Obesity-Associated miR-199a/214 Cluster Inhibits Adipose Browning via PRDM16–PGC-1α Transcriptional Network

Abstract

miRNAs are important regulators of differentiation, development, and function of brown and beige fat cells. In this study, we identify the role of the miR-199a/214 cluster in the regulation of brown and beige adipocyte development and thermogenesis in vitro and in vivo. We show that expression of the miR-199a/214 cluster is dramatically decreased during brown and beige adipocyte differentiation and in response to cold exposure or b-adrenergic receptor activation. The cluster levels are significantly upregulated in the adipose tissues of obese mice and human subjects. Overexpression of the miR-199a/214 cluster suppresses brown adipocyte differentiation and inhibits thermogenic gene expression and mitochondrial respiration, whereas knockdown of the cluster increases thermogenic gene expression and mitochondrial function in beige adipocytes. In addition, inhibition of the miR-199a/214 cluster promotes beiging effects in vivo. We further show that miR-199a/214 suppresses brown adipocyte differentiation and beige fat development by directly targeting PRDM16 and peroxisome PGC-1a, two key transcriptional regulators of adipose browning. Together, these observations reveal that the miR-199a/214 cluster is a key negative regulator of brown and beige fat development and thermogenesis.The global incidence of obesity and obesity-related disorders, including metabolic syndrome and diabetes, gives rise to a demand for effective therapeutic interventions. Brown and brown-like adipocytes (called beige adipocytes) are emerging as potential targets for the treatment of obesity and related metabolic diseases (1-4). Both brown and beige adipocytes trigger a program of mitochondrial respiration and thermogenesis through induction of UCP1 expression and dissipation of chemical energy to produce heat (5,6). Stimulation of brown and beige fat development leads to increased energy expenditure and a lean, healthy phenotype in neonatal mammals, hibernators, rodents, and adult humans (7,8). However, the mechanisms regulating thermogenic fat cells still need to be further elucidated.The differentiation and development of brown and beige adipocytes are regulated by multiple transcriptional factors and cofactors such as PRD1-BF1-RIZ1 homologous domain-containing 16 (PRDM16) and peroxisome proliferator-activated receptor a and g (PPARa and PPARg) coactivator-1a (PGC-1a) (9-11). PRDM16 is a critical determinant of the brown fat lineage and a key transcriptional regulator of brown fat differentiation. It stimulates differentiation of Myf5-positive myogenic precursor cells into brown fat cells while prohibiting myogenic differentiation by robustly inducing expression of brown adipose tissue (BAT)-selective genes such as UCP1 and 13). Increased PRDM16 expression can drive the expression of BAT-selective genes in beige fat cells (14-16). PGC-1a is an important transcriptional coactivator that regulates brown fat thermogenesis (17,18). It interacts with several transcriptional factors and nuclear receptors, thus controlling the entire program of ther...

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Multiple Levels of PGC-1α Dysregulation in Heart Failure

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