Location: Children's Nutrition Research Center2010 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
Our study focuses on the role of circadian dysfunction in the development of obesity and obesity-related diseases. Many biological processes in mammals, including nutrient metabolism and energy expenditure, follow circadian rhythms, and the disruption of this rhythm has been linked to an increased risk of type 2 diabetes. Circadian rhythm is generated by a circadian clock that is within the brain, involving all peripheral tissues in mammals, and these clocks are operated by the circadian genes including the Period (Per) gene. The central clock responds to changes in environmental cues. In FY2010, we studied 1) whether and how the circadian regulators controls the transcriptional activation of leptin which encodes a key peptide hormone signaling to the brain to control energy balance; 2) whether and how the peripheral clock controls bile acids metabolism in the liver, which plays a key role in eliminating cholesterol in the liver and absorption of fat in the gut; 3) whether disruption of circadian behavioral rhythm abolishes the balance of levels of leptin and bile acids; and 4) whether disruption of the circadian clock is linked to increased risk of metabolic syndromes and other diseases. We learned that the peripheral clock indirectly controls leptin transcription by interacting with other transcription factors on the leptin promoter. We also discovered that the peripheral clock controls bile acid synthesis in the liver by regulating the expression of the two specific nuclear receptors (FXR and SHP) that inhibit the expression of an enzyme (Cyp7A1) for bile acid synthesis. Animal models show a significant decrease in the expression of FXR and SHP in the liver which is correlated with a dramatic increase in Cyp7A1 expression and bile acid levels in serum and the liver. The ADODR monitors activities for the project by routine site visits, and review of major purchases of supplies/equipment, use of SCA funds for foreign travel, and submission of grant applications by investigators funded through the SCA.
1. Disruption of circadian rhythm promotes obesity and tumor development. Human studies have indicated that a disruption of the circadian rhythm (our internal 24-hour time clock) increases the risk of obesity and cancer development in individuals that perform shift work during the night. However, the biological mechanisms leading to such risk remains unclear. Researchers at the Children's Nutrition Research Center, Houston, Texas, have recently demonstrated in mice that a disruption of the circadian rhythm induces similar types of tumor development to night-shift human workers. In addition, mice treated with chronic jet-lag also show increased risk of fatty liver development and higher body mass index without changing food choice or amount food-intake, and that uncontrolled activity of the sympathetic nervous system, which aids in the control of most of the body's internal organs, is involved in the increased tumor and obesity development under jet-lag conditions. These findings strongly suggest that educating the public to adopt a healthy life-style is important for both obesity and cancer prevention.