Role of the hypothalamus in the neuroendocrine regulation of body weight and composition during energy deficit

Abstract

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...

Does Diet-Induced Weight Loss Lead to Bone Loss in Overweight or Obese Adults? A Systematic Review and Meta-Analysis of Clinical Trials

“…This is because energy restriction induces hormonal changes that might be expected to decrease bone mass, (18,53) and the effects may be more pronounced with severe than with moderate energy restriction. (99) An additional rationale for this hypothesis is that severe energy restriction induces greater weight loss than MER, (100) which would lead to greater mechanical unloading of bone, with subsequently greater bone loss.…”

“…(14,15) However dietinduced weight loss, not bariatric surgery, with or without concomitant physical activity, is seen as the first treatment option for overweight and obesity. (16) Given that weight loss via lifestyle modification is also known to induce hormonal changes that would be expected to reduce both lean body mass (17) and bone mass, (18,19) an increasing number of studies have investigated changes in bone mass in response to diet-induced weight loss in overweight and obese individuals.…”

Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPARγ signaling pathway

“…control of adiposity (14) and modulation of blood pressure (15), targeting the hypothalamic ghrelin receptor/GHSR1a for treatment of metabolic dysfunction without systemic side effects is challenging. Recent studies suggest alternative pathways for lipid metabolism involving peripheral actions of ghrelin.…”

Effects of energy restriction on activity of the hypothalamo-pituitary-adrenal axis in obese humans and rodents: implications for diet-induced changes in body composition

“…The rationale for this hypothesis is that energy restriction in lean humans or animals is known to up-regulate activity of the HPA axis, with resultant increases in circulating glucocorticoid levels [11]. Moreover, because glucocorticoids per se can cause accretion of white adipose tissue -particularly visceral adipose tissue -as well as loss of lean tissue and bone mass in humans and animals, such increases in circulating glucocorticoid levels probably contribute to the loss of lean tissue and bone in severely energy-restricted people (e.g., patients with anorexia nervosa or elite gymnasts), as well as the preferential accretion of central fat with re-feeding in anorexia nervosa [11]. One might argue that an obese individual undergoing energy restriction to lose excess weight is under a less extreme form of nutritional stress than an already lean or underweight individual in severe energy restriction caused by anorexia nervosa or competitive sports requirements.…”