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

Metabolically healthy fat remodeling is able to maintain a certain degree of systemic metabolic homeostasis, although factors involved in this process have not been fully clarified. Here we demonstrate that adipose Netrin-1, originally known as an axon guidance molecule, is associated with development of obesity and type 2 diabetes. We have observed improved systemic metabolic parameters that are attributable to increased inguinal white adipose tissue (iWAT) mass in male high-fat-fed transgenic mice lacking adipose-specific Netrin-1 expression (Ntn1AKO). Preadipocytes extracted from the Ntn1AKO mice also exhibited increased cell proliferation, accompanied by decreased collagen deposition. Effects of Ntn1 in both adipocytes and preadipocytes were observed to be directly regulated by HIF-1α . Moreover, WAT-specific overexpression of Ntn1 disrupted metabolic equilibrium regardless of fat intake. Further investigation revealed that overexpressing Ntn1 attenuated adipogenesis by inhibiting the PPARγ while activating the Wnt/β-catenin pathways. In summary, our current study suggests that adipose Ntn1 regulate adipogenesis and function and may therefore be considered as a potential therapeutic target for obesity and diabetes.