Effects of hypothalamic neurodegeneration on energy balance.
Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp) or proopiomelanocortin (Pomc), neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.
Xu
Allison Wanting
AW
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Kaelin
Christopher B
CB
Morton
Gregory J
GJ
Ogimoto
Kayoko
K
Stanhope
Kimber
K
Graham
James
J
Baskin
Denis G
DG
Havel
Peter
P
Schwartz
Michael W
MW
Barsh
Gregory S
GS
D054369:Agouti-Related Protein; D000818:Animals; D001835:Body Weight / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004435:Eating; D004734:Energy Metabolism; D017353:Gene Deletion; D017930:Genes, Reporter / Q000235:genetics; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics
C515198:AGRP protein, human; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; C081930:Tfam protein, mouse; D011333:Pro-Opiomelanocortin