Improved Insulin Sensitivity despite Increased Visceral Adiposity in Mice Deficient for the Immune Cell Transcription Factor T-bet

Emilie Stolarczyk,Chi Teng Vong,Esperanza Perucha,Ian Jackson,Michael A Cawthorne,Edward T Wargent,Nick Powell,James B Canavan,Graham M Lord,Jane K Howard

doi:10.1016/j.cmet.2013.02.019

Emilie Stolarczyk, Chi Teng Vong + Show 8 more

Open Access

https://doi.org/10.1016/j.cmet.2013.02.019

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Abstract

SummaryLow-grade inflammation in fat is associated with insulin resistance, although the mechanisms are unclear. We report that mice deficient in the immune cell transcription factor T-bet have lower energy expenditure and increased visceral fat compared with wild-type mice, yet paradoxically are more insulin sensitive. This striking phenotype, present in young T-bet−/− mice, persisted with high-fat diet and increasing host age and was associated with altered immune cell numbers and cytokine secretion specifically in visceral adipose tissue. However, the favorable metabolic phenotype observed in T-bet-deficient hosts was lost in T-bet−/− mice also lacking adaptive immunity (T-bet−/−xRag2−/−), demonstrating that T-bet expression in the adaptive rather than the innate immune system impacts host glucose homeostasis. Indeed, adoptive transfer of T-bet-deficient, but not wild-type, CD4+ T cells to Rag2−/− mice improved insulin sensitivity. Our results reveal a role for T-bet in metabolic physiology and obesity-associated insulin resistance.

Highlights

Obesity is increasingly recognized to be associated with lowgrade inflammation in fat (Osborn and Olefsky, 2012)
We previously showed that the adipose-tissue-derived hormone leptin, which is increased in obesity, favors the development of T helper 1 (Th1) over Th2 T cells (Lord et al, 1998) and is important in T cell development and survival (Howard et al, 1999)
Increased Visceral Adiposity and Because obesity is associated with increased Th1 cells in fat, we determined the impact of T-bet deficiency on the susceptibility to obesity and its associated metabolic complications

Summary

Introduction

Obesity is increasingly recognized to be associated with lowgrade inflammation in fat (Osborn and Olefsky, 2012). Initial studies reported the accumulation of macrophages within adipose tissue and the subsequent liberation of proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-a), which contribute to obesity-associated insulin resistance (Weisberg et al, 2003; Xu et al, 2003). Immune cell infiltration in visceral fat is associated with the adverse metabolic complications of obesity. There is an increasing appreciation of the role of the immune system in the development of obesity-induced inflammation, the molecular drivers of this process are still poorly defined. Immune cells are already present in normal lean adipose tissue prior to the onset of obesity. The role of adipose tissue immune cells in the regulation of normal metabolic physiology, before the onset of obesity, is unknown

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Conclusion