adipose dysfunction and liver steatosis. In conclusion, GS works as a functional dietary supplement with preventative effects against metabolic disorder.

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Double-Stranded RNA-Activated Protein Kinase Is a Key Modulator of Insulin Sensitivity in Physiological Conditions and in Obesity in Mice

Endocrinology ◽

10.1210/en.2012-1400 ◽

2012 ◽

Vol 153 (11) ◽

pp. 5261-5274 ◽

Cited By ~ 43

Author(s):

M. A. Carvalho-Filho ◽

B. M. Carvalho ◽

A. G. Oliveira ◽

D. Guadagnini ◽

M. Ueno ◽

...

Keyword(s):

Insulin Resistance ◽

Insulin Sensitivity ◽

Protein Phosphatase ◽

High Fat Diet ◽

Obese Mice ◽

High Fat ◽

Double Stranded Rna ◽

Physiological Conditions ◽

Phosphatase 2A

Abstract The molecular integration of nutrient- and pathogen-sensing pathways has become of great interest in understanding the mechanisms of insulin resistance in obesity. The double-stranded RNA-dependent protein kinase (PKR) is one candidate molecule that may provide cross talk between inflammatory and metabolic signaling. The present study was performed to determine, first, the role of PKR in modulating insulin action and glucose metabolism in physiological situations, and second, the role of PKR in insulin resistance in obese mice. We used Pkr−/− and Pkr+/+ mice to investigate the role of PKR in modulating insulin sensitivity, glucose metabolism, and insulin signaling in liver, muscle, and adipose tissue in response to a high-fat diet. Our data show that in lean Pkr−/− mice, there is an improvement in insulin sensitivity, and in glucose tolerance, and a reduction in fasting blood glucose, probably related to a decrease in protein phosphatase 2A activity and a parallel increase in insulin-induced thymoma viral oncogene-1 (Akt) phosphorylation. PKR is activated in tissues of obese mice and can induce insulin resistance by directly binding to and inducing insulin receptor substrate (IRS)-1 serine307 phosphorylation or indirectly through modulation of c-Jun N-terminal kinase and inhibitor of κB kinase β. Pkr−/− mice were protected from high-fat diet-induced insulin resistance and glucose intolerance and showed improved insulin signaling associated with a reduction in c-Jun N-terminal kinase and inhibitor of κB kinase β phosphorylation in insulin-sensitive tissues. PKR may have a role in insulin sensitivity under normal physiological conditions, probably by modulating protein phosphatase 2A activity and serine-threonine kinase phosphorylation, and certainly, this kinase may represent a central mechanism for the integration of pathogen response and innate immunity with insulin action and metabolic pathways that are critical in obesity.

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