title: Y1 and Y5 receptors are both required for the regulation of food intake and energy homeostasis in mice.
abstract: Neuropeptide Y (NPY) acting in the hypothalamus is one of the most powerful orexigenic agents known. Of the five known Y receptors, hypothalamic Y1 and Y5 have been most strongly implicated in mediating hyperphagic effects. However, knockout of individual Y1 or Y5 receptors induces late-onset obesity--and Y5 receptor knockout also induces hyperphagia, possibly due to redundancy in functions of these genes. Here we show that food intake in mice requires the combined actions of both Y1 and Y5 receptors. Germline Y1Y5 ablation in Y1Y5(-/-) mice results in hypophagia, an effect that is at least partially mediated by the hypothalamus, since mice with adult-onset Y1Y5 receptor dual ablation targeted to the paraventricular nucleus (PVN) of the hypothalamus (Y1Y5(Hyp/Hyp)) also exhibit reduced spontaneous or fasting-induced food intake when fed a high fat diet. Interestingly, despite hypophagia, mice with germline or hypothalamus-specific Y1Y5 deficiency exhibited increased body weight and/or increased adiposity, possibly due to compensatory responses to gene deletion, such as the decreased energy expenditure observed in male Y1Y5(-/-) animals relative to wildtype values. While Y1 and Y5 receptors expressed in other hypothalamic areas besides the PVN--such as the dorsomedial nucleus and the ventromedial hypothalamus--cannot be excluded from having a role in the regulation of food intake, these studies demonstrate the pivotal, combined role of both Y1 and Y5 receptors in the mediation of food intake.
authors: Neuroscience Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia.
authors: Amy D
authors: AD
authors: Nguyen
authors: Natalie F
authors: NF
authors: Mitchell
authors: Shu
authors: S
authors: Lin
authors: Laurence
authors: L
authors: Macia
authors: Ernie
authors: E
authors: Yulyaningsih
authors: Paul A
authors: PA
authors: Baldock
authors: Ronaldo F
authors: RF
authors: Enriquez
authors: Lei
authors: L
authors: Zhang
authors: Yan-Chuan
authors: YC
authors: Shi
authors: Serge
authors: S
authors: Zolotukhin
authors: Herbert
authors: H
authors: Herzog
authors: Amanda
authors: A
authors: Sainsbury
mesh_terms: D050154:Adiposity / Q000187:drug effects; D000375:Aging / Q000187:drug effects; D000818:Animals; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects; D005215:Fasting; D005247:Feeding Behavior / Q000187:drug effects; D017353:Gene Deletion; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009478:Neuropeptide Y / Q000378:metabolism; D009765:Obesity / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015430:Weight Gain / Q000187:drug effects
chemical_list: D007328:Insulin; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C097212:neuropeptide Y-Y1 receptor; C100568:neuropeptide Y5 receptor; D005947:Glucose