Altered inflammatory profile in adipose tissue is associated with protection from insulin resistance in obese TWEAK knock‐out mice

Tumor necrosis factor‐like weak inducer of apoptosis (TWEAK) is a cytokine of the TNF superfamily. TWEAK and receptor Fn14 are expressed in obese mouse and human adipose tissue (AT). TWEAK knock‐out (KO) mice become obese with high fat diet (HFD) but are protected from associated insulin resistance (IR).1 The present study investigated the potential roles of adipocyte size and AT inflammation in protection against IR. Male C57/BL6J wildtype (WT) or TWEAK KO mice 9–12 wks old were fed a HFD (60% fat kcal) or normal diet (17% fat kcal) for 17 wks. Adipocyte size and gene expression were measured in gonadal AT. Although insulin sensitivity is associated with smaller adipocytes, HFD‐fed KO (KOH) adipocytes are ~30% larger than HFD‐fed WT (WTH) (p<0.001). M1 macrophage (Mϕ) (F4/80, CD11c+) and inflammatory (TNFα, MCP‐1) gene expression are similarly increased in WTH and KOH. Notably, IFNγ is decreased >2‐fold in KOH relative to WTH (p=0.03), and markers of ‘alternative’ M2 Mϕ activation (IL‐13, Ym‐1) increase ~140% and ~220% in KOH relative to WTH (p<0.001; p=0.01, respectively). Despite hypertrophic adipocytes, TWEAK KO mice remain insulin sensitive on a HFD. This protection may reflect selectively attenuated inflammatory polarization of Mϕs within AT. Further characterization of this immune cell phenotype and mechanisms which provide metabolic protection are under investigation. Grant Funding Source : NIH T32 ‐ HL069772 ‐ 06