MiR-22 modulates brown adipocyte thermogenesis by synergistically activating the glycolytic and mTORC1 signaling pathways

Abstract

Background: Brown adipose tissue (BAT) dissipates chemical energy as heat and has the potential to be a protective strategy to prevent obesity. microRNAs (miRNAs) are emerging as important posttranscriptional factors affecting the thermogenic function of BAT. However, the regulatory mechanism underlying miRNA-mediated energy metabolism in BAT is not fully understood. Here, we explored the roles of miR-22 in BAT thermogenesis and energy metabolism. Methods: Using global and conditional knockout mice as in vivo models and primary brown adipocytes as an in vitro system, we investigated the function of miR-22 in BAT thermogenesis in vivo and in vitro . Results: miR-22 expression was upregulated in BAT in response to cold exposure and during brown preadipocyte differentiation. Both global and conditional knockout mice displayed BAT whitening, impaired cold tolerance, and decreased BAT thermogenesis. Moreover, we found that miR-22 deficiency impaired BAT glycolytic capacity, which is critical for thermogenesis. The mechanistic results revealed that miR-22 activated the mTORC1 signaling pathway by directly suppressing Tsc1 and concomitantly directly suppressing Hif1an, an inhibitor of Hif1α, which promotes glycolysis and maintains thermogenesis. Conclusions: Our findings identify miR-22 as a critical regulator in the control of thermogenesis in BAT and as a potential therapeutic target for human metabolic disorders.

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

“…In muscle cells, miR-22 inhibits AMPK/SIRT1/PGC-1α signaling [ 376 , 377 ]. In murine models and primary brown adipocytes, miR-22 activates mTORC1 signaling by directly suppressing TSC1 and HIF1AN , promoting glycolysis, and maintaining thermogenesis [ 378 ]. HIF1AN is also a predicted target of miR-148a [ 297 ].…”

“…HIF1AN is also a predicted target of miR-148a [ 297 ]. The thermogenic activity of miR-22 is of critical importance for the survival of premature infants, and apparently miR-22 via suppressing AMPK and activating mTORC1 may promote β cell proliferation and glycolytic activity of the premature neonatal β cells [ 378 ]. Of note, VHL, which forms a complex with HIF1AN on the promoter of HIF-1α, represses HIF-1α transcriptional activity [ 295 ].…”

Integrated analysis of microRNAs, circular RNAs, long non-coding RNAs, and mRNAs revealed competing endogenous RNA networks involved in brown adipose tissue whitening in rabbits

“…5 D). Some of the miRNAs in these interaction pairs were reported to be involved in the thermogenesis of adipocytes, such as from D0 to D15 dramatically downregulated ocu-miR-378-5p (log2FC = -2.56 in Y2 vs. D0) [ 49 ] and ocu-miR-433-3p (log2FC = -5.39 in Y2 vs. D0) [ 50 ] and from D15 to D85 dramatically upregulated ocu-miR-22-3p (log2FC = 1.69 in Y2 vs. D0) [ 51 ].…”

Augmented CCL5/CCR5 signaling in brown adipose tissue inhibits adaptive thermogenesis and worsens insulin resistance in obesity

“…To determine the mitochondrial respiration activities, the O 2 concentration in both primary brown adipocytes and BAT were measured using XF24 extracellular flux analyzer and XF24e islet capture microplates separately (Seahorse Bioscience, Billerica, MA) as described previously (26). In brief, SVF cells isolated from BAT of WT mice or DKO mice were seeded in an XFe24 cell culture microplate (Agilent) and differentiated into brown adipocytes.…”