Introduction & Objective: Adaptive thermogenesis offer crucial potential to combat metabolic diseases. We have proved G-protein-signaling modulator 1 (GPSM1) regulated metabolic inflammation in macrophages, however, it remains unclear whether GPSM1 mediates thermogenic fat function.
Methods: We generate adipocyte-specific GPSM1 KO and transgenic mice, subject them to a NCD or HFD to monitor thermogenic and metabolic phenotypes. By using molecular, biochemical analyses, and primary cell culture to reveal the role of GPSM1 in adipocytes and elucidate the underlying mechanisms of GPSM1 in regulating thermogenesis.
Results: Adipocyte-specific KO of GPSM1 in mice impairs a broad thermogenesis of adipocytes, including decreased energy expenditure, cold tolerance and UCP1 levels, exacerbates diet-induced obesity, insulin resistance, glucose dysregulation and hepatic steatosis. Mechanistically, GPSM1 controls ER Ca2+ store, resulting in enhanced intracellular Ca2+ levels and consequential promoting Ca2+-dependent myosin II activation, thus mediating mitochondrial respiration and thermogenesis in adipocytes. In contrast, mice with transgenic overexpression of GPSM1 show improved energy expenditure, better cold tolerance, and ameliorated metabolic dysfunctions.
Conclusions: we uncover a novel function of GPSM1 as a positive regulator of adipocyte thermogenesis and metabolic homeostasis.
J. Yan: None. C. Hu: None.
the National ScienceFoundation of China (82370879); Shanghai Rising-Star Program (23QA1407400)
