Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype

Abstract

Energy homeostasis is regulated by a complex network involving peripheral and central signals that determine food intake and energy expenditure. Melanin-concentrating hormone (MCH) plays an essential role in this process. Animals treated with MCH develop hyperphagia and obesity. Ablation of the prepro-MCH gene leads to a lean phenotype, as does ablation of the rodent MCH receptor, MCHR-1. MCH is overexpressed in the leptin-deficient ob/ob mouse, and we hypothesized that ablation of MCH in this animal would lead to attenuation of its obese phenotype. Compared with ob/ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of the ob/ob mouse was unaffected. Instead, leanness was secondary to a marked increase in energy expenditure resulting from both increased resting energy expenditure and locomotor activity. Furthermore, double-null mice showed improvements in other parameters impaired in ob/ob mice. Compared with ob/ob mice, double-null animals had increased basal body temperature, improved response to cold exposure, lower plasma glucocorticoid levels, improved glucose tolerance, and reduced expression of stearoyl-CoA desaturase 1 (SCD-1). These results highlight the importance of MCH in integration of energy homeostasis downstream of leptin and, in particular, the role of MCH in regulation of energy expenditure.

Fig. 1.

Growth, body composition, and glucose tolerance. (A) Photograph showing body size of MCH^–/– ob/ob and ob/ob mice at 16 weeks of age. (B) Weights of ob/ob, MCH^–/– ob/ob, MCH^–/–, and WT mice over the course of 17 weeks. (C) Dual-energy x-ray absorptiometry analysis of 16-week-old WT (black bar), ob/ob (gray bar), and MCH^–/– ob/ob (white bar) mice showing lean tissue mass and fat tissue mass. *, P < 0.015 vs. WT; **, P < 0.0001 vs. WT; #, P = 0.001 vs. ob/ob. (D) Glucose tolerance test of ob/ob (black diamonds) and MCH^–/– ob/ob (black squares) mice at the age of 18 weeks after being fasted from 1700 hours to 0800 hours. *, P < 0.05 vs. MCH^–/– ob/ob.

Fig. 2.

Food intake and motor activity. (A) Food intake of 12- to 14-week-old male WT, MCH^–/– ob/ob, and ob/ob mice measured over 24 h. (B) Locomotor activity of 12- to 14-week-old MCH^–/– ob/ob (n = 6) and ob/ob (n = 6) mice during a 24-h time period while individually housed in the comprehensive laboratory animal monitoring system. (Inset) Cumulative dark-cycle activity for each animal group. *, P < 0.05 vs. WT; #, P < 0.001 vs. ob/ob.

Fig. 3.

VO₂.(A)VO₂ for 12- to 14-week-old MCH^–/– ob/ob (n = 3) and ob/ob (n = 5) mice corrected for the weight of the animal (ml/kg per h). (B) Per-animal, per-hour VO₂, not corrected for body weight. (C) Resting VO₂ for 12- to 14-week-old MCH^–/– ob/ob (n = 3) and ob/ob (n = 5) mice measured per animal (ml per animal per h). *, P = 0.04 vs. ob/ob mice.

Fig. 4.

Thermoregulation and expression of BAT UCP-1 expression. (A) Body temperature of 30-week-old WT, ob/ob, and MCH^–/– ob/ob mice exposed to 4°C, measured every 15 min. (B) UCP-1 protein levels of BAT taken from 34-week-old WT, ob/ob, MCH^–/– ob/ob, and MCH^–/– mice (n = 4 per group). Results are means ± SE for three immunoblots. *, P < 0.05 vs. WT; #, P = 0.002 vs. ob/ob.

Fig. 5.

Corticosterone levels, liver triglyceride, and SCD-1 mRNA expression. (A) Serum corticosterone in WT, ob/ob, and MCH^–/– ob/ob mice. *, P = 0.014 vs. WT; #, P = 0.02 vs. ob/ob. (B) Hepatic triglyceride content of WT, ob/ob, and MCH^–/– ob/ob mice. *, P < 0.0005. (C) Photomicrographs showing liver histology from ob/ob and MCH^–/– ob/ob mice. (D) SCD-1 mRNA expression in the liver of WT, ob/ob, and MCH^–/– ob/ob mice. *, P < 0.007 vs. WT; #, P < 0.02 vs. ob/ob.