Treatment with atrial natriuretic peptide induces adipose tissue browning and exerts thermogenic actions in vivo

Abstract

Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. We recently reported A-type NP (ANP) raises intracellular temperature in cultured adipocytes in a low-temperature-sensitive manner. We herein investigated whether exogenous ANP-treatment exerts a significant impact on adipose tissues in vivo. Mice fed a high-fat-diet (HFD) or normal-fat-diet (NFD) for 13 weeks were treated with or without ANP infusion subcutaneously for another 3 weeks. ANP-treatment significantly ameliorated HFD-induced insulin resistance. HFD increased 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, and hepatic steatosis, all of which were substantially attenuated by ANP-treatment. Likewise, ANP-treatment markedly increased UCP1 expression, a specific marker of BAT, in iWAT (browning). ANP also further increased UCP1 expression in BAT with NFD. Accordingly, cold tolerance test demonstrated ANP-treated mice were tolerant to cold exposure. In summary, exogenous ANP administration ameliorates HFD-induced insulin resistance by attenuating hepatic steatosis and by inducing adipose tissue browning (activation of the adipose tissue thermogenic program), leading to in vivo thermogenesis during cold exposure.

URAT1-selective inhibition ameliorates insulin resistance by attenuating diet-induced hepatic steatosis and brown adipose tissue whitening in mice

“…The serum (supernatant) was collected into new tubes and frozen at −20 °C prior to the measurement. Serum triglyceride (TG) and non-esterified fatty acids (NEFA) were measured at 4 weeks after the initiation of dotinurad treatment using LabAssay Triglyceride (#LABTR G-M1, Fujifilm Wako Pure Chemical Corporation, Tokyo, Japan) and LabAssay NEFA (#294-63601, Fujifilm Wako Pure Chemical Corporation, Tokyo, Japan), respectively, according to the manufacturer's protocol as described previously [ 18 ]. Serum insulin levels were measured using the mouse insulin ELISA kit (Shibayagi, Gunma, Japan) according to the manufacturer's protocol [ 25 ].…”

“…The mice were held in a small mouse pocket on a warming pad thermostatically controlled at 37 °C. Systolic and diastolic pressure and heart rate were calculated at three different times and averaged [ 18 ].…”

“…Four weeks after the initiation of treatment with dotinurad, we performed a glucose tolerance test (IPGTT) and insulin tolerance tests (ITT), as described previously [ 18 , 24 ].…”

“…The liver, eWAT, iWAT, and BAT were excised, washed in ice-cold PBS, and fixed with 10% formalin. The samples were embedded into paraffin, and 4 μm sections were prepared for histological analyses as described previously [ 18 ]. Hematoxylin and eosin-stained sections were visualized using ECLIPS 80i (Nikon Co., Tokyo, Japan).…”

“…Adipose tissues are broadly classified into two categories: white adipose tissue (WAT) serves largely to store calories, and its inflammation is generally responsible for metabolic disorders, whereas brown adipose tissue (BAT) promotes energy utilization and generates heat using metabolic fuel via a BAT-specific protein, uncoupling protein 1 (UCP1) [ 15 , 16 ]. Diet-induced obesity leads to BAT “whitening”, which is associated with the accumulation of large lipid droplets and mitochondrial dysfunction and loss, resulting in impaired glucose metabolism [ 15 , 17 , 18 ]. Diet-induced obesity also causes the dysfunction of WAT per se, leading to the impairment of glucose metabolism, and the activation of URAT1 has been reported to be involved in this pathophysiological mechanism [ 1 , 19 ]; however, the role and functional significance of URAT1 in BAT remains unknown.…”