The effect of photoperiod, but not HFD, on serum IGF-1 levels, is consistent with this effect on lean mass. When fed a HFD, F344 rats adjust food and protein 4-IPP intake downward, as also observed by Togo et al.. This suggests that F344 rats attempt to balance their food intake in terms of energy with the macronutrient requirements for growth. The resulting adiposity observed in this study, implies that while food intake is suppressed, when on a high fat diet, it is not possible to suppress intake sufficiently to prevent gain in body fat. The fact that rats suppress protein intake on a HFD relative to chow fed rats on the same photoperiod, yet manage to achieve the same lean mass, indicates that the HFD must modulate protein uptake or metabolism. Evidence from the literature suggests that a HFD alters not only the structure of the gut, but also can increase amino acid transport across the gut. Thus it is likely that a HFD increases the efficiency of amino acid uptake and this could account for the lower level of protein intake on a HFD relative to chow fed rats. These data contrast with a recent study, which reported F344 rats to be seemingly resistant to diet induced obesity, on the basis of measurements of epididymal fat and serum leptin levels, when fed a diet containing 55% fat.. At present there is no obvious explanation for this difference in response of F344 rats to high fat diets between the two studies. Possible explanations may lie in differences in the high fat diets used and/or differences in the strain of F344 rat. In support of the latter we have previously reported differential responses to photoperiod in different strains of F344 rats, which indicates that F344 rats obtained from commercial suppliers/geographical locations are not genetically homogeneous. The current study also revealed a clear interaction between HFD and photoperiod at the level of GHRH gene expression. In common with Zucker rats there is a reduction in hypothalamic GHRH expression, when fed a HFD. Such an effect has not been seen in either mice or rats fed a HFD. In those cases, GHRH gene expression was measured by Northern blotting or qPCR rather than in situ hybridisation used in this study. The latter is likely to provide more accurate assessment of gene expression in specific regions of the brain. AA 29504 Despite the lower GHRH expression in F344 rats on HFD under both LD and SD, there were no concomitant changes in serum IGF-1 levels over the 4 weeks of the experiment. Nonetheless IGF-1 was clearly suppressed by SD relative to LD, as previously described. Since studies in mice have shown that it can take up to 8 weeks for effects of HFD on circulating IGF-1 levels to become apparent, with no observable change after 4 weeks of HFD, it is possible that changes in IGF-1 in F344 rats may become evident following a longer period of HFD feeding. It is also possible that the temporal mRNA expression profile for GHRH does not correlate fully with the temporal protein expression of GHRH, which could help to explain the lack of correlation of the serum IGF-1 and tissue GHRH mRNA responses.