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.
Address correspondence and reprint requests to Herbert Herzog, Neurobiology Program, Garvan Institute of Medical Research, 384 Victoria St., Darlinghurst NSW 2010, Sydney, Australia. E-mail:.
Received for publication 11 July 2002 and accepted in revised form 10 September 2002.
A.S. and C.S. contributed equally to this study.
AgRP, agouti-related protein; BAT, brown adipose tissue; CART, cocaine- and amphetamine-regulated transcript; CRH, corticotropin-releasing hormone; DEXA, dual-energy X-ray absorptiometry; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; HPA, hypothalamo-pituitary-adrenal; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular nucleus; TRH, thyrotropin-releasing hormone; UCP-1, uncoupling protein-1; WAT, white adipose tissue.