2011 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.
Circadian rhythms are biological rhythms that have a period of about 24 hours. Studies have revealed that frequent disruption of circadian rhythm among human nightshift workers leads to a nearly 2X greater risk of developing metabolic syndromes but, a clear experimental demonstration on the role of circadian dysfunction in promoting metabolic syndromes is lacking. We have shown that both food-intake and energy expenditure follow a circadian rhythm that is coupled with daily physical activities and peaks in the mid-active phase in mice. Disruption of circadian behavioral rhythm in wild-type mice by constantly changing environmental light cues (jet-lag), which mimic the effect of an 8-hour phase advance followed by an 8-hour phase delay in human shift working schedules, uncouples energy intake and expenditure from physical activities over a 24-hour period, increases food-intake in the sleeping phase, and decreases energy expenditure over an entire circadian period. Such circadian disruption of energy homeostasis results in abnormal body weight gain and fat accumulation in the absence of any changes in the amount of daily food-intake or diet choice. In addition, metabolic dysfunction observed among mice treated with jetlag occurs prior to the onset of other diseases, including liver tumor development. This suggests that circadian homeostasis is an independent factor for obesity prevention, and that metabolic dysfunction contributes to tumor promotion. Further studies revealed that disruption of circadian rhythm abolishes the homeostasis of serum levels of hormones controlling the stabilities of fat absorption, food-intake, and energy expenditure, as well as liver metabolism, such as bile acids, Leptin, and insulin. We are also investigating the molecular mechanism of circadian control of leptin expression in the fat tissue as well as bile acid synthesis, metabolism, and signaling in the liver. We have found that the circadian clock is involved in regulating leptin expression and bile acid synthesis at the transcriptional level, and disruption of circadian rhythm disrupts not only the homeostasis of leptin expression and bile activity but also the homeostasis of leptin interaction with brain centers controlling energy balance. Since human nightshift workers also show increased risk of metabolic syndromes and hepatocellular carcinoma, our studies on circadian control of energy homeostasis, in combination with our other research projects that investigate the mechanism of circadian control of cell cycle and tumor suppression will generate significant discoveries that would contribute to developing novel strategies for the prevention and treatment of obesity and its related diseases including hepatocellular carcinoma.
The ADODR monitors project activities by visits, review of purchases of equipment, review of ARS-funded foreign travel, and review of ARS funds provided through the SCA.
Circadian homeostasis is an independent factor for obesity prevention. Obesity and its related diseases are among the most profound public health problems today. Simplistic explanations such as over-consumption of food, poor diet choice, or lack of physical activities are likely inadequate to completely account for the prevalence of obesity in our world. Recent studies have revealed that circadian homeostasis of energy balance may be an important factor for body weight control, but an experimental demonstration of such hypothesis is lacking. Scientists at the Children's Nutrition Research Center in Houston, TX, have found that physical activities, feeding, and energy expenditure in mammals follow a circadian rhythm and that disruption of this rhythm alone could increase the risk of metabolic syndromes and cancers. Further study of the mechanisms of circadian homeostasis on body weight control will have the potential for a very high impact on the prevention and treatment of obesity and obesity-related diseases. This research is important, especially in the US, where nearly 20% of the workforce is on rotating shift schedules, and it is these individuals that are nearly 2X greater risk of developing metabolic syndromes and cancers.