title: Circadian Dysfunction Induces Leptin Resistance in Mice.
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/EBPα-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.
authors.affiliation: Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Kettner
authors.affiliation: Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Mayo
authors.affiliation: Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Hua
authors.affiliation: Program in Neuroscience, Florida State University, College of Medicine, Tallahassee, FL 32306, USA.
authors.forename: Choogon
authors.initials: C
authors.lastname: Lee
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: moore@bcm.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.affiliation: Department of Pediatrics/U.S. Department of Agriculture/Agricultural Research Service/Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: loningf@bcm.edu.
authors.forename: Loning
authors.initials: L
authors.lastname: Fu
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001835:Body Weight; D056926:CLOCK Proteins / Q000378:metabolism; D057906:Circadian Clocks; D002940:Circadian Rhythm; D004734:Energy Metabolism; D020738:Leptin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015533:Transcriptional Activation
chemical_list: D020738:Leptin; D053486:Melanocortins; D056926:CLOCK Proteins