Location: Children's Nutrition Research Center2012 Annual Report
1a. Objectives (from AD-416):
Objective 1: Determine the role of the circadian clock in regulation of food intake and the interaction between diet composition and circadian rhythms of food intake on body weight control during post-weaning and adult life; determine the specific role of central and peripheral clocks, as well as the circadian output pathways in maintaining the homeostasis of food intake. Sub-objective 1.A. Determine the role of the circadian clock in controlling food intake and the development of obesity. Sub-objective 1.B. Study the role of central and peripheral clocks, as well as the circadian output pathways in maintaining the homeostasis of food intake.
1b. Approach (from AD-416):
Children's Nutrition Research Center researchers will determine how the disruption of circadian rhythm disrupts energy homeostasis by measuring food-intake and energy expenditure of wt and Period2-mutant adult mice (10-12 weeks of age) using the Comprehensive Lab Animal Monitoring System (CLAMS). We will study whether disruption of circadian rhythm abolishes the homeostasis of energy homeostasis by measuring serum metabolic parameters in wt and Period2-mutant mice at post-weaning (3-7 weeks of age) and in adulthood (10-12 weeks of age). The interaction of diet composition and food-intake homeostasis will be evaluated by studying the effect of high energy food on body weight and food-intake of wt and Period2-mutant mice. The effect of restricted feeding on the homeostasis of serum metabolic parameters and body weight of wt and Period2-mutant mice will also be analyzed. Our scientists will determine how the disruption of circadian rhythm leads to deregulation of long-term peripheral adiposity signal leptin by investigating the role of the peripheral circadian clock in controlling leptin transcription, the role of the central circadian clock in controlling leptin transcription, and the role of the circadian output pathways in controlling leptin transcription in adipose tissues.
3. Progress Report:
Evolutionary adaptation to dramatic environmental changes over a 24-hour period dictates that most physiological processes in mammals follow a circadian rhythm. Disruption of the circadian rhythm has been linked to increased risks of cancer and metabolic syndrome in humans. Circadian rhythms in mammals are generated by an internal central clock located in the hypothalamus (specifically in the hypothalamic suprachiasmatic nucleus), which controls subordinate clocks active in all peripheral tissues. Both the central and peripheral clocks are based on cyclic expression of circadian genes that operate the molecular clock. This year we demonstrated that food-intake and energy expenditure, the two key body functions required for maintaining body weight balance follow a coupled and robust circadian rhythm. Disruption of circadian behavioral rhythm in wild-type (wt) mice by chronic jet-lag that mimics the human shift work schedules induces obesity by decreasing energy expenditure and increasing energy storage (jet-lag: constantly back-and-forth transfer mice between two animal rooms that are different in the time of light onset for 8 hours). Importantly, the increase in body weight and fat accumulation in jet-lagged wt mice occurred in the absence of changes in the amount of daily food-intake, the choice of diets or total daily physical activity. We found that jet-lagged wt mice show deregulation of the key peripheral adiposity signals, and demonstrated that the serum levels of the best studied peripheral adiposity signals, leptin, is controlled by the internal circadian clock but not as previously assumed by external food cues. In addition, we demonstrated that the peripheral circadian clock directly controls the rhythmic expression of leptin gene in the white adipose tissues. Disruption of circadian rhythm in wt mice by jet-lag abolishes the homeostasis of serum levels of Leptin, uncouples leptin signaling with the activity of food-intake, and induces Leptin resistance, which is a key developmental mechanism for human obesity. Together, our studies in FY2012 demonstrate that circadian disruption promotes obesity development independent of all previous identified obesity risk factors, and identified a key molecular mechanism by which circadian clock controls the energy homeostasis in vivo. Based on our studies, we propose that disruption of circadian control of Leptin expression and signaling is a major contributor to the diverse metabolic consequences of circadian disruption.
1. The expression and function of leptin follow a circadian rhythm in vivo. Leptin is a hormone secreted from the fat tissue and acts on the brain via blood circulation to suppress appetite and stimulate metabolism. The level of Leptin peaks during the day in response to food-intake (which stimulates energy expenditure to prevent obesity) and troughs at night during sleeping, and is also proportional to the size of fat tissue in the body. Researchers at the Children's Nutrition Research Center in Houston, Texas, have found that Leptin is controlled by the circadian clock. The disruption of circadian rhythm induces and maintains obesity in mice even when they have higher levels of Leptin due to increasing fat storage, a phenomenon called "Leptin resistance", which is commonly observed among obese humans. Since the industrial revolution, frequent disruption of circadian rhythm has become common to all human societies, especially nightshift workers who show a nearly two-fold greater risk of developing metabolic syndromes and obesity. Further study the mechanism of circadian control of the expression and function of Leptin will have a very high impact on the prevention and treatment of obesity in humans.