Hypothalamic adrenergic receptor changes in the metabolic syndrome of genetically obese (ob/ob) mice

The genetically, seasonally, and diet-induced obese, glucose-intolerant sta tes in rodents, including ob/ob mice, have each been associated with elevat ed hypothalamic levels of norepinephrine (NE). With the use of quantitative autoradiography on brain slices of 6-wk-old obese (ob/ob) and lean mice, t he adrenergic receptor populations in several hypothalamic nuclei were exam ined. The binding of [ I-125] iodocyanopindolol to beta(1)- and beta(2)-adr energic receptors in ob/ob mice was significantly increased in the paravent ricular hypothalamic nucleus (PVN) by 30 and 38%, in the ventromedial hypot halamus (VMH) by 23 and 72%, and in the lateral hypothalamus (LH) by 10 and 15%, respectively, relative to lean controls. The binding of [I-125] iodo- 4-hydroxyphenyl-ethyl-aminomethyltetralone to alpha(1)-adrenergic receptors was also significantly increased in the PVN (26%), VMH (67%), and LH (21%) of ob/ob mice. In contrast, the binding of [I-125] paraiodoclonidine to al pha(2)-adrenergic receptors in ob/ob mice was significantly decreased in th e VMH (38%) and the dorsomedial hypothalamus (17%) relative to lean control s. This decrease was evident in the alpha(2A)- but not the alpha(2BC)-recep tor subtype. Scatchard analysis confirmed this decreased density of alpha(2 )-receptors in ob/ob mice. Together with earlier studies, these changes in hypothalamic adrenergic receptors support a role for increased hypothalamic NE activity in the development of the metabolic syndrome of ob/ob mice.