Flattening of diurnal glucocorticoid oscillations causes Cd36 and insulin-mediated obesity

Abstract

Chronic stressors flatten circadian glucocorticoid oscillations, which has been correlated with negative health outcomes including obesity. How flatter circadian glucocorticoid oscillations affect metabolism and fat storage remains unknown. Here we aimed to investigate the consequences of flattened glucocorticoid oscillations in mice. We found that flattening glucocorticoid oscillations not only results in body weight gain mainly due to an increase in white fat depot mass, but also leads to fat accumulation in brown adipose tissue and to hyperinsulinemia. A transcriptomic analysis of white and brown adipose tissues revealed that flattened glucocorticoid oscillations resulted in a dysregulated lipid metabolism with a prominent role of Cd36. Indeed, Cd36 knockout mice are partially protected against body weight gain and lipid accumulation in the brown and visceral white fat depots induced by flattened glucocorticoid oscillations. These results provide insights how conditions associated with flattened glucocorticoid levels cause obesity. KEYWORDSObesity, stress, circadian rhythm, hormone oscillations, glucocorticoids, brown adipose tissue, white adipose tissue, lipid metabolism, Cd36 HIGHLIGHTS• Flattening of circadian glucocorticoid oscillations in mice results in body weight gain, lipid accumulation in white and brown adipose tissue, and hyperinsulinemia.• Transcriptomic analysis of BAT and WAT revealed gene expression alterations pointing to dysregulated lipid metabolism caused by flattened glucocorticoid oscillations, including upregulation of Cd36.• Cd36ko mice are partially protected against body weight gain and lipid accumulation in brown adipose tissue and visceral fat upon flattening glucocorticoid oscillations.

MECHANISMS IN ENDOCRINOLOGY: Local and systemic effects of glucocorticoids on metabolism: new lessons from animal models

“…Transcriptomic analysis of BAT from corticosteronetreated mice revealed increases in genes involved in lipid synthesis and degradation, including Lpin1 (encoding lipin-1, which regulates adipose tissue triglyceride metabolism) and Acsm5 (Acyl-CoA synthetase medium chain family member 5). Corticosterone-mediated flattening of circadian rhythm also induced expression of the lipid uptake receptor CD36, and corticosteroneinduced obesity and lipid accumulation in BAT and VAT were partially abrogated in CD36-null mice (113).…”

“…Intriguingly, two recent studies in mice implanted with corticosterone pellets have independently concluded that glucocorticoids stimulate BAT whitening by disrupting circadian rhythms related to lipid uptake (112,113). The uptake of triglyceride-derived fatty acids into BAT displays a circadian rhythm in mice: it is highest in the evening (when endogenous glucocorticoids are elevated), and this pattern was disrupted within a few days of pellet implantation (112,113). Lipid uptake was not perturbed by daily injections of corticosterone in the evening, however, suggesting that continuous elevation of corticosterone levels is required for BAT whitening.…”

Contributions of White and Brown Adipose Tissues to the Circadian Regulation of Energy Metabolism

“…GCs promote adipocyte differentiation ( 68-70 ). Dampened GC rhythms result in increased lipid accumulation and body weight gain due to upregulation of the FA transporter Cd36 ( 71 ). Hypercortisolemia increases lipolysis while at the same time promoting visceral adiposity, probably by enhanced preadipocyte differentiation ( 69 , 72 ).…”