Endocrine Abstracts

The anorexigenic hormone leptin seems to be the principal adiposity indicator and signal of the state of nutrition, as its plasma levels are highly correlated to adipocyte number and fat content. The elucidation of the causes of monogenic forms of obesity has benefited from the positional cloning of a series of mouse obesity genes, including those that encode leptin, the leptin receptor (LEPR). Targeted genetic manipulation has also established the vital regulatory role of molecules such as the melanocortin 4 receptor (MC4R), which is vital in the melanocortin pathway, and the orexigenic protein AGRP. These discoveries were rapidly followed by the identification of rare monogenic recessive forms of human obesity that are caused by mutations in the genes that encode leptin, LEPR, prohormone convertase 1 and POMC, all of which result in a phenotype of excessive energy intake relative to energy expenditure. By contrast, more frequent autosomal-dominant forms of obesity are caused by mutations in the gene that encodes MC4R. MC4R deficiency represents the most common monogenic obesity disorder that has been identified so far. It is present in 1–6% of obese individuals from different ethnic groups, with a higher prevalence in cases with increased severity and earlier age of onset. In children with MC4R mutations, the degree of obesity and hyperphagia correlates with the extent of impairment of MC4R signalling, but the correlation disappears in adult carriers who cannot be phenotypically distinguished from obese non-carriers. The characteristic intense feeling of hunger during childhood in patients with MC4R deficiency seems to lessen in adolescence, and levels of hyperinsulinaemia also become less marked. Interestingly, MC4R-deficient mice are not hyperphagic when fed a low-fat diet, whereas hyperphagia is observed after the introduction of diets that have increased fat content, indicating gene–environment interactions. Although difficult to assess in humans, such environmental effects for genes that are involved in the control of food intake might also contribute to explaining the increase in childhood obesity that has occurred in the past 20 years.