miR-130b/301b Is a Negative Regulator of Beige Adipogenesis and Energy Metabolism In Vitro and In Vivo

Abstract

Thermogenic brown or beige adipocytes dissipate energy in the form of heat and thereby counteract obesity and related metabolic complications. The miRNA cluster miR-130b/301b is highly expressed in adipose tissues and has been implicated in metabolic diseases as a post-transcriptional regulator of mitochondrial biogenesis and lipid metabolism. We investigated the roles of miR-130b/301b in regulating beige adipogenesis in vivo and in vitro. miR-130b/301b declined in adipose progeni-tor cells during beige adipogenesis, while forced over-expression of miR-130b-3p or miR-301b-3p suppressed uncoupling protein 1 (UCP1) and mitochondrial respi-ration, suggesting that a decline in miR-130b-3p or miR-301b-3p is required for adipocyte precursors to de-velop the beige phenotype. Mechanistically, miR-130b/ 301b directly targeted AMP-activated protein kinase (AMPKα1) and suppressed peroxisome proliferator– activated receptor γ coactivator-1α (Pgc-1α), key regulators of brown adipogenesis and mitochondrial biogenesis. Mice lacking the miR-130b/301b miRNA cluster showed reduced visceral adiposity and less weight gain. miR-130b/ 301b null mice exhibited improved glucose tolerance, increased UCP1 and AMPK activation in subcutaneous fat (inguinal white adipose tissue [iWAT]), and increased response to cold-induced energy expenditure. Together, these data identify the miR-130b/301b cluster as a new regulator that suppresses beige adipogenesis involving PGC-1α and AMPK signaling in iWAT and is therefore a potential therapeutic target against obesity and related metabolic disorders.