T Cell Deficiency of STAT1 Reduces Obesity in Mice with High-Fat Diet or Aging

T cells accumulate in adipose tissue (AT) and change phenotypes, with increased polarization to Th1, in obesity, but the mechanisms for these changes and their contribution to metabolic functions remain incompletely understood. We hypothesize that STAT1, a transcription factor, plays a role in AT T cell polarization, thus impacting obesity and related metabolism. Mice with Stat1 knockout in αβT cells (tStat1-KO) were generated by crossbreeding Stat1fl/fl mice and CD4-cre mice. Strikingly, with high-fat diet (HFD) feeding or aging, tStat1-KO, compared to cre noncarrier wild type (WT) littermates, developed less obesity, with lower body weight and fat mass (body weight: 43 ± 0.5 g in KO [n=33] vs 48 ± 0.8 g in WT [n=32] at 12 weeks on HFD and 32 ± 0.7 g in KO [n=27] vs 37 ± 0.6 g in WT [n=25] at the age of 50 weeks [on normal chow], P<0.001; fat mass: 14 ± 0.5 g in KO [n=6] vs 17 ± 0.7 g in WT [n=4] at 12 weeks on HFD, P=0.02 and 4.6 ± 0.3 g in KO [n=9] vs 8.6 ± 1.5 g in WT [n=4] at the age of 50 weeks, P=0.002). Compared to WT, tStat1-KO had similar food intake, but increased energy expenditure with increased white AT browning indicated by elevated UCP1 and PRDM16 levels in inguinal AT. tStat1-KO vs WT with HFD or aging had improved insulin sensitivity and glucose tolerance. Analyses of AT showed a dramatic phenotypic switch from IFNγ+ Th1 to IL-5+ Th2 cells and increased eosinophils in perigonadal and inguinal AT of tStat1-KO vs WT fed HFD. Antibody neutralization of IL-5 reduced eosinophils but did not reverse less obesity in tStat1-KO fed HFD, suggesting that increased IL-5 and eosinophils may not account for reduced obesity in tStat1-KO. Adoptive transfer of Th1 cells in tStat1-KO and tissue culture studies showed that Th1 cells repressed white AT browning and reduced UCP1 in adipocytes. In summary, T cell ablation of STAT1 led to phenotypic switch from Th1 to Th2 cells in AT, correlated with reduced obesity, in mice with HFD or aging. These data support a role of STAT1 in AT T cell polarization, which may affect obesity development induced by HFD or aging. Disclosure Z.Lian: None. V.O'brien: None. X.D.Perrard: None. P.Saha: None. S.M.Hartig: None. C.M.Ballantyne: Consultant; Alnylam Pharmaceuticals, Inc., Althera Pharmaceuticals, Amarin Corporation, Amgen Inc., Arrowhead Pharmaceuticals, Inc., AstraZeneca, ESPERION Therapeutics, Inc., 89bio, Inc., Abbott Diagnostics, Denka Seiken, Genentech, Inc., Gilead Sciences, Inc., Illumina, Matinas BioPharma Inc, Merck & Co., Inc., New Amsterdam Pharma, Novartis, Novo Nordisk, Pfizer Inc., Regeneron, Roche Diagnostics, Research Support; Abbott Diagnostics, Akcea, Amgen Inc., Arrowhead Pharmaceuticals, Inc., ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, Merck & Co., Inc., Novartis, Novo Nordisk, Regeneron, Roche Diagnostics. H.Wu: None. Funding American Diabetes Association (1-17-IBS-082 to H.W.); National Institutes of Health (R01DK121348, R01AG065197); American Heart Association (968367)