miR-26 suppresses adipocyte progenitor differentiation and fat production by targeting Fbxl19

Purpose: Fat storage in adult mammals is a highly regulated process that involves the mobilization of adipocyte progenitor cells (APCs) that differentiate to produce new adipocytes. Here we report an unexpected role for the broadly conserved miR-26 family of microRNAs (miR-26a-1, miR-26a-2, and miR-26b) as key regulators of APC differentiation. Global loss of miR-26 resulted in a dramatic expansion of adipose tissue in adult mice fed normal chow. Conversely, transgenic overexpression of miR-26a protected mice from high fat diet-induced obesity. These effects were attributable to a cell-autonomous function of miR-26 as a potent inhibitor of APC differentiation. miR-26 blocks adipogenesis, at least in part, by repressing expression of Fbxl19, a conserved miR-26 target without a previously known role in adipocyte biology that encodes a component of SCF-type E3 ubiquitin ligase complexes. These findings have therefore revealed a new pathway that plays a critical role in regulating adipose tissue formation in vivo and suggest new potential therapeutic targets for obesity and related disorders. Overall design: Method: miR-26 targets in adipocyte progenitor cell differentiation were identified by RNA seq analysis of primary stromal vascular fraction cultured in vitro from i) wild-type C57BL/6 and miR-TKO mice, and ii) M2rtTA; eGFP.miR-26a mice with or without 1 mg/mL dox treatment for 4 days.