Role of the CNS melanocortin system in the response to overfeeding

Abstract

The voluntary suppression of food intake that accompanies involuntary overfeeding is an effective regulatory response to positive energy balance. Because the pro-opiomelanocortin (POMC)-derived melanocortin system in the hypothalamus promotes anorexia and weight loss and is an important mediator of energy regulation, we hypothesized that it may contribute to the hypophagic response to overfeeding. Two groups of rats were overfed to 105 and 116% of control body weight via a gastric catheter. In the first group, in situ hybridization was used to measure POMC gene expression in the rostral arcuate (ARC). Overfeeding increased POMC mRNA in the ARC by 180% relative to levels in control rats. For rats in the second group, the overfeeding was stopped, and they were infused intracerebroventricularly with SHU9119 (SHU), a melanocortin (MC) antagonist at the MC3 and MC4 receptor, or vehicle. Although SHU (0.1 nmol) had no effect on food intake of control rats, intake of overfed rats increased by 265% relative to CSF-treated controls. This complete reversal of regulatory hypophagia not only maintained but actually increased the already elevated weight of overfed rats, whereas CSF-treated overfed rats lost weight. These results indicate that CNS MCs mediate hypophagic signaling in response to involuntary overfeeding and support the hypothesis that MCs are important in the central control of energy homeostasis.

Fig. 1.

Mean (+ SE) mRNA for POMC in the arcuate nucleus of the hypothalamus for control rats and rats overfed to 105% of body weight of controls. Values represent area × density measures derived from computer densitometry. **p < 0.01.

Fig. 2.

A, Mean (± SE) daily spontaneous kilocalories of intake for the overfed and control group during the course of the first overfeeding episode. B, Mean (± SE) body weight for the overfed and control group over the course of the first and second overfeeding episodes. ***p < 0.001.

Fig. 3.

Mean (+SE) 24 hr chow intake of rats treated with 0.5 nmol i3vt SHU or CSF vehicle. *p < 0.05; **p < 0.01; ***p < 0.001.

Fig. 4.

Mean (+ SE) grams of 24 hr chow intake of control and overfed rats on the third day of i3vt lower dose (0.1 nmol) SHU or CSF vehicle. ***p < 0.001.

Fig. 5.

Mean (+ SE) 24 hr chow intake in animals treated i3vt with 0.1 nmol SHU9119 or CSF vehicle on 3 consecutive days. Error bars represent the percentage of each group’s mean control intake. **p < 0.01; ***p < 0.001.

Fig. 6.

Mean (+ SE) of the percentage body weight gained or lost after 3 d of 0.1 nmol i3vt SHU infusions relative to the weight of each group’s CSF-treated animals before the infusion. Percentages were derived from the formula {[% body weight gain or loss per animal] − (mean % body weight gain for CSF-treated groups)} × 100. ***p < 0.001.