Netrin-1 disrupt high-fat-diet-induced adipogenesis via the PPARγ and Wnt/β-catenin signaling pathways.

The present study reports a detrimental role of adipose-derived Netrin-1 in adipose remodeling. Following an 8-week high-fat feeding period of male transgenic mice lacking adipose Netrin-1 expression (Ntn1(AKO)), improved metabolic parameters were observed, accompanied by systemic weight gain and increased inguinal white adipose tissue (WAT) mass. The Ntn1(AKO) preadipocytes exhibit increased cell proliferation with decreased collagen deposition. WAT Netrin-1 overexpression using adeno-associated virus (with an aP2 promoter) results in impaired glucose tolerance in both high fat and normal chow-fed mice. Netrin-1 overexpression attenuates adipogenesis via inhibition of the PPARγ activity and activation of the Wnt/β-catenin pathway. Moreover, Netrin-1 is directly responsive to the hypoxic regulator HIF-1α in both adipocytes and preadipocytes. The present study suggests that Netrin-1 disrupts adipogenesis and adipocyte function by inhibiting compensatory adipose remodeling during excessive calorie intake and may be considered a potential therapeutic target for high fat diet-induced obesity and type 2 diabetes.