Abstract 450: Adipose Tissue Browning Induced by Natriuretic Peptide Exerts Thermogenic Actions and Improves Insulin Resistance in an in vivo Model of Diet-Induced Obese Mice

Although natriuretic peptides (NPs) classically act on renal and cardiovascular systems, increasing evidence suggest that NPs also largely coordinate inter-organ metabolic cross-talk with adipose tissues. We recently reported that A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature sensitive manner. We herein investigated whether ANP exerts a significant impact on adipose tissues in vivo, using diet-induced obese mice. C57BL/6 mice were exposed to high-fat diet (HFD) or normal-fat diet (NFD) for 13 weeks, and treated with or without ANP infusion for 3 weeks (0.5 ug/kg/min via osmotic-pump). The ANP infusion significantly increased its serum concentration both in NFD and HFD group. Histological analyses revealed that HFD induced increased brown adipose tissue (BAT) cell size with accumulation of lipid droplets (whitening). ANP treatment significantly suppressed this whitening response (re-browning). Similarly, HFD induced enlarged inguinal white adipose tissue (WAT) lipid droplets, which was significantly reduced by ANP. This was associated with a substantial increase in uncoupling protein-1(UCP1) expression in WAT confirmed by immunohistochemical analysis (browning, n=3 each) and UCP1mRNA analysis (NFD+NP 2.7±0.4 fold vs NFD, P<0.01; HFD+NP 6.4±2.2 fold vs HFD, P<0.05, n=5 each). To determine the functional significance of browning effects of ANP, intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were performed and showed that ANP treatment substantially improved insulin resistance in HFD (p<0.05, n=9 each). Moreover, cold tolerance test (at 4°C for 4 hours) demonstrated that the ANP-treated mice were tolerant to cold exposure, which was more salient in HFD with ANP (Decrease in rectal temperature from baseline [°C]: NFD+ANP –2.4±0.6, HFD –2.5±0.4, HFD+ANP –2.1±0.4, versus NFD –9.2±2.2, P<0.01 each, n=9 each). In conclusion, ANP induces WAT browning and preserves BAT function in obese models, leading to in vivo thermogenesis as well as improvement in insulin resistance. These findings reveal the compensatory roles of natriuretic peptides against the core body temperature fall and insulin resistance in a state of heart failure.