Hoodia gordonii is a supplement of natural origin which is known for its appetite suppressant activity. Owing to its anorectic activity, the aim of this study was to evaluate the effect of H. gordonii supplementation on metabolic changes and appetite regulatory peptides during calorie restriction. Male albino rats were divided into three groups (n = 12 in each) - Control, Calorie Restricted (CR, 25% for 5 days), Calorie Restricted and H. gordonii supplemented (CR + HG, organic solvent extract given orally for 5 days at a dose of 100 mg/kg bwt.). The regulatory peptides i.e. ghrelin, leptin, CCK, NPY, insulin, IGF-1, corticosterone, thyroid hormones, adiponectin, serotonin were determined. On comparison with CR rats, modulations were noticed in the appetite regulatory peptides and biochemical variables of the CR + HG rats. A significant decline in ghrelin and increase in CCK was observed. The CR group exhibited a significant decrease in leptin, IGF-1, plasma and whole brain serotonin with a significant increase in the ghrelin and thyroxin levels. These changes indicate altered metabolic responses and hunger suppression which seem to be caused by H. gordonii with CR along with the changes occurring due to CR itself. It is concluded that H. gordonii can modulate hunger during CR and may be used for better adherence to dietary restriction regime. (c) 2014 SAAB. Published by Elsevier B.V. All rights reserved.