The melanocortin system and energy balance

Abstract

The melanocortins, a family of peptides produced from the post-translational processing of pro-opiomelanocortin (POMC), regulate ingestive behavior and energy expenditure. Loss of function mutations of genes encoding POMC, or of either of two melanocortin receptors expressed in the central nervous system (MC3R, MC4R), are associated with obesity. The analyses of MC4R knockout mice indicate that activation of this receptor is involved in the regulation of appetite, the adaptive metabolic response to excess caloric consumption, and negative energy balance associated with cachexia induced by cytokines. In contrast, MC3R knockout mice exhibit a normal, or even exaggerated, response to signals that induce a state of negative energy balance. However, loss of the MC3R also results in an increase in adiposity. This article discusses the regulation of energy balance by the melanocortins. Published and newly presented data from studies analyzing of energy balance of MC3R and MC4R knockout mice indicate that increased adiposity observed in both models involves an imbalance in fat intake and oxidation.

Fig. 1

Growth curve of MC3R mutants and wild type littermates on a mixed 129; B6 background. Some of the data for this growth curve was published in the initial analysis [9]. Male and female Mc3r^−/− mice (n = 9−18), heterozygotes (Mc3r^+/−, n = 22−31), and wild type (Mc3r^+/+, n = 9−18) mice were weaned onto mouse breeder chow (Purina 5015, 25% kJ/fat) and body weights recorder every 7–10 days.

Fig. 2

Diet-dependent hyperphagia of lean male Mc3r^−/− mice that is restricted to the lights-on period. (A) Disproportionate weight gain of male Mc3r^−/− mice on the B6 background when fed high fat diet is due to increase in fat mass, as determined by NMR. Mice were weaned on purified low fat diet (10% kJ/fat), and body composition measured at 8 week. Mice were then fed a purified high fat diet (45% kJ/fat) for 6 week (n = 6/group). (B) Cumulative food intake (in kJ) of purified low fat or high fat diet was measured for 3 days periods indicated hyperphagia of Mc3r^−/− mice relative to wild type littermates on the high fat diet. (C and D) Mean intake during the lights-on (L) or dark (D) periods was calculated, showing a significant increase in food consumption of Mc3r^−/− mice during the lights on period. Historical data suggest that Mc3r^−/− mice exhibit a modest reduction in longitudinal growth and lean mass [9,11]. For the mice used in this experiment, fat free mass (FFM) was significantly lower in Mc3r^−/− mice compared to wild type littermates (FFM in g: 17.4 ± 0.4 g compared to 19.2 ± 0.4 g, P < 0.01), accompanied by a modest increase in fat mass (FM) (FM in g: 5.3 ± 0.2 g compared to 4.0 ± 0.2 g, P < 0.01). When energy consumption was adjusted for fat free mass, energy consumption per gram of FFM was significantly higher irrespective of diet. Significantly different from wild type (WT), *P < 0.05, **P < 0.01.

Fig. 3

Energy expenditure of lean male Mc3r^−/− mice fed a low-fat or high-fat diet. Lean male Mc3r^−/− mice exhibit a normal diurnal variation in energy expenditure which is not affected by dietary fat content (A), but exhibit a modest increase in the RER consistent with reduced fatty acid oxidation (B). The dark periods are indicated by the bars shown in (A). Spontaneous physical activity, indicated by movements in the X-axis (C) and Z-axis (D) was reduced for Mc3r^−/− mice in the period.

Fig. 4

Impaired changes in substrate oxidation in melanocortin receptor knockout mice are associated with increased fat balance. Obese female Mc4r^−/− mice exhibit a delayed reduction in the RER following the transition from a low- to high-fat diet (A). (B) The balance of nutrient intake and oxidation is calculated using the mean RER over 3d for mice fed the high fat diet; the balance of carbohydrate intake and oxidation is comparable between all Mc4r^−/− and wild type mice, with an imbalance limited to fat metabolism. In A and B, obese female leptin deficient (Lep^ob/Lep^ob) mice were included in the study as an obese control. (C) Lean male Mc3r^−/− mice exhibit a comparable imbalance of fat intake and oxidation when fed a high fat diet. In an experiment using lean male Mc3r^−/− and wild type littermates at 3 months of age, fat balance was significantly higher in Mc3r^−/− mice compared to wild type, whereas the balance of carbohydrate intake and oxidation was similar between strains. (A and B) reproduced with permission from [2]. Significantly different intake (B), or between groups indicated by bars (C), *P < 0.05.