Obesity as a Central Nervous System (CNS) Disorder
Obesity is increasingly recognized as a disorder of central nervous system regulation of appetite and energy expenditure. The brain plays a critical role in governing many fundamental processes throughout the body. The hypothalamus, in the middle of the brain and just above the brainstem, receives chemical and hormonal stimuli from various sources, including glucose, insulin, leptin and peptides secreted by the gut as it processes food. In turn the hypothalamus regulates a person's appetite, satiety and energy expenditure, to control body weight. The brain governs body weight by establishing a setpoint, much like a thermostat in an air conditioning system. The body then tries to maintain this level constant even when the food supply or physical activity is variable. However, malfunctioning of this system may allow the setpoint to slide up or down, causing overeating and obesity on the one hand or progressive weight loss and cachexia, a physical wasting disorder, on the other.
Two basic opposing neuronal populations work through the melanocortin 4 receptor (MC-4) in concert to maintain the body’s weight at a constant level. Proopiomelanocortin or POMC neurons function to reduce appetite and increase energy output. Neuropeptide Y/Agouti-Related Peptide (NPY/AgRP) neurons increase hunger and conserve energy when energy reserves, stored as fat, are low.
The Orexigen Approach
Orexigen uses combination drug candidates to leverage the brain’s normal circuitry and biochemistry to reduce appetite, expend more calories and block compensating mechanisms that attempt to prevent long term, sustained weight loss.