The emerging role of circadian rhythms in the development and function of thermogenic fat

Abstract

Circadian rhythms regulate many biological processes in response to ambient influences. A disrupted circadian rhythm has been shown to be associated with obesity and obesity-related metabolic disorders. Thermogenic fat, including brown and beige fat, may play an important role in this process since it displays a high capacity to burn fat and release the stored energy as heat, contributing to the combat against obesity and its associated metabolic disorders. In this review, we summarize the relationship between the circadian clock and thermogenic fat and the prominent mechanisms which are involved in the regulation of the development and function of thermogenic fat by circadian rhythms, which may provide novel therapeutics for the prevention and treatment of metabolic diseases by targeting thermogenic fat in a circadian manner.

Keywords: brown/beige fat; circadian clock; circadian rhythms; obesity; thermogenesis.

Figure 1

Circadian rhythms in thermogenic fat. SCN is mainly entrained by light signals and synchronizes the circadian rhythms of thermogenic fat and other peripheral tissues. SCN and other factors like time of food intake and peripheral tissues carefully regulate the thermogenic adipocyte clock. The molecular mechanism lies in TTFL including a positive arm such as CLOCK, BMAL1, and ROR and a negative arm like PER, CRY, and REV-ERB. Circadian rhythms including glucose uptake, fatty acid synthesis, lipid clearance, and thermogenesis are present in thermogenic fat. Circadian disruptions caused by abnormal light/dark cycle, clock gene mutation, and behavioral misalignments like shift work and jet lag cause circadian dysregulation of thermogenic fat, contributing to obesity and related metabolic disorders. SCN, suprachiasmatic nuclei; TTFL, transcriptional–translational feedback loop. Figures were created with BioRender (https://biorender.com/).

Figure 2

Circadian regulation of thermogenic fat. Clock proteins directly influence thermogenic fat function by regulating transcription. CLOCK, PER2, and CRY1/2 positively regulate thermogenesis, while RORα, BMAL1, and REV-ERBα inhibit thermogenesis. SNS activates thermogenic fat by releasing norepinephrine. FA released from lipid droplets can activate UCP1. The TG-rich lipoproteins promote FA uptake by LPL and replenish intracellular lipid stores. Melatonin, FGF21, and insulin bind to their receptors and contribute to thermogenesis, while glucocorticoids and ghrelin suppress thermogenesis. SNS, sympathetic nervous system; TG, triglyceride; FA, fatty acids; UCP1, uncoupling protein 1; LPL, lipoprotein lipase; FGF21; fibroblast growth factor 21. Figures were created with BioRender (https://biorender.com/).