Abstract
Mitochondria are critical in heat generation in brown and beige adipocytes. Mitochondrial number and function are regulated in response to external stimuli, such as cold exposure and β3 adrenergic receptor agonist. However, the molecular mechanisms regulating mitochondrial biogenesis during browning, especially by microRNAs, remain unknown. We investigated the role of miR-494-3p in mitochondrial biogenesis during adipogenesis and browning. Intermittent mild cold exposure of mice induced PPARγ coactivator1-α (PGC1-α) and mitochondrial TFAM, PDH, and ANT1/2 expression along with uncoupling protein-1 (Ucp1) in inguinal white adipose tissue (iWAT). miR-494-3p levels were significantly downregulated in iWAT upon cold exposure (p < 0.05). miR-494-3p overexpression substantially reduced PGC1-α expression and its downstream targets TFAM, PDH and MTCO1 in 3T3-L1 white and beige adipocytes (p < 0.05). miR-494-3p inhibition in 3T3-L1 white adipocytes resulted in increased PDH (p < 0.05). PGC1-α, TFAM and Ucp1 mRNA levels were robustly downregulated by miR-494-3p overexpression in 3T3-L1 beige adipocytes, along with strongly decreased oxygen consumption rate. PGC1-α and Ucp1 proteins were downregulated by miR-494-3p in primary beige cells (p < 0.05). Luciferase assays confirmed PGC1-α as a direct gene target of miR-494-3p. Our findings demonstrate that decreased miR-494-3p expression during browning regulates mitochondrial biogenesis and thermogenesis through PGC1-α.
Highlights
Recent studies have elucidated the various critical processes underlying adaptation to cold environment through examining the transition of white adipocytes into beige/brite adipocytes[1]
To investigate whether miR-494-3p contributes to mitochondrial biogenesis in adipocyte browning in vivo, C57BL/6 J mice were subjected to either acute mild cold exposure (6 h at 12 °C, Fig. 1A–E) or chronic intermittent mild cold exposure (6 h/day at 12 °C for 2 weeks, Fig. 1F–J) and adipose tissues were analysed
Inguinal white adipose tissue from the acute cold exposure group showed almost no change compared with control inguinal white adipose tissue (iWAT), but the chronic cold group showed high density of haematoxylin and eosin-stained structures along with increased Ucp[1] staining in iWAT (Fig. 1C,H)
Summary
Recent studies have elucidated the various critical processes underlying adaptation to cold environment through examining the transition of white adipocytes into beige/brite adipocytes[1]. White adipose tissue (WAT) is distributed throughout the body, and subcutaneous WAT accounts for about 85% of all body fat as the main storage organ of energy in a wide range of adiposity[2] Upon physiological stimuli such as chronic cold exposure or pharmacological treatment such as peroxisome proliferator-activated receptor γ (PPARγ) agonist β3-adrenergic receptor (β3-AR) stimulation, white adipocytes are re-programmed to beige adipocytes, which contain abundant mitochondria similar to brown adipose tissue (BAT), a major contributor of non-shivering thermogenesis[3,4]. Previous studies showed that uncoupling protein-1 (Ucp1) plays a significant role in the adaptive thermogenesis against cold through generation of heat by dissipating the proton-motive force over the mitochondrial membrane in BAT8. Here we examined this hypothesis using several beige adipocyte models
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