STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

Aaron R. Cox; Natasha Chernis; David A. Bader; Pradip K. Saha; Peter M. Masschelin; Jessica B. Felix; Robert Sharp; Zeqin Lian; Vasanta Putluri; Kimal Rajapakshe; Kang Ho Kim; Dennis T. Villareal; Reina Armamento-Villareal; Huaizhu Wu; Cristian Coarfa; Nagireddy Putluri; Sean M. Hartig

doi:10.2337/db20-0384

STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

Aaron R. Cox, Natasha Chernis, David A. Bader, Pradip K. Saha, Peter M. Masschelin, Jessica B. Felix, Robert Sharp, Zeqin Lian, Vasanta Putluri, Kimal Rajapakshe, Kang Ho Kim, Dennis T. Villareal, Reina Armamento-Villareal, Huaizhu Wu, Cristian Coarfa, Nagireddy Putluri, Sean M. Hartig

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

Abstract

Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1^a-KO) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1^a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to wholebody insulin sensitivity.

Original language	English (US)
Pages (from-to)	2630-2641
Number of pages	12
Journal	Diabetes
Volume	69
Issue number	12
DOIs	https://doi.org/10.2337/db20-0384
State	Published - Dec 2020
Externally published	Yes

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

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Cox, A. R., Chernis, N., Bader, D. A., Saha, P. K., Masschelin, P. M., Felix, J. B., Sharp, R., Lian, Z., Putluri, V., Rajapakshe, K., Kim, K. H., Villareal, D. T., Armamento-Villareal, R., Wu, H., Coarfa, C., Putluri, N., & Hartig, S. M. (2020). STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity. Diabetes, 69(12), 2630-2641. https://doi.org/10.2337/db20-0384

Cox, AR, Chernis, N, Bader, DA, Saha, PK, Masschelin, PM, Felix, JB, Sharp, R, Lian, Z, Putluri, V, Rajapakshe, K, Kim, KH, Villareal, DT, Armamento-Villareal, R, Wu, H, Coarfa, C, Putluri, N & Hartig, SM 2020, 'STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity', Diabetes, vol. 69, no. 12, pp. 2630-2641. https://doi.org/10.2337/db20-0384

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title = "STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity",

abstract = "Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to wholebody insulin sensitivity.",

author = "Cox, {Aaron R.} and Natasha Chernis and Bader, {David A.} and Saha, {Pradip K.} and Masschelin, {Peter M.} and Felix, {Jessica B.} and Robert Sharp and Zeqin Lian and Vasanta Putluri and Kimal Rajapakshe and Kim, {Kang Ho} and Villareal, {Dennis T.} and Reina Armamento-Villareal and Huaizhu Wu and Cristian Coarfa and Nagireddy Putluri and Hartig, {Sean M.}",

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year = "2020",

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doi = "10.2337/db20-0384",

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AU - Chernis, Natasha

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AU - Felix, Jessica B.

AU - Sharp, Robert

AU - Lian, Zeqin

AU - Putluri, Vasanta

AU - Rajapakshe, Kimal

AU - Kim, Kang Ho

AU - Villareal, Dennis T.

AU - Armamento-Villareal, Reina

AU - Wu, Huaizhu

AU - Coarfa, Cristian

AU - Putluri, Nagireddy

AU - Hartig, Sean M.

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N2 - Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to wholebody insulin sensitivity.

AB - Obesity fosters low-grade inflammation in white adipose tissue (WAT) that may contribute to the insulin resistance that characterizes type 2 diabetes. However, the causal relationship of these events remains unclear. The established dominance of STAT1 function in the immune response suggests an obligate link between inflammation and the comorbidities of obesity. To this end, we sought to determine how STAT1 activity in white adipocytes affects insulin sensitivity. STAT1 expression in WAT inversely correlated with fasting plasma glucose in both obese mice and humans. Metabolomic and gene expression profiling established STAT1 deletion in adipocytes (STAT1a-KO) enhanced mitochondrial function and accelerated tricarboxylic acid cycle flux coupled with reduced fat cell size in subcutaneous WAT depots. STAT1a-KO reduced WAT inflammation, but insulin resistance persisted in obese mice. Rather, elimination of type I cytokine interferon-γ activity enhanced insulin sensitivity in diet-induced obesity. Our findings reveal a permissive mechanism that bridges WAT inflammation to wholebody insulin sensitivity.

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STAT1 dissociates adipose tissue inflammation from insulin sensitivity in obesity

Abstract

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