In the field of obesity research, two separate lines of study have emerged which explore the mechanism by which food intake is regulated: short-term control of food intake, and the central regulation of energy balance. The former studies the satiety response during consumption of meals, whereby satiety signalling originating in the gut is transduced into a neural signal that modulates satiety pathways in the brainstem. This review describes a neuroanatomically based model in which leptin and insulin signalling in the hypothalamus governs long-term regulation of energy balance via mechanisms that are integrated with satiety hormone signalling in the brainstem. The functional outcome of this integration is a cumulative meal-to-meal regulation of food intake, that over relatively long intervals serves to maintain stable adipose stores. Our model provides a context within which continued investigation of neuroendocrine mechanisms that control food intake and body weight can be explored, and has potential application to our current understanding of clinical obesity and its treatment.