Y2 Receptor Deletion Attenuates the Type 2 Diabetic Syndrome of ob/ob Mice

  1. Amanda Sainsbury,
  2. Christoph Schwarzer,
  3. Michelle Couzens and
  4. Herbert Herzog
  1. From the Neurobiology Program, Garvan Institute of Medical Research, St. Vincent’s Hospital, Sydney, Australia

    Abstract

    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.

    Footnotes

    • 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: h.herzog{at}garvan.org.au.

      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.

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