Endocrine Abstracts (2002) 3 OC43

CGRP-alpha inhibits food intake via the paraventricular nucleus (PVN) of the hypothalamus partly through the CGRP-type 1 receptor

WS Dhillo, CJ Small, SH Russell, A Seth, KG Murphy, MA Ghatei & SR Bloom

Endocrine Unit, Imperial College Faculty of Medicine, London, UK.

CGRP-alpha is a 37 amino acid peptide generated by alternative splicing of calcitonin gene transcripts. CGRP-alpha is present in a number of areas of the brain involved in the regulation of appetite, including the PVN. CGRP(8-37) is a competitive antagonist of CGRP-alpha at the CGRP-type 1 receptor. CGRP-alpha is known to inhibit food intake when given intracerebroventricularly, but the anatomical localisation of this effect is not known. Aims To investigate the effects of CGRP-alpha on food intake when administered directly into the PVN (iPVN) and if this effect was mediated via the CGRP-type 1 receptor. Methods Study 1: 24 hour fasted male Wistar rats were administered CGRP-alpha (0.03, 0.1, 0.3 or 1 nmol) or saline iPVN. Food intake was measured 1, 2, 4, 8 and 24 hours post-injection. Study 2: 24 hour fasted male Wistar rats were administered 2 iPVN injections at time 0 and 60 minutes later. The injection regimen in the four groups was as follows: saline/saline, saline/CGRP(0.3nmol), CGRP(8-37)(10nmol)/saline, CGRP(8-37)(10nmol)/CGRP(0.3nmol). Food was presented after the second iPVN injection and food intake was measured 1, 2, 4, 8 and 24 hours later. Results Study 1: CGRP-alpha dose-dependently reduced food intake 1hour post-injection compared to saline (food intake 0-1hour: saline 5.1 plus/minus 0.3g, CGRP-alpha (0.03nmol) 4.1 plus/minus 0.6g, CGRP-alpha (0.1nmol) 3.7 plus/minus 0.7g, CGRP-alpha (0.3nmol) 2.2 plus/minus 0.6g (p<0.001 vs. saline), CGRP-alpha (1nmol) 1.2 plus/minus 0.3g (p<0.001 vs. saline)). Study 2: The reduction in food intake by CGRP-alpha was attenuated by prior administration of CGRP(8-37), whilst CGRP(8-37) had no effect when administered alone (food intake 0-1 hour: saline/saline 5.1 plus/minus 0.8g, saline/CGRP-alpha 1.1 plus/minus 0.5g (p<0.001 vs. saline/saline), CGRP(8-37)/saline 6.2 plus/minus 0.7g, CGRP-alpha/CGRP(8-37) 3.0 plus/minus 0.8g (p<0.05 vs. saline/CGRP). Conclusion This is the first report localising the anorectic effect of CGRP-alpha to the PVN. This effect is partly mediated by the CGRP-1 receptor.

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