Anorexia-cachexia associated with cancer and other diseases is a common and often fatal condition representing a large area of unmet medical need. It occurs most commonly in advanced cancer and is probably a consequence of molecules released by tumour cells, or tumour-associated interstitial or immune cells. These may then act directly on muscle to cause atrophy and/or may cause anorexia, which then leads to loss of both fat and lean mass. Although the aetiological triggers for this syndrome are not well characterized, recent data suggest that MIC-1/GDF15, a transforming growth factor-beta superfamily cytokine produced in large amounts by cancer cells and as a part of other disease processes, may be an important trigger. This cytokine acts on feeding centres in the hypothalamus and brainstem to cause anorexia leading to loss of lean and fat mass and eventually cachexia. In animal studies, the circulating concentrations of MIC-1/GDF15 required to cause this syndrome are similar to those seen in patients with advanced cancer, and at least some epidemiological studies support an association between MIC-1/GDF15 serum levels and measures of nutrition. This article will discuss its mechanisms of central appetite regulation, and the available data linking this action to anorexia-cachexia syndromes that suggest it is a potential target for therapy of cancer anorexia-cachexia and conversely may also be useful for the treatment of severe obesity.

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...

Very low energy diets (VLEDs), commonly achieved by replacing all food with meal replacement products and which result in fast weight loss, are the most effective dietary obesity treatment available. VLEDs are also cheaper to administer than conventional, food-based diets, which result in slow weight loss. Despite being effective and affordable, these diets are underutilized by healthcare professionals, possibly due to concerns about potential adverse effects on body composition and eating disorder behaviors. This paper describes the rationale and detailed protocol for the TEMPO Diet Trial (Type of Energy Manipulation for Promoting optimal metabolic health and body composition in Obesity), in a randomized controlled trial comparing the long-term (3-year) effects of fast versus slow weight loss. One hundred and one post-menopausal women aged 45–65 years with a body mass index of 30–40 kg/m2 were randomized to either: (1) 16 weeks of fast weight loss, achieved by a total meal replacement diet, followed by slow weight loss (as for the SLOW intervention) for the remaining time up until 52 weeks (“FAST” intervention), or (2) 52 weeks of slow weight loss, achieved by a conventional, food-based diet (“SLOW” intervention). Parameters of body composition, cardiometabolic health, eating disorder behaviors and psychology, and adaptive responses to energy restriction were measured throughout the 3-year trial.