Endocrine Abstracts (2002) 3 OC46

Chronic CNS administration of Agouti related protein (Agrp) reduces energy expenditure

CJ Small1, YL Liu2, SA Stanley1, IP Connoley2, A Kennedy1, MJ Stock2 & SR Bloom1

1Department of Metabolic Medicine, Imperial College School of Medicine, Hammersmith Hospital, London; 2Department of Physiology, St Georges Hospital Medical School, University of London, UK.

The hypothalamic melanocortin system is a regulator of energy homeostasis. Chronic CNS administration of Agouti related peptide (Agrp) causes increased food intake, increased body adiposity, an inhibition of the HPT axis and a suppression of BAT UCP-1. The ability of Agrp to alter oxygen consumption, a measure of energy expenditure, is unknown.

Chronic daily ICV administration of Agrp (1nmol) caused a 54% increase in food intake (food intake, day 7: Agrp 34.9 ± 1.6g vs. saline 22.6 ± 0.7g). This was associated with a 12% increase in body weight. Oxygen consumption (VO2) was determined in closed circuit respirometers on day one and day eight. An 8% decrease in VO2 measurements was observed in the Agrp treated group on day one compared to the saline controls following ICV Agrp injection (Agrp 1nmol 112.4% ± 5.7 vs. saline 104.0% ± 3.0. p<0.01). On day eight, there was a reduction in basal VO2 and again a significant (7%) decrease in the VO2 measurements following ICV administration of Agrp (1nmol).

BRL 35135, a beta-3-adrenoreceptor agonist, has previously been found to directly activate BAT thermogenesis, double BAT uncoupling protein mRNA and increase core temperature. We administered BRL 35135 (40mg/kg) IP to rats that had previously received Agrp treatment. In the saline treated controls the beta 3 agonist stimulated colonic temperature by 0.5 ± 0.1oC (2 hour mean). In the rats that had previously received the Agrp treatment BRL 35135 was only able to stimulate the colonic temperature by 0.08 ± 0.1oC (2 hour mean).

We have found that chronic CNS administration of Agrp decreased oxygen consumption and decreased the capacity of BAT to expend energy. This reduction in oxygen consumption leading to a reduction in energy expenditure, together with the stimulation in food intake, may be the mechanisms by which Agrp causes an increase in body weight and adiposity.

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