How is the brain important for the regulation of appetite?

We know that maintaining energy balance is essential for keeping a healthy weight i.e. for not developing obesity with all its negative consequences on our life expectancy and mental and physical health.

We also know that brain is a key organ which regulates the energy balance.

But what evidence do we have that convinces us that it is specifically the brain that is the key regulator of energy balance?

There are many lines of evidence which establish the brain, in particular the hypothalamus, as the key regulator of energy balance. However, among the most convincing examples are probably genetic studies of some of the most common monogenic causes of human obesity.

These studies link specific proteins to brain circuits responsible for the regulation of energy balance, specifically to the hypothalamic leptin–melanocortin signalling pathway (see the figure).

In this pathway, leptin, which is secreted from the adipose tissue in proportion to the size of the fat deposits, stimulates leptin receptors on proopiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus (ARC), a key site of central regulation of energy balance. Subsequently, prohormone convertase 1 (PC1) cleaves the POMC protein into α and β melanocyte stimulating hormones (MSHs). MSHs stimulate melanocortin 4 receptors (MC4Rs), expressed exclusively in the brain, to ultimately reduce food intake and increase energy expenditure.

Deficiency in these components of the pathway – namely leptin, leptin receptor (LepR), pro-opiomelanocortin (POMC), prohormone convertase 1 (PC1), melanocyte stimulating hormone (MSH) and melanocortin 4 receptor (MC4R) – result in positive energy balance and consequently in obesity (Montague et al., 1997; Clement et al., 1998; Krude et al., 1998; Jackson et al., 1997; Yeo et al., 1998).


Figure legend: Most common human monogenetic causes of obesity are linked to the brain, supporting the role ot the brain in the regulation of energy balance. Protein deficiencies resulting in human monogenetic obesity are highlighted in red (adapted from Oswald and Yeo, 2007).