Fetal development of subcutaneous white adipose tissue is dependent on Zfp423.

Objective: is a multi zinc-finger transcription factor expressed in preadipocytes and mature adipocytes . Our recent work has revealed a critical role for in maintaining the fate of white adipocytes in adult mice through suppression of the beige cell thermogenic gene program; loss of in mature adipocytes of adult mice results in a white-to-beige phenotypic switch. However, the exact requirements of in the fetal stages of early adipose development have not been clarified.

Method: Here, we utilize two models that confer adipose-specific inactivation during fetal adipose development (-Cre; and -rtTA; TRE-Cre; ). We assess the impact of fetal adipose deletion on the initial formation of adipose tissue and evaluate the metabolic consequences of challenging these animals with high-fat diet feeding.

Results: Deletion of during fetal adipose development results in a different phenotype than is observed when deleting in adipocytes of adult mice. Inactivation of Zfp423 during fetal adipose development results in arrested differentiation, specifically of inguinal white adipocytes, rather than a white-to-beige phenotypic switch that occurs when is inactivated in adult mice. This is likely explained by the observation that driven Cre expression is active at an earlier stage of the adipocyte life cycle during fetal subcutaneous adipose development than in adult mice. Upon high-fat diet feeding, obese adipose -deficient animals undergo a pathological adipose tissue expansion, associated with ectopic lipid deposition and systemic insulin resistance.

Conclusions: Our results reveal that is essential for the terminal differentiation of subcutaneous white adipocytes during fetal adipose tissue development. Moreover, our data highlight the striking adverse effects of pathological subcutaneous adipose tissue remodeling on visceral adipose function and systemic nutrient homeostasis in obesity. Importantly, these data reveal the distinct phenotypes that can occur when driven transgenes are activated in fetal vs. adult adipose tissue.