The literature presented in this paper argues that our limited ability to maintain energy balance in a weight-reduced state is the product of our difficulty in compensating for the weight loss-induced reduction in total energy expenditure. The end result, translated into the overwhelming complexity of preserving long-term weight loss, is presented as being a consequence of compromised appetite control. Given the present-day food landscape and the resultant susceptibility to passive overconsumption, the focus of this review will be on the peripheral ("bottom-up") signals (leptin, PYY, ghrelin, and GILP-1) and the evidence highlighting their influence on feeding behaviour. As we continue studying paradigms of body mass reduction, specifically the data emerging from patients of bariatric surgery, it is becoming clearer that counter-regulatory adaptations, possibly through down-(leptin, PYY, and GLP-1) or upregulation (ghrelin) of peptides, have an impact on energy balance. In itself, food deprivation influences some of the peptides that ultimately provide the physiological input for the overt expression of feeding behaviour; these peripheral adaptations are expected to serve as feeding cues - cues that, in the end, can serve to compromise the maintenance of energy balance. In a potentially novel intervention to increase compliance to long-term reductions in energy intake, it is proposed that manipulating the pattern of food intake to favourably alter the profile of gastrointestinal peptides would lead to better dietary control.