Background: Obesity treatments aim to maximize fat loss, particularly abdominal or visceral fat, without compromising lean or bone mass. However, the literature contains numerous examples of obesity treatments that -in addition to fat loss -result in loss of lean mass and/or bone mass. Materials and methods: Because of the known effects of energy restriction to increase activity of the hypothalamopitutiary adrenal (HPA) axis in lean humans and animals, and because increases in circulating glucocorticoid levels could potentially contribute to adverse body compositional changes with obesity treatments, we conducted a systematic PubMed search to determine whether HPA axis activation also occurs in response to energy restriction in obese humans and animals. Results and conclusions:In most studies in obese humans, short-term severe energy restriction increased circulating cortisol levels, and this response was also seen in two longer-term human studies involving severe or moderate energy restriction. These fi ndings parallel studies on short-or long-term energy restriction in obese rodents, with most studies showing increases in circulating corticosterone concentrations, and no change or actual increases in hypothalamic expression of corticotropin-releasing hormone, urocortin 3 or their receptors. However, a signifi cant proportion of studies involving longer-term severe or moderate energy restriction in obese humans showed no change or decreases in HPA axis function. There was variability among human studies in the duration of energy restriction and timing of the HPA axis investigations (i.e., during energy restriction, or aft er a period of post-restriction weight maintenance). In order to unambiguously determine changes in HPA axis function with energy restriction in obese humans, it will be important to assess HPA axis function at multiple time points during energy restriction, given that obese individuals may spend many