Glucocorticoid/Adiponectin Axis Mediates Full Activation of Cold-Induced Beige Fat Thermogenesis.

Liping Luo,Lu Wang,Estevan Romero,Xin Yang,Meilian Liu,Yan Luo

doi:10.3390/biom11111573

Abstract

Glucocorticoids (GCs), a class of corticosteroids produced by the adrenal cortex in response to stress, exert obesity-promoting effects. Although adaptive thermogenesis has been considered an effective approach to counteract obesity, whether GCs play a role in regulating cold stress-induced thermogenesis remains incompletely understood. Here, we show that the circulating levels of stress hormone corticosterone (GC in rodents) were significantly elevated, whereas the levels of adiponectin, an adipokine that was linked to cold-induced adaptive thermogenesis, were decreased 48 h post cold exposure. The administration of a glucocorticoid hydrocortisone downregulated adiponectin protein and mRNA levels in both WAT and white adipocytes, and upregulated thermogenic gene expression in inguinal fat. In contrast, mifepristone, a glucocorticoid receptor antagonist, enhanced adiponectin expression and suppressed energy expenditure in vivo. Mechanistically, hydrocortisone suppressed adiponectin expression by antagonizing PPARγ in differentiated 3T3-L1 adipocytes. Ultimately, adiponectin deficiency restored mifepristone-decreased oxygen consumption and suppressed the expression of thermogenic genes in inguinal fat. Taken together, our study reveals that the GCs/adiponectin axis is a key regulator of beige fat thermogenesis in response to acute cold stress.

Highlights

Brown and beige adipocytes, referred to as lipid-burning cells, dissipate energy in the form of heat, and are widely recognized as a potential therapeutic approach for the treatment of obesity and its associated disorders
Circulating levels of adiponectin were suppressed by cold exposure [42,43], and this provides a mechanism underlying cold-induced adipose-resident group 2 innate lymphoid cells (ILC2) activation and thermogenesis [35]
Similar to norepinephrine levels in white adipose tissue (WAT) [34], circulating levels of corticosterone were increased by cold exposure for 48 h in male mice (Figure 1A), while the levels of T3 and adiponectin in serum were decreased by acute cold stress (Figure 1B,C)

Summary

Introduction

Brown and beige adipocytes, referred to as lipid-burning cells, dissipate energy in the form of heat, and are widely recognized as a potential therapeutic approach for the treatment of obesity and its associated disorders. SNS releases norepinephrine in adipose tissue, thereby, activating β3 adrenoceptor signaling and thermogenic program in adipocytes [1,2]. The neuroendocrine hormones, including the thyroid hormones triiodothyronine (T3) and thyroxine (T4), glucocorticoids (GCs), and the adrenal medullary hormones catecholamine and dopamine, play a pivotal role in metabolic homeostasis maintenance [3,4,5]. The mechanisms underlying neuroendocrine regulation of thermogenic program and cold adaptation remain largely unknown. GCs are a class of corticosteroids that are critical for the regulation of metabolic, cardiovascular, immunologic, and homeostatic functions in response to various types. Biomolecules 2021, 11, 1573 of stress in humans and in rodents [6,7].

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