title: Defense of Elevated Body Weight Setpoint in Diet-Induced Obese Rats on Low Energy Diet Is Mediated by Loss of Melanocortin Sensitivity in the Paraventricular Hypothalamic Nucleus.
abstract: Some animals and humans fed a high-energy diet (HED) are diet-resistant (DR), remaining as lean as individuals who were naïve to HED. Other individuals become obese during HED exposure and subsequently defend the obese weight (Diet-Induced Obesity- Defenders, DIO-D) even when subsequently maintained on a low-energy diet. We hypothesized that the body weight setpoint of the DIO-D phenotype resides in the hypothalamic paraventricular nucleus (PVN), where anorexigenic melanocortins, including melanotan II (MTII), increase presynaptic GABA release, and the orexigenic neuropeptide Y (NPY) inhibits it. After prolonged return to low-energy diet, GABA inputs to PVN neurons from DIO-D rats exhibited highly attenuated responses to MTII compared with those from DR and HED-naïve rats. In DIO-D rats, melanocortin-4 receptor expression was significantly reduced in dorsomedial hypothalamus, a major source of GABA input to PVN. Unlike melanocortin responses, NPY actions in PVN of DIO-D rats were unchanged, but were reduced in neurons of the ventromedial hypothalamic nucleus; in PVN of DR rats, NPY responses were paradoxically increased. MTII-sensitivity was restored in DIO-D rats by several weeks' refeeding with HED. The loss of melanocortin sensitivity restricted to PVN of DIO-D animals, and its restoration upon prolonged refeeding with HED suggest that their melanocortin systems retain the ability to up- and downregulate around their elevated body weight setpoint in response to longer-term changes in dietary energy density. These properties are consistent with a mechanism of body weight setpoint.
authors.affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dirk W
authors.initials: DW
authors.lastname: Luchtman
authors.affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Melissa J S
authors.initials: MJ
authors.lastname: Chee
authors.affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Barbora
authors.initials: B
authors.lastname: Doslikova
authors.affiliation: Papé Family Pediatric Research Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd. Portland, Oregon, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Marks
authors.affiliation: Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Vickie E
authors.initials: VE
authors.lastname: Baracos
authors.affiliation: Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: William F
authors.initials: WF
authors.lastname: Colmers
mesh_terms: D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism / Q000503:physiopathology; D001835:Body Weight / Q000502:physiology*; D031204:Caloric Restriction / Q000379:methods; D004032:Diet / Q000379:methods; D004041:Dietary Fats / Q000378:metabolism; D020738:Leptin / Q000378:metabolism; D053486:Melanocortins / Q000378:metabolism*; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000503:physiopathology*; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism* / Q000503:physiopathology*; D010456:Peptides, Cyclic / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044105:Receptor, Melanocortin, Type 4 / Q000378:metabolism; D014697:Ventromedial Hypothalamic Nucleus / Q000378:metabolism / Q000503:physiopathology; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D020738:Leptin; D053486:Melanocortins; D009478:Neuropeptide Y; D010456:Peptides, Cyclic; D044105:Receptor, Melanocortin, Type 4; C079282:melanotan-II; D005680:gamma-Aminobutyric Acid; D000521:alpha-MSH