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Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet.

ABSTRACT: Low-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.

SUBMITTER: Stolarczyk E

PROVIDER: S-EPMC3685808 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet.

Stolarczyk Emilie E Vong Chi Teng CT Perucha Esperanza E Jackson Ian I Cawthorne Michael A MA Wargent Edward T ET Powell Nick N Canavan James B JB Lord Graham M GM Howard Jane K JK

Cell metabolism 20130401 4

Low-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 secretio ...[more]

PMID: 23562076

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Project description:ContextA central/visceral fat distribution and excess free fatty acid (FFA) availability are associated with dyslipidemia and insulin resistance. However, these two characteristics often coexist, making it difficult to detect the independent contributions of each. Whether FFA suppression is more closely linked to metabolic abnormalities is not clear.ObjectiveThe aim of the study was to examine the relationship between FFA suppression, body fat distribution, and fitness as contributors toward insulin resistance and hypertriglyceridemia.DesignWe measured systemic palmitate turnover using an iv infusion of [9,10-(3)H]palmitate; upper body sc adipose tissue (UBSQ) and visceral adipose tissue (VAT) with dual-energy x-ray absorptiometry and a single-slice abdominal computed tomography scan; fitness with a graded exercise treadmill test; and insulin sensitivity with both the iv glucose tolerance test (IVGTT) (SI(IVGTT)) and mixed meal tolerance test (SI(Meal)).SettingThe study was conducted at a General Clinical Research Center.ParticipantsBaseline data were obtained from 140 elderly adults (age, 60-88 yr; 83 males) and 60 young adults (age, 18-31 yr; 31 males) who participated in a previously published trial assessing the effects of 2-yr supplementation of dehydroepiandrosterone or testosterone on body composition, glucose metabolism, and bone density.InterventionsThere were no interventions.Main outcome measuresWe measured fasting plasma triglyceride (TG) concentrations, SI(IVGTT), and SI(Meal).ResultsUsing multivariate regression analysis, the strongest combined predictors of TG concentrations were VAT, postmeal nadir FFA concentrations, sex, and age. The best predictors of SI(IVGTT) were IVGTT nadir palmitate concentration, VAT, UBSQ fat, fitness, and age, whereas the best predictors of SI(Meal) were meal nadir palmitate concentration, UBSQ fat, fitness, and sex.ConclusionsFFA suppression is associated with both fasting TG concentrations and insulin sensitivity, independent of measures of adiposity.

Dataset Information

Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet.

Publications

Improved insulin sensitivity despite increased visceral adiposity in mice deficient for the immune cell transcription factor T-bet.

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