This study investigates the role of the circadian clock gene, Clock, in regulating energy balance and metabolism in mice. Mice with a homozygous Clock mutation exhibit a significantly attenuated diurnal feeding rhythm, hyperphagia, and obesity, along with a metabolic syndrome characterized by hyperleptinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. These mice also show reduced expression of hypothalamic peptides involved in energy balance. The results suggest that the circadian clock gene network plays a critical role in maintaining energy homeostasis, involving multiple central and peripheral tissues. Disruption of this network can lead to obesity and metabolic syndrome. The circadian clock, located in the suprachiasmatic nucleus (SCN), regulates key aspects of energy homeostasis, including the sleep-wake cycle, thermogenesis, feeding, and glucose and lipid metabolism. The discovery that clock genes regulate circadian rhythms in various tissues, including those involved in nutrient homeostasis, indicates a link between circadian and metabolic processes at multiple levels. The study also shows that changes in the ratio of oxidized to reduced NAD(P) control the transcriptional activity of the bHLH protein NPAS2, a homologue of the Clock gene, suggesting that cell redox may couple the expression of metabolic and circadian genes. The Clock mutant mice show profound changes in circadian rhythmicity, including a 1-hour increase in the free-running rhythm of locomotor activity in heterozygous animals and a 3–4 hour increase in circadian period in homozygous animals. These mice also show altered diurnal rhythms in feeding behavior, with 53% of food intake occurring during the dark phase, compared to 75% in wild-type mice. Energy expenditure is also reduced in Clock mutant mice, leading to a net 10% decrease in energy expenditure. Clock mutant mice fed a regular or high-fat diet show increased energy intake and body weight compared to wild-type controls. The weight gain in Clock mutants is primarily due to visceral adiposity, with a 20–25% increase in lipid content on either diet. The mutation does not affect fetal growth or nutrition, as body weights of Clock mutant and wild-type pups are similar in the first five weeks of life, but Clock mutants are significantly heavier at 6 weeks of age. The study also reveals significant changes in the expression of neuropeptides involved in appetite regulation and energy balance in the hypothalamus. The expression levels of Per2, orexin, and ghrelin are dramatically reduced in Clock mutant mice. These findings suggest that the circadian clock system plays an important role in regulating not only the timing of food intake and metabolic processes but also in maintaining energy homeostasis at multiple levels. The results indicate that a dysfunctional circadian system may be a risk factor equivalent to poor diet in causing weight gain and obesity.This study investigates the role of the circadian clock gene, Clock, in regulating energy balance and metabolism in mice. Mice with a homozygous Clock mutation exhibit a significantly attenuated diurnal feeding rhythm, hyperphagia, and obesity, along with a metabolic syndrome characterized by hyperleptinemia, hyperlipidemia, hepatic steatosis, and hyperglycemia. These mice also show reduced expression of hypothalamic peptides involved in energy balance. The results suggest that the circadian clock gene network plays a critical role in maintaining energy homeostasis, involving multiple central and peripheral tissues. Disruption of this network can lead to obesity and metabolic syndrome. The circadian clock, located in the suprachiasmatic nucleus (SCN), regulates key aspects of energy homeostasis, including the sleep-wake cycle, thermogenesis, feeding, and glucose and lipid metabolism. The discovery that clock genes regulate circadian rhythms in various tissues, including those involved in nutrient homeostasis, indicates a link between circadian and metabolic processes at multiple levels. The study also shows that changes in the ratio of oxidized to reduced NAD(P) control the transcriptional activity of the bHLH protein NPAS2, a homologue of the Clock gene, suggesting that cell redox may couple the expression of metabolic and circadian genes. The Clock mutant mice show profound changes in circadian rhythmicity, including a 1-hour increase in the free-running rhythm of locomotor activity in heterozygous animals and a 3–4 hour increase in circadian period in homozygous animals. These mice also show altered diurnal rhythms in feeding behavior, with 53% of food intake occurring during the dark phase, compared to 75% in wild-type mice. Energy expenditure is also reduced in Clock mutant mice, leading to a net 10% decrease in energy expenditure. Clock mutant mice fed a regular or high-fat diet show increased energy intake and body weight compared to wild-type controls. The weight gain in Clock mutants is primarily due to visceral adiposity, with a 20–25% increase in lipid content on either diet. The mutation does not affect fetal growth or nutrition, as body weights of Clock mutant and wild-type pups are similar in the first five weeks of life, but Clock mutants are significantly heavier at 6 weeks of age. The study also reveals significant changes in the expression of neuropeptides involved in appetite regulation and energy balance in the hypothalamus. The expression levels of Per2, orexin, and ghrelin are dramatically reduced in Clock mutant mice. These findings suggest that the circadian clock system plays an important role in regulating not only the timing of food intake and metabolic processes but also in maintaining energy homeostasis at multiple levels. The results indicate that a dysfunctional circadian system may be a risk factor equivalent to poor diet in causing weight gain and obesity.