Dopaminergic Agonists Normalize Elevated Hypothalamic Neuropeptide Y and Corticotropin-Releasing Hormone, Body Weight Gain, and Hyperglycemia in ob/ob Mice

Abstract

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 D₁/D₂ 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 D₁/D₂ 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 D₁/D₂ receptor coactivation may improve hyperphagia, hyperglycemia, and obesity in the ob/ob mouse, in part, by normalizing elevated levels of both NPY and CRH.

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

“…The finding that positive modulation of D 1 receptor function contributed to the anorexic effect of tesofensine is in agreement with the role of D 1 receptor receptors on feeding behavior. Accordingly, D 1 receptor stimulation reduces food intake and weight gain in mouse models of obesity (Scislowski et al, 1999;Bina and Cincotta, 2000;Kuo, 2002). The inhibitory effect of D 1 receptor activation on feeding is most likely linked to stimulated hypothalamic DA function, which can lead to suppression of hypothalamic orexigenic signaling (Kuo, 2002;Alberto et al, 2006).…”

Food reinforcement and eating: A multilevel analysis.

“…Dopamine may also inhibit feeding through its influence on other central mediators of appetite. In the hyperphagic obese leptin-deficient mouse model, increasing central dopaminergic tone with dopamine agonists eliminates the hyperphagia via inhibition of Neuropeptide Y, one of the most potent orexigenic (appetite stimulating) agents known (Bina & Cincotta, 2000). Central dopamine activity may also be involved in the appetite suppression associated with Interleukin-1 alpha-associated anorexia (Yang et al, 1999) and with the central effects of cholecystokinin (Chung et al, 1994).…”

Inhibition of Dopamine and Norepinephrine Reuptake Produces Additive Effects on Energy Balance in Lean and Obese Mice

“…The therapeutic potential for treatments that affect dopaminergic and noradrenergic signaling is apparent in that DA receptor agonists reduce elevated levels of the orexigenic neuropeptide, neuropeptide Y (NPY), in the hypothalamus and normalizes the hyperphagia, body weight gain, and hyperglycemia observed in obese ob/ob mice (Bina and Cincotta, 2000). In addition, the anorectic effects of the only centrally acting Food and Drug Administration (FDA)-approved weight-loss drug, sibutramine (an NE and serotonin reuptake inhibitor), are abolished when rats are pretreated with an a 1 -adrenoceptor antagonist (Jackson et al, 1997).…”