title: Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding.
abstract: Leptin, a hormone mainly produced by fat cells, shows cell-specific effects to regulate feeding and metabolic activities. We propose that an important feature of metabolic dysregulation resulting in obesity is the loss of the circadian rhythm of biopotentials. This was tested in the pan-leptin receptor knockout (POKO) mice newly generated in our laboratory. In the POKO mice, leptin no longer induced pSTAT-3 signaling after intracerebroventricular injection. Three basic phenotypes were observed: the heterozygotes had similar weight and adiposity as the wild-type (WT) mice (>60% of the mice); the homozygotes were either fatter (∼30%), or rarely leaner (<5%) than the WT mice. By early adulthood, the POKO mice had higher average body weight and adiposity than their respective same-sex WT littermate controls, and this was consistent among different batches. The homozygote fat POKO showed significant reduction of midline estimating statistic of rhythm of circadian parameters, and shifts of ultradian rhythms. The blunted circadian rhythm of these extremely obese POKO mice was also seen in their physical inactivity, longer feeding bouts, and higher food intake. The extent of obesity correlated with the blunted circadian amplitude, accumulative metabolic and locomotor activities, and the severity of hyperphagia. This contrasts with the heterozygote POKO mice which showed little obesity and metabolic disturbance, and only subtle changes of the circadian rhythm of metabolic activity without alterations in feeding behavior. The results provide a novel aspect of leptin resistance, almost manifesting as an "all or none" phenomenon.
authors.affiliation: Blood-Brain Barrier Group, Pennington Biomedical Research Center, Baton Rouge, Louisiana.
authors.forename: Hung
authors.initials: H
authors.lastname: Hsuchou
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
authors.forename: Germaine G
authors.initials: GG
authors.lastname: Cornelissen-Guillaume
authors.forename: Abba J
authors.initials: AJ
authors.lastname: Kastin
authors.forename: Eunjin
authors.initials: E
authors.lastname: Jang
authors.forename: Franz
authors.initials: F
authors.lastname: Halberg
authors.forename: Weihong
authors.initials: W
authors.lastname: Pan
mesh_terms: D050154:Adiposity / Q000502:physiology; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002940:Circadian Rhythm / Q000502:physiology*; D004041:Dietary Fats / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005247:Feeding Behavior / Q000502:physiology*; D020738:Leptin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D054411:Receptors, Leptin / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013851:Thinness / Q000378:metabolism / Q000503:physiopathology
chemical_list: D004041:Dietary Fats; D020738:Leptin; D054411:Receptors, Leptin
keywords: circadian rhythm; leptin; metabolic activity; obesity; physical inactivity