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

TL;DR

This study shows that Netrin-1 in fat tissue worsens obesity and diabetes by disrupting fat cell development and function.

Contribution

The novel contribution is identifying Netrin-1 as a key regulator of adipogenesis through PPARγ and Wnt/β-catenin pathways in high-fat diet contexts.

Findings

Mice lacking adipose Netrin-1 show improved metabolic parameters and increased white adipose tissue mass.

Netrin-1 overexpression impairs glucose tolerance and inhibits adipogenesis via PPARγ inhibition and Wnt/β-catenin activation.

Netrin-1 is regulated by HIF-1α, linking hypoxia to disrupted adipose remodeling.

Abstract

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 (Ntn1AKO), improved metabolic parameters were observed, accompanied by systemic weight gain and increased inguinal white adipose tissue (WAT) mass. The Ntn1AKO 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.

Modulation of Netrin-1 expression in male mouse adipose tissue elucidates its mechanistic role in adipogenesis under high-fat diet.

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