AimThe aim of this trial was to investigate the mechanism of action for body weight loss with semaglutide.Materials and methodsThis randomised, double‐blind, placebo‐controlled, two‐period crossover trial investigated the effects of 12 weeks of treatment with once‐weekly subcutaneous semaglutide, dose‐escalated to 1.0 mg, in 30 subjects with obesity. Ad libitum energy intake, ratings of appetite, thirst, nausea and well‐being, control of eating, food preference, resting metabolic rate, body weight and body composition were assessed.ResultsAfter a standardised breakfast, semaglutide, compared with placebo, led to a lower ad libitum energy intake during lunch (−1255 kJ; P < .0001) and during the subsequent evening meal (P = .0401) and snacks (P = .0034), resulting in a 24% reduction in total energy intake across all ad libitum meals throughout the day (−3036 kJ; P < .0001). Fasting overall appetite suppression scores were improved with semaglutide vs placebo, while nausea ratings were similar. Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high‐fat foods. Resting metabolic rate, adjusted for lean body mass, did not differ between treatments. Semaglutide led to a reduction from baseline in mean body weight of 5.0 kg, predominantly from body fat mass.ConclusionAfter 12 weeks of treatment, ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide. In addition to reduced energy intake, likely mechanisms for semaglutide‐induced weight loss included less appetite and food cravings, better control of eating and lower relative preference for fatty, energy‐dense foods.

2Exercise is widely regarded as one of the most valuable components of behaviour that can influence body weight and therefore help in the prevention and management of obesity. Indeed long term controlled trials show a clear dose related effect of exercise on body weight. However, there is a suspicion, particularly fuelled by media reports, that exercise serves to increase hunger and drive up food intake thereby nullifying the energy expended through activity. Not everyone performing regular exercise will lose weight, and several investigations have demonstrated a huge individual variability in the response to exercise regimes. What accounts for this heterogeneous response? First, exercise (or physical activity) through the expenditure of energy will influence the energy balance equation with the potential to generate an energy deficit. However, energy expenditure also influences the control of appetite (i.e. the physiological and psychological regulatory processes underpinning feeding) and energy intake. This dynamic interaction means that the prediction of a resultant shift in energy balance, and therefore weight change, will be complicated. In changing EI, exercise will impact on the biological mechanisms controlling appetite. It is becoming recognized that the major influences on the expression of appetite arise from fat-free mass and fat mass, Resting Metabolic Rate, gastric adjustment to ingested food, changes in episodic peptides including insulin, ghrelin, CCK, GLP-1 and PYY, as well as tonic peptides such as leptin. Moreover there is evidence that exercise will influence all of these components which, in turn, influence the drive to eat through the modulation of hunger (a conscious sensation reflecting a mental urge to eat) and adjustments in post-prandial satiety via an interaction with food composition. The specific actions of exercise on each physiological component will vary in strength from person to person (according to individual physiological characteristics) and with the intensity and duration of exercise. Therefore, individual responses to exercise will be highly variable and difficult to predict. Background Issues

The idea of body weight regulation implies that a biological mechanism exerts control over energy expenditure and food intake. This is a central tenet of energy homeostasis. However, the source and identity of the controlling mechanism have not been identified, although it is often presumed to be some long-acting signal related to body fat, such as leptin. Using a comprehensive experimental platform, we have investigated the relationship between biological and behavioural variables in two separate studies over a 12-week intervention period in obese adults (total n 92). All variables have been measured objectively and with a similar degree of scientific control and precision, including anthropometric factors, body composition, RMR and accumulative energy consumed at individual meals across the whole day. Results showed that meal size and daily energy intake (EI) were significantly correlated with fat-free mass (FFM, P values ,0·02-0·05) but not with fat mass (FM) or BMI (P values 0·11-0·45) (study 1, n 58). In study 2 (n 34), FFM (but not FM or BMI) predicted meal size and daily EI under two distinct dietary conditions (high-fat and low-fat). These data appear to indicate that, under these circumstances, some signal associated with lean mass (but not FM) exerts a determining effect over self-selected food consumption. This signal may be postulated to interact with a separate class of signals generated by FM. This finding may have implications for investigations of the molecular control of food intake and body weight and for the management of obesity.

We propose that RMR (largely determined by fat-free mass) may be a marker of energy intake and could represent a physiologic signal for hunger. These results may have implications for additional research possibilities in appetite, energy homeostasis, and obesity. This trial was registered under international standard identification for controlled trials as ISRCTN47291569.

A long-running issue in appetite research concerns the influence of energy expenditure on energy intake. More than 50 years ago, Otto G. Edholm proposed that “the differences between the intakes of food [of individuals] must originate in differences in the expenditure of energy”. However, a relationship between energy expenditure and energy intake within any one day could not be found, although there was a correlation over 2 weeks. This issue was never resolved before interest in integrative biology was replaced by molecular biochemistry. Using a psychobiological approach, we have studied appetite control in an energy balance framework using a multi-level experimental system on a single cohort of overweight and obese human subjects. This has disclosed relationships between variables in the domains of body composition [fat-free mass (FFM), fat mass (FM)], metabolism, gastrointestinal hormones, hunger and energy intake. In this Commentary, we review our own and other data, and discuss a new formulation whereby appetite control and energy intake are regulated by energy expenditure. Specifically, we propose that FFM (the largest contributor to resting metabolic rate), but not body mass index or FM, is closely associated with self-determined meal size and daily energy intake. This formulation has implications for understanding weight regulation and the management of obesity.