Effects of selective modulation of the central melanocortin-3-receptor on food intake and hypothalamic POMC expression

Abstract

Hypothalamic POMC neurons regulate energy balance via interactions with brain melanocortin receptors (MC-Rs). POMC neurons express the MC3-R which can function as an inhibitory autoreceptor in vitro. We now demonstrate that central activation of MC3-R with ICV infusion of the specific MC3-R agonist, [D-Trp(8)]-gamma-MSH, transiently suppresses hypothalamic Pomc expression and stimulates food intake in rats. Conversely, we also show that ICV infusion of a low dose of a selective MC3-R antagonist causes a transient decrease in feeding and weight gain. These data support a functional inhibitory role for the MC3-R on POMC neurons that leads to changes in food intake.

Figure 1. Effects of ICV [D-Trp⁸]-γ-MSH Infusion in Experiment 1

(A). Food Intake: On day 1, there was a decline in food intake characteristic of the animals’ response to ketamine/xylazine anesthesia in both the [D-Trp⁸]-γ-MSH and the saline control groups. On day 2, a trend toward greater food intake among [D-Trp⁸]-γ-MSH rats vs. saline controls was noted but this was not significant (n = 8/group; p = 0.24). (B & C). Hypothalamic Pomc and Agrp Expression (expressed as pg/100 pg Cyc): Pomc mRNA levels were significantly decreased in [D-Trp⁸]-γ-MSH animals compared to controls (*p = 0.012); Agrp mRNA levels tended to be lower in the [D-Trp⁸]-γ-MSH group but this was not significant (p = 0.1).

Figure 2. Effects of ICV [D-Trp⁸]-γ-MSH Infusion in Experiment 2

(A). Mean Body Weight: [D-Trp⁸]-γ-MSH infusion did not have any significant effect on body weight or weight gain which was similar to that of saline controls. (B). Mean Food Intake: A significant increase in food intake among [D-Trp⁸]-γ-MSH rats (28.7 ± 0.6 g; *p = 0.003; n = 10) compared to saline controls (25.7 ± 0.6 g; n = 9) was observed on day 2 of infusion. In contrast to Exp. 1, there was also no decline in food intake by either [D-Trp⁸]-γ-MSH or saline rats on the day after pump exchange in this experiment using inhaled isoflurane anesthesia.

Figure 3. Effects of ICV High Dose PG-932 Infusion

Infusion of 0.5 μg/hr of peptide PG-932 vs. saline. (A) Weight Gain: PG-932 caused significant increases in cumulative weight gain (p < 0.0001) and (B) Food Intake: PG-932 resulted in a significant increase in cumulative food intake (p < 0.0001)(n = 10/group).

Figure 4. Effects of ICV Low Dose PG-932 Infusion

(A) Body Weight: Rats treated with PG-932 at a dose of 0.5 ng/hr demonstrated significant weight loss (−5.8 ± 1.1 g; *p < 0.05, n = 6) compared to saline (−0.5 ± 2.0 g; n = 6) as well as to rats infused with PG-932 at 2.0 ng/hr (1.2 ± 2.0 g; n = 7) (p < 0.05). (B) Food Intake: A significant decline in food intake in the rats treated with the 0.5 ng/hr dose compared to the 2.0 ng/hr dose was noted 24 hours after infusion (*p < 0.05) as well as a tendency towards decreased food intake compared to saline controls (p = 0.07).