miR-125b impairs brite adipocyte formation and function

Type 2 diabetes mellitus and the associated beta-cell failure is attributable up to 90% to weight gain and has increased in parallel with the epidemic of obesity. We are now aware that healthy adult humans possess active brown adipose tissue (BAT) presenting a high glucose uptake. Furthermore, in rodents and humans, islands of brown adipocytes, termed “brite” (brown-in-white), emerge within white adipose tissue (WAT) depots after cold or β3-adrenergic stimulation. Therefore, the identification of regulatory factors, which allows converting white to brite adipocytes, would be of great interest for the treatment of obesity related type 2 diabetes. microRNAs are a novel class of modulators of adipose tissue development and function. Using hMADS cells, we identified miR-125b as down-regulated upon this conversion. In human and rodent, miR-125b expression was down regulated in BAT compared to WAT. miR-125b mimic/inhibitor transfection in hMADS adipocytes impacts significantly basal and maximal mitochondrial oxygen consumption. We showed that after β3-adrenergic receptor stimulation in mice in vivo, miR-125b levels were down-regulated in subcutaneous (sc) WAT and in BAT. Finally, we found that injection of miR-125b mimic in scWAT inhibited, while of the inhibitor induced, brown adipocyte marker expression and mitochondriogenesis.

Our observations highlight an important role of miR-125b in the control of white to brite adipocyte conversion via regulation of mitochondriogenesis. This study allows a better understanding of the mechanisms underlying the role of miR-125b in the browning of white adipocytes, paving a way for the development of new therapies against obesity and type 2 diabetes.