IMPA2 Ameliorates High-Fat Diet-Induced Obesity by Enhancing Adaptive Thermogenesis in a Ca2+-activated Mitochondrial Biogenesis Pathway

The identification of thermogenic adipocytes in humans proves that enhanced adaptive thermogenesis may help mitigate obesity. Although some evidence suggests a role for IMPA2 in cellular metabolism, its specific impact on obesity and the underlying mechanisms remain underexplored. High-fat-diet (HFD)-induced obese mice were employed as experimental models. Cold exposure (4°C) or administration of the β3-adrenoceptor agonist CL316,243 was used to stimulate adipose thermogenesis. In vivo modulation of IMPA2 function was achieved through subcutaneous injection of adeno-associated virus (AAV). Body weight and energy metabolism were monitored, and browning was determined. The role and mechanisms of IMPA2 in thermogenesis were examined through adenovirus (Adv) treatment, followed by in vitro and in vivo analyses. Thermogenic stimulation increased IMPA2 level in murine inguinal white adipose tissue (iWAT), whereas obesity resulted in its downregulation. IMPA2 overexpression in iWAT accelerated WAT browning and thermogenesis, conferring protection against HFD-induced obesity and metabolic disturbances. Conversely, silencing IMPA2 reduced thermogenic gene levels in iWAT and inhibited WAT browning. Mechanistically, IMPA2 elevated myo-inositol (MI), inositol-1,4,5-trisphosphate (IP3) and intracellular calcium ion (Ca²⁺) levels, which subsequently activated Ca²⁺/calmodulin-dependent protein kinase IIα (CamKIIα) and PGC1α axis to increase mitochondrial biogenesis and thermogenic capacity in adipocytes. In conclusion, IMPA2 improves obesity and metabolic disorders, with its thermogenic enhancement mediated by the Ca²⁺-activated mitochondrial biogenesis pathway.