Abstract
Disruption of circadian clock enhances the risk of metabolic syndrome, obesity, and type 2 diabetes. Circadian clocks rely on a highly regulated network of transcriptional and translational loops that drive clock-controlled gene expression. Among these transcribed clock genes are cryptochrome (CRY) family members, which comprise Cry1 and Cry2. While the metabolic effects of deletion of several core components of the clock gene machinery have been well characterized, those of selective inactivation of Cry1 or Cry2 genes have not been described. In this study, we demonstrate that ablation of Cry1, but not Cry2, prevents high-fat diet (HFD)-induced obesity in mice. Despite similar caloric intake, Cry1−/− mice on HFD gained markedly less weight (−18%) at the end of the 16-week experiment and displayed reduced fat accumulation compared to wild-type (WT) littermates (−61%), suggesting increased energy expenditure. Analysis of serum lipid and glucose profiles showed no difference between Cry1−/− and WT mice. Both Cry1−/− and Cry2−/− mice are indistinguishable from WT controls in body weight, fat and protein contents, and food consumption when they are allowed unlimited access to a standard rodent diet. We conclude that although CRY signaling may not be essential for the maintenance of energy homeostasis under steady-state nutritional conditions, Cry1 may play a role in readjusting energy balance under changing nutritional circumstances. These studies reinforce the important role of circadian clock genes in energy homeostasis and suggest that Cry1 is a plausible target for anti-obesity therapy.
Highlights
The biological clock is an extensive molecular network that provides circadian time-keeping, controlling and maintaining daily rhythms of many behavioral and physiological processes
Mammalian clocks reside in the suprachiasmatic nucleus (SCN), in which the clock is determined by light signals through the retinohypothalamic tract, but they have been identified in a wide array of peripheral organs including heart, lung, kidney, liver, and pancreas, where their timing is set by metabolic cues [2,3,4]
Utilizing Cry1−/− and Cry2−/− mice, we demonstrate for the first time that Cry1−/− loss interferes with high-fat diet (HFD)-induced obesity, and that the physiological basis of this effect is not related to reduced energy intake
Summary
The biological clock is an extensive molecular network that provides circadian time-keeping, controlling and maintaining daily rhythms of many behavioral and physiological processes In mammals, it comprises a complex circuitry of transcriptional and translational regulatory feedback loops, including the core transcriptional activators CLOCK and BMAL1, which activate expression of three Period (Per1–3) and two cryptochrome (Cry and Cry2) genes [1]. There are several studies on the consequences of Cry, Cry, and Cry1/2 deletion, mainly on behavioral and molecular rhythmicity, only one has investigated the effects of Cry1−/−Cry2−/− double mutation on metabolism [18] These authors showed that deficiency in CRY resulted in increased susceptibility to diet-induced obesity as a consequence of increased insulin secretion and lipid storage
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