OS 36-09 DEFICIENCY OF THERMOGENESIS AND HEAT SENSATION ACCELERATES OBESITY AND HIGH BLOOD PRESSURE.

Objective: Obesity is global healthy problem. Uncoupling protein 1 (UCP1) mainly expresses on brown adipose tissue (BAT), uncouples energy substrate oxidation from mitochondrial ATP production and results in the loss of potential energy as heat. Transient receptor potential vanilloid subfamily, member 1 (TRPV1) is the heat-gated cation ion channel. The aim of this study was to investigate the in vivo role of TRPV1 and UCP1 co-action in obesity. Design and Method: We generated and characterized UCP1−/− mice lacking TRPV1 activity (TRPV1−/−/UCP1−/− mice). The core-body temperature and the locomotor activity were simultaneously measured by the telemetry system. The rate of mitochondrial respiration was measured using the Oxygraph-2k. Cytosol superoxide anion was determined by DHE and mitochondrial superoxide anion was measured by MitoSOX. The levels of ATP in primary cultured brown adipocytes were measured using a firefly luciferase-based ATP assay kit. Primary brown adipocytes were cultured and the fluorescence measurements of cells were made using a fluorescent plate reader. Results: TRPV1 and UCP1 double knockout would appear obesity in advance and more severe comparing with WT, TRPV1−/− and UCP1−/− mice. TRPV1 and UCP1 double knockout in mice reduced functional BAT generation to cause BAT white, and decreased lipolysis comparing with the other three groups. TRPV1−/−/UCP1−/− mice significantly decreased resting oxygen consumptions, heat production and locomotor activities. Mitochondrial respiratory function seriously disordered in BAT of TRPV1−/−/UCP1−/− mice. TRPV1 and UCP1 double knockout resulted in dramatically reduced Ca2+mito uptake in low [Ca2+]cyto that was coupled with H+mito extrusion, which affected ATP generation and oxidative stress in BAT mitochondria. TRPV1 knockout caused to a Ca2+mito uptake compensatory rise. Conclusions: The results of our genetic manipulation studies provide in vivo evidence for the pathogenesis of TRPV1 and UCP1 double knockout in mice caused obesity and offer a novel target to manipulate obesity and associated complications.