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1 Department of Integrative Pharmacology, AstraZeneca R&D, Molndal, Sweden
2 AstraZeneca Transgenic and Comparative Genomics Centre, AstraZeneca R&D, Molndal, Sweden
3 Department of Medicine, SU/Sahlgrenska, Gothenburg, Sweden
* To whom correspondence should be addressed. E-mail: david.ga.morgan{at}astrazeneca.com.
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 characterised by increased energy expenditure and modestly increased caloric intake. Since MCH is expressed in the lateral hypothalamic area, which also has an important role in the regulation of the autonomic nervous system, heart rate & 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-hr period - wt: 495±4 vs MCHR1-/- 561±8BPM (p<0.001); dark phase - wt: 506±8 vs MCHR1-/- 582±9 BPM (p<0.001); light phase - wt: 484±13 vs MCHR1-/- 539±9 BPM (p<0.005)), with no significant difference in mean arterial pressure (wt: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. Upon fasting, wild-type animals rapidly down-regulated body-temperature & heart rate. MCHR1-/- mice displayed a distinct delay in the onset of this downregulation. In order 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.
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