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

Haruka Kimura,Hirotake Takahashi,Akira Yoshii,Toshikazu D Tanaka,Michihiro Yoshimura,Yoshiro Tanaka,Tomohisa Nagoshi,Yuhei Oi,Yusuke Kashiwagi

doi:10.1038/s41598-021-96970-9

Haruka Kimura, Hirotake Takahashi + Show 7 more

Open Access

https://doi.org/10.1038/s41598-021-96970-9

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Journal: Scientific Reports	Publication Date: Aug 31, 2021
Citations: 29	License type: open-access

Affiliation: Jikei University School of Medicine

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.

Highlights

Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism
We found that exogenous A-type NP (ANP) administration significantly improved the HFD-induced insulin resistance by attenuating hepatic steatosis and inducing adipose tissue browning in association with the activation of the brown fat thermogenic program
The mice treated with ANP developed tolerance to cold exposure, indicating the adaptive heat-retaining property of NPs when body temperature falls via interorgan metabolic crosstalk with adipose tissues

Summary

Introduction

Increasing evidence suggests natriuretic peptides (NPs) coordinate inter-organ metabolic crosstalk with adipose tissues and play a critical role in energy metabolism. A-type natriuretic peptide (ANP) as well as B-type natriuretic peptide (BNP), which are hormones produced in the heart, regulate blood pressure and fluid homeostasis through vasodilatory and diuretic actions, and improve cardiac remodeling[1,2,3,4] In addition to these classical actions of hemodynamic regulation on the renal and cardiovascular systems, growing evidence suggests that natriuretic peptides (NPs) regulate the energy balance and glucose homeostasis as well as thermogenesis through interorgan metabolic crosstalk with adipose tissues, in which NP receptors (NPR-A) are e xpressed[4,5,6,7,8,9,10,11,12]. Several studies showed that ANP/BNP promote triglyceride lipolysis as well as uncoupling of mitochondrial respiration by inducing adipose tissue browning, which results in ameliorating insulin resistance and activating the thermogenic program[4,5,6,7,13,14,17,18,19,20,21]. A series of these studies indicated that NPs play a central role in “myocardial-adipose crosstalk”

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