Energy balance and body weight are regulated in short, intermediate, and long cycles that are superimposed on each other. We propose that the brain is the primary center of this regulation. The brain has evolved mechanisms for sensing the energy status of the body using neural and metabolic signals such as glucose, insulin, and leptin. It has central processing and storage capacity for handling this afferent information and can change both structurally and functionally in response to its internal and external milieu. The brain regulates energy balance through its control of energy intake on the one hand and expenditure and storage on the other using neurohumoral mechanisms that include the autonomic nervous system. Work in animal models suggests that the brain of obese individuals largely ignores signals of excess adiposity from the periphery, keeping the body weight set point at pathologically high levels. Disordered regulation of neuropeptide Y and monoamine metabolism within the ventromedial hypothalamus is a consistent finding in the brains of obesity-prone and obese rodents. Such dysregulation causes inappropriate neurohumoral control of metabolism and autonomic output to organs such as the pancreas, resulting in increased metabolic efficiency and persistent adiposity. The high recidivism rate in the treatment of obesity suggests that central dysfunction may be due to long-term reorganization of the nervous system in such a way as to perpetuate the abnormally high set point of body weight.
Calorie restriction-mediated restoration of hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation is not effective for lowering the body weight set point in IRS-2 knockout obese mice
