Deficiency of Stat1 in CD11c+ Cells Alters Adipose Tissue Inflammation and Improves Metabolic Dysfunctions in Mice Fed High-Fat Diet

10.2337/figshare.13348094 ◽

2020 ◽

Author(s):

Antu Antony ◽

Zeqin Lian ◽

Xiaoyuan Dai Perrard ◽

Jerry Perrard ◽

Hua Liu ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Th2 Cells ◽

High Fat ◽

Interleukin 5 ◽

Triglyceride Content ◽

Metabolic Dysfunctions

<a>CD11c<sup>+</sup> macrophages/dendritic cells (MDCs) are increased and display classically activated M1-like phenotype in obese adipose tissue (AT) and may contribute to AT inflammation and insulin resistance. Stat1 is a key transcription factor for MDC polarization into M1-like phenotype. Here, we examined the role of Stat1 in obesity-induced AT MDC polarization and inflammation and insulin resistance using mice with specific knockout of Stat1 in MDCs (cKO). Stat1 was upregulated and phosphorylated, indicating activation, early and persistently in AT and AT MDCs of wild-type mice fed high-fat diet (HFD). Compared to littermate controls, cKO mice fed HFD (16 weeks) had reductions in MDC (mainly CD11c<sup>+</sup> macrophage) M1-like polarization and interferon-</a>g–expressing T helper type 1 (Th1) cells, but increases in interleukin-5–expressing Th2 cells and eosinophils in perigonadal and inguinal AT, and enhanced inguinal AT browning, with increased energy expenditure. cKO mice compared with controls also had significant reductions in triglyceride content in the liver and skeletal muscle and exhibited improved insulin sensitivity and glucose tolerance. Taken together, our results demonstrated that Stat1 in MDCs plays an important role in obesity-induced MDC M1-like polarization and AT inflammation and contributes to insulin resistance and metabolic dysfunctions in obese mice.

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Role of brown adipose tissue in modulating adipose tissue inflammation and insulin resistance in high-fat diet fed mice

European Journal of Pharmacology ◽

10.1016/j.ejphar.2019.02.044 ◽

2019 ◽

Vol 854 ◽

pp. 354-364 ◽

Cited By ~ 7

Author(s):

Kripa Shankar ◽

Durgesh Kumar ◽

Sanchita Gupta ◽

Salil Varshney ◽

Sujith Rajan ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Brown Adipose Tissue ◽

High Fat Diet ◽

Adipose Tissue Inflammation ◽

High Fat ◽

Tissue Inflammation ◽

Brown Adipose

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Role of Muscle c-Jun NH2-Terminal Kinase 1 in Obesity-Induced Insulin Resistance

Molecular and Cellular Biology ◽

10.1128/mcb.01162-09 ◽

2009 ◽

Vol 30 (1) ◽

pp. 106-115 ◽

Cited By ~ 100

Author(s):

Guadalupe Sabio ◽

Norman J. Kennedy ◽

Julie Cavanagh-Kyros ◽

Dae Young Jung ◽

Hwi Jin Ko ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Wild Type ◽

High Fat ◽

Akt Activation ◽

Peripheral Insulin Resistance ◽

Diet Induced Obesity

ABSTRACT Obesity caused by feeding of a high-fat diet (HFD) is associated with an increased activation of c-Jun NH2-terminal kinase 1 (JNK1). Activated JNK1 is implicated in the mechanism of obesity-induced insulin resistance and the development of metabolic syndrome and type 2 diabetes. Significantly, Jnk1 − / − mice are protected against HFD-induced obesity and insulin resistance. Here we show that an ablation of the Jnk1 gene in skeletal muscle does not influence HFD-induced obesity. However, muscle-specific JNK1-deficient (MKO) mice exhibit improved insulin sensitivity compared with control wild-type (MWT) mice. Thus, insulin-stimulated AKT activation is suppressed in muscle, liver, and adipose tissue of HFD-fed MWT mice but is suppressed only in the liver and adipose tissue of MKO mice. These data demonstrate that JNK1 in muscle contributes to peripheral insulin resistance in response to diet-induced obesity.

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RGC32 deficiency protects against high-fat diet-induced obesity and insulin resistance in mice

Journal of Endocrinology ◽

10.1530/joe-14-0548 ◽

2014 ◽

Vol 224 (2) ◽

pp. 127-137 ◽

Cited By ~ 21

Author(s):

Xiao-Bing Cui ◽

Jun-Na Luan ◽

Jianping Ye ◽

Shi-You Chen

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Adipose Tissue ◽

High Fat Diet ◽

Tolerance Test ◽

High Fat ◽

Diet Induced Obesity

Obesity is an important independent risk factor for type 2 diabetes, cardiovascular diseases and many other chronic diseases. Adipose tissue inflammation is a critical link between obesity and insulin resistance and type 2 diabetes and a contributor to disease susceptibility and progression. The objective of this study was to determine the role of response gene to complement 32 (RGC32) in the development of obesity and insulin resistance. WT and RGC32 knockout (Rgc32−/− (Rgcc)) mice were fed normal chow or high-fat diet (HFD) for 12 weeks. Metabolic, biochemical, and histologic analyses were performed. 3T3-L1 preadipocytes were used to study the role of RGC32 in adipocytes in vitro. Rgc32−/− mice fed with HFD exhibited a lean phenotype with reduced epididymal fat weight compared with WT controls. Blood biochemical analysis and insulin tolerance test showed that RGC32 deficiency improved HFD-induced dyslipidemia and insulin resistance. Although it had no effect on adipocyte differentiation, RGC32 deficiency ameliorated adipose tissue and systemic inflammation. Moreover, Rgc32−/− induced browning of adipose tissues and increased energy expenditure. Our data indicated that RGC32 plays an important role in diet-induced obesity and insulin resistance, and thus it may serve as a potential novel drug target for developing therapeutics to treat obesity and metabolic disorders.

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Growth Hormone Is Necessary for the p53-Mediated, Obesity-Induced Insulin Resistance in Male C57BL/6J × CBA Mice

Endocrinology ◽

10.1210/en.2013-1220 ◽

2013 ◽

Vol 154 (11) ◽

pp. 4226-4236 ◽

Cited By ~ 16

Author(s):

Fausto Bogazzi ◽

Francesco Raggi ◽

Dania Russo ◽

Mohammad Bohlooly-Y ◽

Chiara Sardella ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

High Fat Diet ◽

Normal Diet ◽

Male Mice ◽

High Fat ◽

P53 Expression ◽

Signal Transducers ◽

Increased Sensitivity

Insulin resistance is a key marker of both obesity and GH excess. The purpose of the study was to assess the role of GH on p53-mediated insulin resistance of male mice with obesity due to a high-fat diet. C57BL/6J × CBA male mice fed on a high-fat diet (Obe) were studied; male mice fed a normal diet (Lean) or transgenic mice for bovine GH under the same genetic background (Acro) served as controls. The convergence of p53 and GH pathways was evaluated by Western blot. Obe mice had insulin resistance, which was sustained by a selective increased expression of p53 in adipose tissue. Normal insulin sensitivity was restored, and adipose p53 expression normalized when the GH pathway was blocked. Only the adipose p53 expression was sensitive to the GH blockage, which occurred through the p38 pathway. Adipose tissue of Obe mice had a coordinate overexpression of suppressors of cytokine signal 1–3 and signal transducers and activators of transcription-1, -3, and -5b, not different from that of Acro mice, suggesting an increased sensitivity of adipose tissue to GH. On the contrary, Lean mice were unaffected by changes of GH action. GH seems to be necessary for the increased adipose p53 expression and for insulin resistance of obese mice.

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TRPM2 Ca2+ channel regulates energy balance and glucose metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00239.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. E807-E816 ◽

Cited By ~ 46

Author(s):

Zhiyou Zhang ◽

Wenyi Zhang ◽

Dae Young Jung ◽

Hwi Jin Ko ◽

Yongjin Lee ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Glucose Metabolism ◽

Energy Expenditure ◽

High Fat Diet ◽

High Fat ◽

Diet Induced Obesity ◽

Gsk 3Β ◽

Fat Feeding

TRPM2 Ca2+-permeable cation channel is widely expressed and activated by markers of cellular stress. Since inflammation and stress play a major role in insulin resistance, we examined the role of TRPM2 Ca2+ channel in glucose metabolism. A 2-h hyperinsulinemic euglycemic clamp was performed in TRPM2-deficient (KO) and wild-type mice to assess insulin sensitivity. To examine the effects of diet-induced obesity, mice were fed a high-fat diet for 4–10 mo, and metabolic cage and clamp studies were conducted in conscious mice. TRPM2-KO mice were more insulin sensitive partly because of increased glucose metabolism in peripheral organs. After 4 mo of high-fat feeding, TRPM2-KO mice were resistant to diet-induced obesity, and this was associated with increased energy expenditure and elevated expressions of PGC-1α, PGC-1β, PPARα, ERRα, TFAM, and MCAD in white adipose tissue. Hyperinsulinemic euglycemic clamps showed that TRPM2-KO mice were more insulin sensitive, with increased Akt and GSK-3β phosphorylation in heart. Obesity-mediated inflammation in adipose tissue and liver was attenuated in TRPM2-KO mice. Overall, TRPM2 deletion protected mice from developing diet-induced obesity and insulin resistance. Our findings identify a novel role of TRPM2 Ca2+ channel in the regulation of energy expenditure, inflammation, and insulin resistance.

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