Objective: Brown adipose tissue (BAT) produces heat using chemical energy of lipids and glucose, a function induced by cold exposure or diet. The brown adipogenesis is tightly controlled in a coordinated interplay between several transcriptional factors. It is not known what enables and coordinates this robust program of concerted cooperation between the transcriptional factors and co-regulators necessary for the brown adipogenesis.
Materials/methods: A. In vivo studies--we investigated the expression levels of miR-27a and b in mice after cold exposure. B. Using gene expression and functional studies together with high throughput imaging in primary preadipocytes, and cell culture models, we investigated the role of miR-27 in beige and brown adipogenesis. C. Using gene silencing and rescue experiments we dissected the molecular mechanisms of the miR-27 action.
Results: After cold exposure, miR-27 is downregulated in BAT and subcutaneous white adipose tissue (SAT). MiR-27 is also downregulated during brown adipogenesis of primary preadipocytes in vitro, and it directly targets and negatively regulates the essential components of the brown transcriptional network: Prdm16, Pparα, Creb, and in part Pgc1β. Together with its direct effect on Pparγ, and indirect on Pgc1α, mir-27 decreases brown differentiation of cultured cells and of primary SAT preadipocytes.
Conclusions: Our results point to miR-27 as a central upstream regulator of the transcriptional network involved in beige and brown adipogenesis after cold exposure, and suggest miR-27 inhibition as a novel therapeutic approach for metabolic diseases aiming at increasing the beige/brown fat mass.
Keywords: 3′ untranslated region; 3′UTR; Adipocyte protein 2 (Fabp4, Fatty acid binding protein 4); Adipogenesis; Adrb3; BAT; Beige; Brown; Brown adipose tissue; C/EBPs; CCAAT/enhancer-binding proteins; Creb; Cyclic adenosine monophosphate; Fat; IBMX; Mouse Primary Immortalized Brown Adipocytes; Myf5; Myogenic factor 5; OCR; PIBA; PPARγ-coactivators-1; PRDI-BF1-RIZ1 (PR) domain containing 16; Peroxisome proliferator-activated receptor-a and γ; Pgc1; Pparα and γ; Prdm16; SAT; SVF; Subcutaneous adipose tissue; Ucp1; Uncoupling protein 1; VAT; Visceral adipose tissue; WAT; White adipose tissue; aP2; beta-3 adrenergic receptor; cAMP; cAMP responsive element binding protein; isobutylmethylxanthine; miRNAs; microRNAs; oxygen consumption rates; primary stromal–vascular fraction.
© 2014.