SummaryEnergy deficit in lean or obese animals or humans stimulates appetite, reduces energy expenditure and possibly also decreases physical activity, thereby contributing to weight regain. Often overlooked in weight loss trials for obesity, however, is the effect of energy restriction on neuroendocrine status. Negative energy balance in lean animals and humans consistently inhibits activity of the hypothalamo--pituitary--thyroid, --gonadotropic and --somatotropic axes (or reduces circulating insulin--like growth factor--1 levels), while concomitantly activating the hypothalamo--pituitary--adrenal axis, with emerging evidence of similar changes in overweight and obese people during lifestyle interventions for weight loss. These neuroendocrine changes, which animal studies show may result in part from hypothalamic actions of orexigenic (e.g. neuropeptide Y, agouti--related peptide) and anorexigenic peptides (e.g. alpha--melanocyte--stimulating hormone, and cocaine and amphetamine--related transcript), can adversely affect body composition by promoting the accumulation of adipose tissue (particularly central adiposity) and stimulating the loss of lean body mass and bone. As such, current efforts to maximize loss of excess body fat in obese people may inadvertently be promoting long--term complications such as central obesity and associated health risks, as well as sarcopenia and osteoporosis. Future weight loss trials would benefit from assessment of the effects on body composition and key hormonal regulators of body composition using sensitive techniques. Introduction A major challenge in the treatment of obesity is that the human body responds to energy restriction and weight loss with a diverse range of adaptive responses that oppose ongoing weight loss and promote regain. Such changes include robust increases in appetite, marked reductions in energy expenditure, and new studies also suggest reductions in physical activity (1,2) and the energy cost of activity (3,4), as recently reviewed (5-7). It is commonly assumed among healthcare professionals, the weight loss industry and members of the public alike that such energy--conserving adaptations only occur after extensive or rapid weight loss in lean individuals, as in the Minnesota starvation study published in 1950 (8). However, such adaptations have been shown to occur even in overweight and obese people after loss of as little as 6-12% of body weight (1,6,9-12), and even when weight loss is achieved using moderate energy restriction, with or without physical activity (1,9,10). As the extent of the weight--loss--induced increases in appetite (13,14) or reductions in energy expenditure (13-16) predict subsequent weight regain, and as low levels of non--exercise activity thermogenesis also predict subsequent weight gain in rodents, monkeys and possibly also in humans (7), it is likely that these adaptive responses contribute to the low success rate of non--surgical treatments for overweight and obesity.Besides effects on energy intake, physical activity and en...