1628-P: Deletion of STAT1 in T-Cells Leads to a Reduction in Obesity and Improvement in Insulin Resistance in Mice with Aging
Authors: LIAN ZEQIN , GAO FENG , O'BRIEN VERONICA , PERRARD XIAOYUAN , LITCHFIELD BENJAMIN A. , XIAO JING , SAHA PRADIP , HARTIG SEAN M. , BALLANTYNE CHRISTIE M. , WU HUAIZHU 
Published: June 2024

T cells accumulate in adipose tissue (AT) and change phenotypes with obesity, but the mechanisms for these changes and their contribution to obesity and metabolic functions, particularly related to aging, remain poorly defined. STAT1 is a transcription activator that mediates cellular responses to interferons (IFNs) and other cytokines. Hence, we sought to determine the role of STAT1 in AT T cell phenotypic changes and obesity with aging. Mice with specific Stat1 knockout in αβT cells (tStat1-KO) were generated by crossbreeding Stat1fl/fl mice with CD4-cre mice. Notably, with aging, tStat1-KO mice compared to wild-type (WT) littermates exhibited less obesity, with reduced body weight (31.80 ± 4.6 g in tStat1-KO [n=28] vs 36.21 ± 3.23 g in WT [n=22] at the age of 50 weeks [on normal chow], P&lt;0.01) and decreased fat mass (4.56 ± 0.96 g in tStat1-KO [n=9] vs 8.63 ± 2.91 g in WT [n=4], P&lt;0.05), and improved insulin sensitivity and glucose tolerance indicated by insulin- or glucose-tolerance test. Western blot showed that UCP1 levels were increased in subcutaneous AT of tStat1-KO compared to WT mice at the age of 50 weeks. Flow cytometric analysis indicated that compared to young (~12-week-old) WT mice, aged (~50-week-old) WT mice had higher percentages of total CD3+ T cells and CD4+ and CD8+ T cells in AT stromal vascular fractions (SVF) and even higher percentage of regulatory T cells (Treg) in CD4+ T cells (n=5-12/group, P&lt;0.05). The percentages of total CD3+ T cells and CD8+ cells, but not CD4+ T cells, in AT SVF were even higher in aged tStat1-KO than WT mice (P&lt;0.05). In contrast, the percentage of Treg in CD4+ cells tended to be lower in AT of aged tStat1-KO than of aged WT (P=0.08). The proportions of macrophages in AT were not significantly different among young WT, aged WT, and aged tStat1-KO mice. In summary, T cell knockout of Stat1 in mice reduced aging-associated obesity and improved insulin resistance, with changes in AT T cells, particularly CD8+ T cells and Treg.

Disclosure
Z. Lian: None. F. Gao: None. V. O'Brien: None. X. Perrard: None. B.A. Litchfield: None. J. Xiao: None. P. Saha: None. S.M. Hartig: None. C.M. Ballantyne: Research Support; Abbott Diagnostics. Consultant; Abbott Diagnostics. Research Support; Akcea Thearpeutics, Inc., Amgen Inc. Consultant; Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Consultant; Arrowhead Pharmaceuticals, Inc., AstraZeneca, Denka Seiken, Eli Lilly and Company, ESPERION Therapeutics, Inc., Genentech, Inc., Illumina. Research Support; Ionis Pharmaceuticals. Consultant; Ionis Pharmaceuticals. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Research Support; New Amsterdam. Consultant; New Amsterdam. Research Support; Novartis Pharmaceuticals Corporation. Consultant; Novartis Pharmaceuticals Corporation. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Research Support; Regeneron Pharmaceuticals Inc., Roche Diagnostics. Consultant; Roche Diagnostics, TenSixteen Bio, Alnylam Pharmaceuticals, Inc. H. Wu: None.

Funding
American Diabetes Association (11-23-PDF-75); National Institutes of Health (R01DK121348, R01AG065197) (Wu H), American Heart Association (968367) (Wu H),