Obesity: a disease of the ponderostat and the regulation of energy balance.

Energy balance and thermodynamic laws regulate body weight. Therefore, obesity must occur over a sufficiently long period of time in which energy intake exceeds energy expenditure. It is clear that a strict application of the law of energy balance cannot fully explain what is observed in real life. One possible hypothesis is that some individuals may have an energy-sparing metabolism, predisposing them to obesity. Furthermore, energy balance can be regulated to maintain body weight within a fixed individual range, a set point, which is influenced by genetic or epigenetic factors. An energy balance regulator, the ponderostat, may be able to increase or decrease both energy expenditure and energy intake, depending on food availability (e.g., periods of famine or low-calorie diet, periods of overeating), to maintain body weight within the set point. The ponderostat is regulated by a complex neuroendocrine system that includes central structures located in the frontal cortex, hypothalamus, and diencephalic region, with peripheral afferents and efferents. Therefore, in many cases, obesity could be considered the consequence of a dysregulated ponderostat. This narrative review proposes a unifying perspective that considers obesity as a biological condition with an abnormal set point and dysregulated energy balance due to abnormalities in ponderostat function. Current and future antiobesity pharmacological treatments may be considered curative for ponderostat dysregulation.