Abstract
The biological clock plays an important role in integrating nutrient and energy metabolism with other cellular processes. Previous studies have demonstrated that core clock genes are rhythmically expressed in peripheral tissues, including the liver, skeletal muscle, pancreatic islets, and white and brown adipose tissues. These peripheral clocks are entrained by physiological cues, thereby aligning the circadian pacemaker to tissue functions. The mechanisms that regulate brown adipose tissue clock in response to physiological signals remain poorly understood. Here we found that the expression of core clock genes is highly responsive to cold exposure in brown fat, but not in white fat. This cold-inducible regulation of the clock network is mediated by adrenergic receptor activation and the transcriptional coactivator PGC-1α. Brown adipocytes in mice lacking a functional clock contain large lipid droplets accompanied by dysregulation of genes involved in lipid metabolism and adaptive thermogenesis. Paradoxically, the “clockless” mice were competent in maintaining core body temperature during cold exposure. These studies elucidated the presence of adrenergic receptor/clock crosstalk that appears to be required for normal thermogenic gene expression in brown fat.
Highlights
Obesity and its associated metabolic disorders have become a global epidemic that elevates the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease
The expression of Ucp1 was higher in Brain and muscle Arntlike 1 (Bmal1) null adipocytes following norepinephrine treatments (Fig. 5D). These results suggest that, while Bmal1 is not required for the differentiation of brown adipocytes and the formation of brown adipose tissue, it is required for maintaining normal expression of genes involved in thermogenesis and lipid metabolism
We demonstrated that the brown fat clock is highly responsive to cold exposure and adrenergic receptor activation
Summary
Obesity and its associated metabolic disorders have become a global epidemic that elevates the risk for type 2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease. Brown adipose tissue (BAT) plays an important role in adaptive thermogenesis that maintains core body temperature in cold environment and contributes to whole body energy homeostasis [1,2]. Clusters of UCP1positive brown adipocyte-like cells emerge in white fat depots in response to chronic cold exposure or adrenergic stimulation [7,8,9]. These ‘‘beige’’ adipocytes originate from progenitor pools that are developmentally distinct from brown adipocytes in BAT [10,11]. Several transcriptional factors and cofactors have been identified to regulate different aspects of brown fat development, including Prdm, C/EBPb, Foxc, Twist, PGC-1a and PGC-1b [10,12,13,14,15,16,17,18]
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