Y2 receptor deletion attenuates the type 2 diabetic syndrome of ob/ob mice.
Hypothalamic neuropeptide Y (NPY) is implicated in the regulation of a variety of physiological functions, notably energy homeostasis and reproduction. Chronically elevated NPY levels in the hypothalamus, as in genetically obese ob/ob mice, are associated with obesity, a syndrome of type 2 diabetes, and infertility. However, it is not known which of the five cloned Y receptors mediate these effects. Here, we show that crossing the Y2 receptor knockout mouse (Y2(-/-)) onto the ob/ob background attenuates the increased adiposity, hyperinsulinemia, hyperglycemia, and increased hypothalamo-pituitary-adrenal (HPA) axis activity of ob/ob mice. Compared with lean controls, ob/ob mice had elevated expression of NPY and agouti-related protein (AgRP) mRNA in the arcuate nucleus and decreased expression of proopiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) mRNA. Y2 deletion in ob/ob mice significantly increased the hypothalamic POMC mRNA expression, with no effect on NPY, AgRP, or CART expression. [Y2(-/-)ob/ob] mice were no different from ob/ob littermates with respect to food intake and body weight, and Y2 receptor deficiency had no beneficial effect on the infertility or the reduced hypothalamo-pituitary-gonadotropic function of ob/ob mice. These data demonstrate that Y2 receptors mediate the obese type 2 diabetes phenotype of ob/ob mice, possibly via alterations in melanocortin tonus in the arcuate nucleus and/or effects on the HPA axis.
Sainsbury
Amanda
A
Neurobiology Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst NSW 2010, Sydney, Australia.
Schwarzer
Christoph
C
Couzens
Michelle
M
Herzog
Herbert
H
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology* / Q000503:physiopathology*; D005260:Female; D017353:Gene Deletion; D006062:Gonadotropins / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010446:Peptide Fragments; D019894:Peptide YY / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D017476:Receptors, Neuropeptide Y / Q000235:genetics*; D013577:Syndrome; D022722:Thermogenesis; D013972:Thyrotropin / Q000378:metabolism
D001786:Blood Glucose; D006062:Gonadotropins; D007328:Insulin; D009479:Neuropeptides; D010446:Peptide Fragments; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; C061785:peptide YY (3-36); D013972:Thyrotropin