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

Abstract

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 a role for the broadly conserved miR-26 family of microRNAs (miR-26a-1, miR-26a-2, and miR-26b) as major regulators of APC differentiation and adipose tissue mass. Deletion of all miR-26-encoding loci in mice resulted in a dramatic expansion of adipose tissue in adult animals fed normal chow. Conversely, transgenic overexpression of miR-26a protected mice from high-fat dietinduced 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 novel pathway that plays a critical role in regulating adipose tissue formation in vivo and suggest new potential therapeutic targets for obesity and related disorders.

Pancreatic β cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving β cell function

“…However, these two targets appear insufficient to account for the potent beneficial phenotypes of RIP TG mice. Of note, we and others have demonstrated that miR-26a can directly target several regulators critical for liver and adipose metabolism [22,64,65], which play important roles in obesity and diabetes. It is likely that these known miR-26a targets, together with certain undescribed targets, cooperate to mediate the functions of exosomal miR-26a in peripheral tissues.…”

Regulatory microRNAs in Brown, Brite and White Adipose Tissue

“…MiR-26 : MiR-26a and MiR-26b are identified as key regulators of human white and beige adipocyte differentiation, constituting positive regulators of brown adipogenesis that targets ADAM metallopeptidase domain 17 (ADAM17) [ 123 ], which is an anti-adipogenic and anti-browning factor [ 129 ]. The MiR-26 family consists of three members (MiR-26a1, MiR-26a2 and MiR-26b), which are upregulated in early adipogenesis, and their inhibition prevents lipid accumulation, whilst their overexpression accelerates it [ 124 ]. MiR-26 levels increase during WAT differentiation, and MiR-26a is enriched in BAT and induced in WAT upon cold response [ 123 ].…”

“…Of note, a recent study by Acharya and colleagues reported that MiR-26 plays a critical role in regulating adipogenesis in vitro and in vivo by suppressing adipocyte progenitor cell differentiation and fat production by targeting Fbxl19 (gene encoding the F-box and leucine rich repeat protein 19; FBXL19), which encodes a component of Skp–Cullin–F-box-containing (SCF) E3 ubiquitin ligase complexes [ 124 ]. Indeed, FBXL19 mediates targeted ubiquitylation of proteins destined for proteasomal degradation [ 130 ], and appears to be a novel MiR-26 target that functions downstream from this miRNA to drive adipogenesis [ 124 ]. Interestingly, loss of MiR-26 results in dramatic AT expansion early in adult life and triggers precocious adipocyte progenitor cell differentiation, resulting in adipocyte hyperplasia and WAT expansion in a manner that resembles the physiologic response to caloric excess [ 124 ].…”

AGO HITS-CLIP in Adipose Tissue Reveals miR-29 as a Post-Transcriptional Regulator of Leptin

“…miR-133 represses BAT function by directly targeting Prdm16 and inhibiting expression of thermogenic genes 2 . miR-196a induces browning of WAT by targeting Hoxc8 1 , and miR-26 protects mice from diet-induced obesity by blocking adipogenesis 10 . These studies, and most others in adipose tissue, rely on computational predictions and low-throughput validation to identify miRNA targets.…”