TLR4-Induced Local Adipose Inflammation Critically Regulates Glucose Homeostasis

Acute adipose inflammation is beneficial for adipose tissue remodeling, while chronic unsolved inflammation may lead to systemic insulin resistance. Toll-like receptor 4 (TLR4) may be an important mediator for obesity-associated chronic low grade inflammation and insulin resistance. However, up to date, we do not have a model available that allows us to study systemic consequences of adipose tissue inflammation originating selectively at the level of the adipocyte. Here, using cre-loxP and doxycycline-inducible system, we generated a new mouse model, which exclusively expresses physiological levels of TLR4 in adipocytes of adult mice in the background of an otherwise global TLR4 null mouse (“ATLR4 mice”). Upon LPS injection, ATLR4 mice show modest acute inflammation in local adipose tissue, but no inflammatory response at the systemic level. However, when exposed long-term to a HFD diet, ATLR4 mice show reduced body weight gain as well as improved glucose and insulin tolerance. This beneficial effect may - at least in part - be due to increased browning of subcutaneous white adipocytes. Under thermoneutral conditions (when we minimize the contributions of the browning effects), the ALTR4 mice show a slightly higher body weight gain, but still preserve better glucose tolerance. RNAseq data indicates the beneficial effect of ATLR4 mice may be associated with enhancing acetyl-coA synthesis pathway to promote PPARgamma acetylation and adipogenesis. Based on that, we conclude that adipose tissue inflammation originating in the adipocyte contributes only minimal, if any, effects on systemic inflammation. In contrast, TLR4-induced local inflammation signaling results in improvements in glucose homeostasis.