Circadian rhythms of hormone secretion and obesity

Abstract

The adipose tissue homeostasis is profoundly affected by circadian rhythms of corticosteroid secretion and chronic loss of hormonal oscillations is associated with obesity. How adipose tissue differentially responds to pulsatile vs continuous presence of glucocorticoids is poorly defined. To address this question, Bahrami-Nejad et al studied differentiation of pre-adipocytes, containing endogenously tagged CCAAT/enhancer binding protein and peroxisome proliferator-activated receptor (PPAR) γ (key regulators of adipocyte differentiation), in response to corticosteroids that were delivered either in an oscillatory fashion or continuously. The authors show that the bi-stable state of differentiation of pre-adipocytes and adipocytes was regulated by a combination of fast and slow positive feedback networks, that determined unique threshold of PPARγ in these cells. Evidently, pre-adipocytes used the fast feedback loop to reject differentiation cues of oscillating pulses of glucocorticoids and failed to differentiate into fat cells. In contrast, when glucocorticoids were delivered continuously, precursor cells exploited the slow feedback loop to embark on a path of maximal differentiation. This differential differentiation response of pre-adipocytes to pulsatile vs continuous exposure to glucocorticoids was corroborated in vivo. Thus, mice receiving non-oscillating doses of exogenous glucocorticoids, for 21 d, elicited excessive accumulation of visceral and subcutaneous fat. These data shed new light on the mechanisms of obesity caused by putative misalignment of circadian secretion of glucocorticoids or their persistently high levels due to chronic stress or Cushing’s disease.

Keywords: Circadian rhythms, Glucocorticoids, Adipose tissue, Pre-adipocytes, Stem cells, Terminal differentiation

Core tip: Bahrami-Nejad et al examined pre-adipocytes for their ability to differentiate into fat cells in response to hormonal stimuli that were presented either in a pulsatile manner, mimicking circadian rhythms, or delivered continuously. These experiments revealed that adipocyte differentiation program, made up of slow and fast feedback circuits, was able to distinguish between the oscillating and continuous hormonal signals. The authors showed that pre-adipocytes apparently used the fast, positive feedback network to reject the oscillating hormonal cues. In contrast, if delivered continuously, similar strength glucocorticoids impinged on the slow positive feedback circuit to trigger maximal differentiation of pre-adipocytes into bone fide fat cells. The pulsatile vs continuous hormone stimuli were similarly discriminated in vivo since mice receiving glucocorticoids in a non-oscillating manner for 21 d elicited increased accumulation of subcutaneous and visceral fat. These data elucidate a potential mechanism underling the development of obesity associated with chronic stress or Cushing’s disease.