2013 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.
Our studies this year have led to the discovery that leptin resistance plays a significant role in circadian dysfunction-induced obesity. Mounting evidence suggests that the disruption of circadian homeostasis increases the risk of obesity and metabolic syndromes. However, the mechanism of circadian dysfunction-induced obesity is still not clear. Our study using mouse models during the previous fiscal year suggests that circadian dysfunction may promote leptin resistance, a hallmark of obesity in humans, as mice lacking circadian homeostasis display phenotypes of loss of diurnal profiles in food-intake, physical activity, serum level of leptin, and energy expenditure which are coupled with increased whole body or organ-specific obesity. This year, we have made several important discoveries that support a role for circadian disruption in the development of leptin resistance. First, the core circadian regulators BMAL1 and CLOCK rhythmically regulate leptin transcription in the fat tissue in vivo. Second, loss of function in the peripheral clock leads to dampened and arrhythmic leptin expression in the fat tissue and serum independent of changes in food cues and the amount of food-intake. Third, the hypothalamic energy homeostasis center responds to diurnal serum leptin signaling to generate a robust circadian rhythm of energy expenditure in the active phase during a day under normal physiological conditions. Fourth, circadian gene-mutant mouse models prone to obesity fail to increase the rate of energy expenditure in response to high level of endogenous serum leptin or exogenous leptin administration to reduce food-intake and increase energy expenditure, which is a hallmark of leptin resistance. Most importantly, we have demonstrated that leptin resistance described above can be also induced in wild-type mice treated with chronic jet-lag that follows a schedule resembling human night-shift working schedules. Together, our findings suggest that in addition to the lack of physical activity and high energy diet intake, chronic disruption of circadian homeostasis is a key risk factor for the development of leptin resistance and obesity prevalence in modern societies. The evolutionary adaptation to dramatic environmental changes over a 24 hour period dictates that most biological processes essential for survival including energy homeostasis follow a circadian rhythm. Dramatic changes in lifestyles since the industrial revolution has led to frequent disruption of endogenous circadian homeostasis, which is closely related to increased risk of obesity, hypoinsulinemia and diabetes in both humans and animal models. Especially, human night-shift workers display nearly a two-fold increase in the risk of obesity and metabolic syndromes. Therefore, our discoveries are especially relevant for understanding the mechanism of obesity prevalence in the post-industrialized societies in which frequent disruption of circadian homeostasis affect all human races, and to the development of more efficient approaches for obesity prevention and treatment.
Frequent disruption of circadian homeostasis increases the risk of leptin resistance. Research is lacking on whether circadian disruption is an independent risk factor for the development of leptin resistance, which is common in overweight and obese people where the brain consistently receives hunger messages that lead to overeating and weight gain. Scientists at the Children's Nutrition Research Center in Houston, Texas, have demonstrated that disruption of circadian homeostasis induces leptin resistance, a hallmark of obesity for humans, in the absence of gene mutations or changes in food-intake, diet choice, and daily activity. We have also characterized the molecular pathways for the circadian clock to control the homeostasis of leptin signaling. This discovery is novel and helps to explain the obesity prevalence in the modern societies, and will have significant impact on both basic research and clinic practice for human obesity prevention and treatment in the future.