Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

Palanivel, Rengasamy; Fullerton, Morgan D.; Galić, Sandra; Honeyman, Jane; Hewitt, Karen; Jørgensen, Sebastian Beck; Steinberg, Gregory R.

doi:10.1007/s00125-012-2665-3

Cited by 45 publications

(33 citation statements)

References 51 publications

(82 reference statements)

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“…2C). We also detected reduced Socs3, which is expressed in adipocytes and has been linked to obesity-induced insulin resistance (24,25), and increased Socs1 expression in VAT of Stat3 −/− mice compared with Stat3 +/+ mice on a HFD (Fig. 2C).…”

Section: Stat3 In T Cellsmentioning

confidence: 69%

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Priceman¹,

Kujawski²,

Shen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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Dysregulated inflammation in adipose tissue, marked by increased proinflammatory T-cell accumulation and reduced regulatory T cells (Tregs), contributes to obesity-associated insulin resistance. The molecular mechanisms underlying T-cell-mediated inflammation in adipose tissue remain largely unknown, however. Here we show a crucial role for signal transducer and activator of transcription 3 (Stat3) in T cells in skewing adaptive immunity in visceral adipose tissue (VAT), thereby contributing to diet-induced obesity (DIO) and insulin resistance. Stat3 activity is elevated in obese VAT and in VAT-resident T cells. Functional ablation of Stat3 in T cells reduces DIO, improves insulin sensitivity and glucose tolerance, and suppresses VAT inflammation. Importantly, Stat3 ablation reverses the high Th1/Treg ratio in VAT of DIO mice that is likely secondary to elevated IL-6 production, leading in turn to suppression of Tregs. In addition, Stat3 in T cells in DIO mice affects adipose tissue macrophage accumulation and M2 phenotype. Our study identifies Stat3 in VAT-resident T cells as an important mediator and direct target for regulating adipose tissue inflammation, DIO, and its associated metabolic dysfunctions.

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Section: Stat3 In T Cellsmentioning

confidence: 69%

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Priceman¹,

Kujawski²,

Shen³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Since STRA6 has been proposed to signal through a JAK2/ STAT5 pathway (15) and the STAT5 target gene encoding suppressor of cytokine signaling 3 (SOCS3) modulates insulin sensitivity in adipocytes (46)(47)(48), we determined the expression of SOCS3. SOCS3 expression was lower in isolated adipocytes from adipose-Stra6 Ϫ/Ϫ mice than in those from controls (Fig.…”

Section: Stra6 Tissue Distributionmentioning

confidence: 99%

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Zemany

Kraus

Norseen

et al. 2014

Molecular and Cellular Biology

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bTo investigate the mechanisms by which elevated retinol-binding protein 4 (RBP4) causes insulin resistance, we studied the role of the high-affinity receptor for RBP4, STRA6 (stimulated by retinoic acid), in insulin resistance and obesity. In high-fat-diet-fed and ob/ob mice, STRA6 expression was decreased 70 to 95% in perigonadal adipocytes and both perigonadal and subcutaneous adipose stromovascular cells. To determine whether downregulation of STRA6 in adipocytes contributes to insulin resistance, we generated adipose-Stra6 ؊/؊ mice. Adipose-Stra6 ؊/؊ mice fed chow had decreased body weight, fat mass, leptin levels, insulin levels, and adipocyte number and increased expression of brown fat-selective markers in white adipose tissue. When fed a highfat diet, these mice had a mild improvement in insulin sensitivity at an age when adiposity was unchanged. STRA6 has been implicated in retinol uptake, but retinol uptake and the expression of retinoid homeostatic genes (encoding retinoic acid receptor ␤ [RAR␤], CYP26A1, and lecithin retinol acyltransferase) were not altered in adipocytes from adipose-Stra6 ؊/؊ mice, indicating that retinoid homeostasis was maintained with STRA6 knockdown. Thus, STRA6 reduction in adipocytes in adipose-Stra6 ؊/؊ mice fed chow resulted in leanness, which may contribute to their increased insulin sensitivity. However, in wild-type mice with high-fat-diet-induced obesity and in ob/ob mice, the marked downregulation of STRA6 in adipocytes and adipose stromovascular cells does not compensate for obesity-associated insulin resistance.T hree hundred fifty million people worldwide have diabetes (1), and the impact will be staggering if we do not develop more effective methods for early detection and treatment. Serum retinol-binding protein 4 (RBP4) is elevated in humans and rodents with insulin resistance and type 2 diabetes (2-4), and data suggest that it may play a causative role (4, 5). Injection of purified RBP4 or overexpression of RBP4 in mice causes insulin resistance (4). Furthermore, a gain-of-function polymorphism in the RBP4 promoter is associated with an 80% increased risk of developing diabetes in humans (5). In addition, epidemiologic studies in several ethnic backgrounds indicate that elevated RBP4 is an early marker of prediabetes (6) and metabolic syndrome (7,8) and is associated with a 3.6-fold increased risk of myocardial infarction (9).The mechanisms by which RBP4 causes insulin resistance and whether the actions of RBP4 depend on a receptor are questions of high interest in the field. STRA6 is a high-affinity cell surface receptor for RBP4 that mediates vitamin A uptake (10). STRA6 is highly expressed in blood-organ barriers and in the brain, eye, kidney, testis, and female reproductive tract, and it is absent from the liver (11). STRA6 is upregulated in some tumors, and its expression can be induced by retinoids and increased Wnt-1 expression in mammary epithelial cells (12). RBP4 mediates insulin resistance through STRA6-independent (13, 14) and STRA6-dependent pathwa...

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“…Cross-sectional area was determined by measuring the circumference of ϳ200 adipocytes per sample using Nikon Elements software (Nikon, Melville, NY) as previously described (31).…”

Section: Study Design and Generation Of Ampk-mko Model The Mcmaster mentioning

confidence: 99%

Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance

Bujak

Blümer

Marcinko

et al. 2014

Journal of Applied Physiology

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Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance

Cited by 45 publications

References 51 publications

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance

Downregulation of STRA6 in Adipocytes and Adipose Stromovascular Fraction in Obesity and Effects of Adipocyte-Specific STRA6 Knockdown In Vivo

Reduced skeletal muscle AMPK and mitochondrial markers do not promote age-induced insulin resistance

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