Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice.
Hypothalamic neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) influence feeding and levels of plasma glucose, insulin, free fatty acids, and triglycerides. Treatment of genetically obese, ob/ob mice, with dopamine receptor D(1)/D(2) agonists normalizes hyperphagia, body weight gain, hyperglycemia, and hyperlipidemia. We therefore examined whether levels of NPY and CRH immunoreactivity in discrete hypothalamic nuclei are altered in ob/ob mice, and whether dopaminergic treatment reverses this alteration. Female ob/ob mice were treated daily at 1 h after light onset with the D(1)/D(2) agonists, SKF-38393 (20 mg/kg) and bromocriptine (15 mg/kg), respectively or vehicle for 2 weeks. Such treatment, while normalizing body weight gain and hyperglycemia, also significantly reduced elevated NPY immunoreactivity in the suprachiasmatic (by 39%), intergeniculate (by 43%), paraventricular (PVN; by 31%), and arcuate (by 41%) nuclei in obese mice to levels observed in lean mice. This treatment also caused a 45-50% decline in levels of CRH in the PVN and dorsomedial hypothalamus compared to obese controls to levels observed in lean mice. Taken together, these findings suggest that dopaminergic D(1)/D(2) receptor coactivation may improve hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by normalizing elevated levels of both NPY and CRH.
Bina
K G
KG
Ergo Science Corporation, N. Andover, Mass., USA.
Cincotta
A H
AH
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D001786:Blood Glucose; D003346:Corticotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D065127:Dopamine D2 Receptor Antagonists; D004302:Dorsomedial Hypothalamic Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004435:Eating; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006943:Hyperglycemia / Q000378:metabolism*; D007031:Hypothalamus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors*; D013493:Suprachiasmatic Nucleus / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D015430:Weight Gain
D001786:Blood Glucose; D065127:Dopamine D2 Receptor Antagonists; D009478:Neuropeptide Y; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D003346:Corticotropin-Releasing Hormone