Hypothalamic Agouti related protein (AGRP) and pre-opio melanocortin (POMC) expressing neurons are key components of appetite regulation along with satiety signaling from the intestine. Choleocystokinin (CCK) and its receptor CCKAR are part of the satiety signaling system from the intestine. Genetic mapping using 16 generations of crossing between fast and slower growing strains of chicken identified a haplotype on chromosome 4 that includes the CCKAR gene which explained a 19% difference in body weight at 12 weeks of age.
In animals bred from heterozygotes at the locus those homozygotic for the haplotype associated with high growth expressed less CCKAR mRNA than the low growth haplotype homozygotes (Basal hypothalamus, P<0.001; Hind brain, P=0.014; Pancreas, P<0.001; Cecum, P<0.001; Duodenum, P=0.03) and less observable immunoreactive CCKAR neurons in the paraventricular nucleus of the hypothalamus (P=0.04). When CCK was administered intra-peritoneally to animals with the high growth haplotype they did not respond by a reduction in food intake which was the case in the low growth haplotype (P=0.013). This suggested that the satiety set point differs between haplotypes. We hypothesized that the difference in feedback mediated by the genetic difference in CCKAR expression would change expression of AGRP and POMC in the hypothalamic feeding centre. Indeed expression of orexigenic AGRP in the basal hypothalamus was higher in the high than the low growth haplotype (P=0.009).
By understanding the neuroendocrine consequences of a genetic locus for a quantitative trait we have increased our knowledge on the control of growth. This result confirms the belief that changes in appetite have been selected for during domestication and, at least in birds, this suggests that CCK and its receptor has a major part to play in determining the ‘set point’ for body weight.
Funded by BBSRC strategic grants, Pfizer and Wellcome Trust student grants.