Treatment With Atrial Natriuretic Peptide Induces Adipose Tissue Browning and Exerts Thermogenic Actions in Vivo.

Background: Although natriuretic peptides (NPs) classically act on the renal and cardiovascular systems, increasing evidence suggests that NPs also largely coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported that A-type NP (ANP) raises the intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether or not exogenous ANP treatment exerts a significant impact on adipose tissues in vivo using diet-induced obese mice.Methods and Results: C57BL/6 mice fed a high-fat diet (HFD) or normal-fat diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously via osmotic pump for another 3 weeks (0.5 μg/kg/min). The intraperitoneal glucose tolerance test and insulin tolerance test showed that ANP treatment significantly ameliorated HFD-induced insulin resistance. Histological analyses revealed that HFD increased the brown adipose tissue (BAT) cell size with the accumulation of lipid droplets (whitening), which was suppressed by ANP treatment (re-browning). Furthermore, HFD induced enlarged lipid droplets in inguinal white adipose tissue (iWAT), crown-like structures in epididymal WAT (eWAT), and hepatic steatosis, all of which were substantially attenuated by ANP treatment. Likewise, ANP treatment markedly increased the expression of uncoupling protein-1 (UCP1), a specific marker of BAT, in iWAT (browning). ANP also further increased the UCP1 expression in BAT with an NFD. Accordingly, the cold tolerance test (at 4 °C for 4 h) demonstrated that the ANP-treated mice were tolerant to cold exposure.Conclusions: Exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis as well as by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.