Mice lacking melanin-concentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity

1 Department of Integrative Pharmacology and 2 AstraZeneca Transgenic and Comparative Genomics Centre, AstraZeneca Research and Development, SE-431 83 Mölndal; and 3 Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45 Gothenburg Sweden Submitted 27 February 2004 ; accepted in final form 22 April 2004 Melanin-concentrating hormone (MCH) plays an important role in energy balance. The current studies were carried out on a new line of mice lacking the rodent MCH receptor (MCHR1 –/– mice). These mice confirmed the previously reported lean phenotype characterized by increased energy expenditure and modestly increased caloric intake. Because MCH is expressed in the lateral hypothalamic area, which also has an important role in the regulation of the autonomic nervous system, heart rate and blood pressure were measured by a telemetric method to investigate whether the increased energy expenditure in these mice might be due to altered autonomic nervous system activity. Male MCHR1 –/– mice demonstrated a significantly increased heart rate [24-h period: wild type 495 ± 4 vs. MCHR1 –/– 561 ± 8 beats/min ( P < 0.001); dark phase: wild type 506 ± 8 vs. MCHR1 –/– 582 ± 9 beats/min ( P < 0.001); light phase: wild type 484 ± 13 vs. MCHR1 –/– 539 ± 9 beats/min ( P < 0.005)] with no significant difference in mean arterial pressure [wild type 110 ± 0.3 vs. MCHR1 –/– 113 ± 0.4 mmHg ( P > 0.05)]. Locomotor activity and core body temperature were higher in the MCHR1 –/– mice during the dark phase only and thus temporally dissociated from heart rate differences. On fasting, wild-type animals rapidly downregulated body temperature and heart rate. MCHR1 –/– mice displayed a distinct delay in the onset of this downregulation. To investigate the mechanism underlying these differences, autonomic blockade experiments were carried out. Administration of the adrenergic antagonist metoprolol completely reversed the tachycardia seen in MCHR1 –/– mice, suggesting an increased sympathetic tone. melanin-concentrating hormone; sympathetic; fasting Address for reprint requests and other correspondence: D. G. A. Morgan, Dept. of Integrative Pharmacology, AstraZeneca R&D Mölndal, S-431 83 Mölndal, Sweden (E-mail david.ga.morgan{at}astrazeneca.com )