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Research Project: Molecular, Cellular, and Regulatory Aspects of Nutrition During Development

Location: Children's Nutrition Research Center

Title: Circadian dysfunction induces leptin resistance in mice

item KETTNER, NICOLE - Children'S Nutrition Research Center (CNRC)
item MAYO, SARA - Children'S Nutrition Research Center (CNRC)
item HUA, JACK - Children'S Nutrition Research Center (CNRC)
item CHOOGON, LEE - Florida State University
item MOORE, DAVID - Baylor College Of Medicine
item FU, LONING - Children'S Nutrition Research Center (CNRC)

Submitted to: Cell Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/9/2015
Publication Date: 9/1/2015
Citation: Kettner, N.M., Mayo, S.A., Hua, J., Choogon, L., Moore, D.L., Fu, L. 2015. Circadian dysfunction induces leptin resistance in mice. Cell Metabolism. 22:1-12.

Interpretive Summary: The major message delivered in this article is that circadian disruption which has reached epidemic levels in the U.S., increases the risk of obesity independent of gene mutation, diet choice and amount of physical exercise. Circadian dysfunction disrupts neuroendocrine stabilities to promote obesity. Especially, the circadian clock controls the expression of leptin, a small hormone in the fat tissue which acts on the central nervous system to promote energy expenditure and reduce energy storage. Disruption of circadian homeostasis desensitizes the brain centers to leptin signal and promotes weight gain without changes in the amount of food-intake and physical activity. Our study demonstrated that circadian homeostasis of physiology is an important and yet neglected endogenous factor in body weight control. Thus, our findings will stimulate the development of new and more efficient weight watching programs for obesity prevention and treatment.

Technical Abstract: Circadian disruption is associated with obesity, implicating the central clock in body weight control. Our comprehensive screen of wild-type and three circadian mutant mouse models, with or without chronic jet lag, shows that distinct genetic and physiologic interventions differentially disrupt overall energy homeostasis and Leptin signaling. We found that BMAL1/CLOCK generates circadian rhythm of C/EBPa-mediated leptin transcription in adipose. Per and Cry mutant mice show similar disruption of peripheral clock and deregulation of leptin in fat, but opposite body weight and composition phenotypes that correlate with their distinct patterns of POMC neuron deregulation in the arcuate nucleus. Chronic jet lag is sufficient to disrupt the endogenous adipose clock and also induce central Leptin resistance in wild-type mice. Thus, coupling of the central and peripheral clocks controls Leptin endocrine feedback homeostasis. We propose that Leptin resistance, a hallmark of obesity in humans, plays a key role in circadian dysfunction-induced obesity and metabolic syndromes.