MicroRNA-378 controls classical brown fat expansion to counteract obesity

Abstract

Both classical brown adipocytes and brown-like beige adipocytes are considered as promising therapeutic targets for obesity; however, their development, relative importance, and functional coordination are not well understood. Here we show that a modest expression of miR-378/378* in adipose tissue specifically increases classical brown fat (BAT) mass, but not white fat (WAT) mass. Remarkably, BAT expansion, rather than miR-378 per se, suppresses formation of beige adipocytes in subcutaneous WAT. Despite this negative feedback, the expanded BAT depot is sufficient to prevent both genetic and high fat diet-induced obesity. At the molecular level, we find that miR-378 targets phosphodiesterase Pde1b in BAT, but not in WAT. Indeed, miR-378 and Pde1b inversely regulate brown adipogenesis in vitro in the absence of phosphodiesterase inhibitor IBMX. Our work identifies miR-378 as a key regulatory component underlying classical BAT-specific expansion and obesity resistance, and adds novel insights into the physiological cross-talk between BAT and WAT.

Eicosapentaenoic Acid Potentiates Brown Thermogenesis through FFAR4-dependent Up-regulation of miR-30b and miR-378

“…Based on study by Kim et al (7), fish oil supplementation is linked with sympathetic activation and Adrb3 signaling in brown and inguinal white adipocytes. This implies the activation of cAMP production and its potential role of miR-378, specifically in brown fat (12). To support this notion, sequestration of miR-378 by the LNA inhibitor triggered a partial reduction of Ucp1 expression (Fig.…”

“…1B). Despite a significant increase of miR-378, its proposed target of Pdeb1b (12) did not differ from the vehicle control (Fig. 2D).…”

“…In addition to suppression of myogenic lineage commitment, miR-196a promotes brown adipogenesis by inhibiting white adipocyte commitment (11). The brown transcriptional program could be corroborated by miR-378 that increases cAMP production via targeted degradation of phosphodiesterase 1B (Pde1b) (12) or by miR-30b that promotes degradation of Rip140, a transcriptional corepressor (13). Conversely, decreased levels of miR-133, miR-27a, miR-106b/93, and miR-155 have shown to enhance brown adipogenesis by preventing targeted degradation of transcription factors of Prdm16 (14), Ppar␥ (15), Ppar␣ (16), and C/ebp␤ (17), respectively (see Fig.…”

MiR-378a-3p enhances adipogenesis by targeting mitogen-activated protein kinase 1

“…Some miRNAs enhance adipogenesis [13][14][15][16], whereas others exert negative effects by targeting essential adipogenic genes directly [17,18]. MiR-378 plays an important role in adipogenesis and lipogenesis [19][20][21][22], Both MIR378a-3p and MIR378a-5p originate from a common hairpin RNA precursor which is embedded in the first intron of PGC1b (Peroxisome proliferator-activated receptor gamma coactivator 1-beta) gene Overexpression of miR-378a-3p or miR-378a-5p in ST2 cells increases the size of lipid droplets and the accumulation of triacylglycerol, whereas knockout of these miRNAs decreases triacylglycerol accumulation [19]. Recent study report that miR-378 counterbalances the metabolic actions of PPARGC1B; hence, miR-378a gene knockout mice are resistant to high fat diet (HFD) induced obesity via counterbalancing the metabolic actions of PGC-1 b [23].…”

Breaking BAT: can browning create a better white?

“…Whether recruited beige adipocytes can contribute significantly to whole-body energy expenditure in vivo therefore remains controversial, particularly since convincing direct measurements of its thermogenic contribution are currently lacking. There are three major reasons for this gap in knowledge: the complex relationship between BAT and browning of WAT, which clearly interfere with each other (Pan et al 2014), the use of cold exposure and pharmacological agents such as b3-adrenergic agonists, which act on both brown and beige fat in parallel, and the use of UCP1 mRNA as a readout of thermogenic activity .…”