MicroRNA networks regulate development of brown adipocytes

Abstract

Brown adipose tissue (BAT) is specialized for heat generation and energy expenditure as a defense against cold and obesity; in both humans and mice increased amounts of BAT are associated with a lean phenotype and resistance to development of the metabolic syndrome and its complications. Here we summarize recent research showing that several BAT-expressed microRNAs (miRNAs) play important roles in regulating differentiation and metabolism of brown and beige adipocytes; we discuss the key mRNA targets downregulated by these miRNAs and show how these miRNAs affect directly or indirectly transcription factors important for BAT development. We suggest that these miRNAs could be part of novel therapeutics to increase BAT in humans.

Keywords: adipocyte; adipogenesis; beige; brown; microRNA.

Figure 1. MiR-193b stimulates brown adipogenesis

Graphical representation of the miR-196b/365 pathway. Runx1t1 is an inhibitor of brown adipogenesis, while Cdon and Igfbp5 are pro-myogenic factors. Increased miR-193b expression during adipogenesis directly inhibits CDON, IGFBP5, and Runx1t1 expression, thus increasing the levels of PRDM16 and PPARα. The resulting increase in the levels of these two transcription factors promotes brown adipogenesis, and further up-regulates miR-193/365 expression as part of a positive feedback loop.

Figure 2. Decreased miR-133 expression during cold exposure promotes brown adipogenesis

Graphical representation of the miR-133 pathway. Cold exposure and beta adrenergic stimulation increase cyclic AMP levels, leading to a decrease in MEF2C expression and resulting in marked downregulation of miR-133. Since miR-133 represses expression of the master brown adipocyte differentiation factor PRMD16 in both MYF5 positive, and MYF5 negative progenitor cells, this leads to increased brown and beige adipocyte differentiation, respectively.

Figure 3. MiR-196a upregulation induces beige cell formation

Graphical representation of the miR-196a pathway. Hoxc8 targets and represses C/EBPβ expression in cooperation with histone deacetylase 3 (HDAC3) through a C/EBPβ 3' regulatory sequence. Cold exposure and adrenergic stimulation lead to an increase in miR-196a expression, which directly suppresses Hoxc8 expression and thereby de-represses C/EBPβ expression. This leads to induction of beige adipogenesis exclusively in MYF5 negative progenitor cells.

Figure 4. miR-155 controls the development of brown and beige cells

Graphical representation of the miR-155 pathway. MiR-155 expression is positively regulated by TGFβ1, and suppresses the translation of C/EBPβ as it’s direct target. C/EBPβ induction during brown and beige adipogenesis inhibits transcription of the miR-155 gene, thereby forming a bistable loop for the regulation of adipogenesis either maintaining preadipocytes in an undifferentiated precursor state or initiating the brown adipogenic program.