The hypothalamus is a key part of the brain that integrates neural and hormonal signals from peripheral organs such as the gut and adipose tissue to regulate body weight. Critically, the hormone leptin, which is produced by adipose tissue, is an indicator of nutritional state. Fasting leads to a fall in leptin which triggers a set of responses in the brain which act to restore energy balance.
Leptin acts on neurons within the hypothalamic arcuate nucleus which act as primary sensors of alterations in energy stores. In the fasting state, a fall in leptin stimulates neurons expressing agouti related peptide (AgRP) to increase food intake. At the same time, leptin inhibits POMC neurons, reducing the amount of α-MSH (melanocyte stimulating hormone), which normally suppresses food intake. These signals are integrated by second order neurons which express the melanocortin-4 receptors (MC4R).
In this way, fasting leads to an increase in food intake which restores energy balance. Disruption of MC4R in mice leads to obesity demonstrating that this pathway is critical for the control of appetite and body weight. These findings in animals paved the way for studies in humans and in 1998, we and colleagues in France identified the first mutations in the MC4R gene in people with severe obesity from early childhood.