title: Effects of chronic weight perturbation on energy homeostasis and brain structure in mice.
abstract: Maintenance of reduced body weight in lean and obese human subjects results in the persistent decrease in energy expenditure below what can be accounted for by changes in body mass and composition. Genetic and developmental factors may determine a central nervous system (CNS)-mediated minimum threshold of somatic energy stores below which behavioral and metabolic compensations for weight loss are invoked. A critical question is whether this threshold can be altered by environmental influences and by what mechanisms such alterations might be achieved. We examined the bioenergetic, behavioral, and CNS structural responses to weight reduction of diet-induced obese (DIO) and never-obese (CON) C57BL/6J male mice. We found that weight-reduced (WR) DIO-WR and CON-WR animals showed reductions in energy expenditure, adjusted for body mass and composition, comparable (-10-15%) to those seen in human subjects. The proportion of excitatory synapses on arcuate nucleus proopiomelanocortin neurons was decreased by ∼50% in both DIO-WR and CON-WR mice. These data suggest that prolonged maintenance of an elevated body weight (fat) alters energy homeostatic systems to defend a higher level of body fat. The synaptic changes could provide a neural substrate for the disproportionate decline in energy expenditure in weight-reduced individuals. This response to chronic weight elevation may also occur in humans. The mouse model described here could help to identify the molecular/cellular mechanisms underlying both the defense mechanisms against sustained weight loss and the upward resetting of those mechanisms following sustained weight gain.
authors.affiliation: 1Department of Pediatrics, Division of Molecular Genetics, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Ravussin
authors.forename: R
authors.initials: R
authors.lastname: Gutman
authors.forename: S
authors.initials: S
authors.lastname: Diano
authors.forename: M
authors.initials: M
authors.lastname: Shanabrough
authors.forename: E
authors.initials: E
authors.lastname: Borok
authors.forename: B
authors.initials: B
authors.lastname: Sarman
authors.forename: A
authors.initials: A
authors.lastname: Lehmann
authors.forename: C A
authors.initials: CA
authors.lastname: LeDuc
authors.forename: M
authors.initials: M
authors.lastname: Rosenbaum
authors.forename: T L
authors.initials: TL
authors.lastname: Horvath
authors.forename: R L
authors.initials: RL
authors.lastname: Leibel
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000033:anatomy & histology / Q000166:cytology / Q000502:physiology; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000033:anatomy & histology* / Q000502:physiology; D031204:Caloric Restriction; D004041:Dietary Fats / Q000494:pharmacology; D004734:Energy Metabolism / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009474:Neurons / Q000166:cytology / Q000502:physiology; D013569:Synapses / Q000502:physiology; D015430:Weight Gain / Q000502:physiology*; D015431:Weight Loss / Q000502:physiology*
chemical_list: D004041:Dietary Fats