Monogenic Effects that Result in Obesity

As human genes have not changed appreciably over the last few decades, the recent increase in the prevalence of obesity has been attributed to obesigenic environmental and lifestyle factors, namely, excessive caloric intake and reduced physical activity. However, the significant variability between humans in their propensity to gain weight suggests that susceptibility to obesigenic environmental challenges is largely determined by genetic factors.

“Common” obesity is thought to arise from mutations in multiple genetic loci (polygenic obesity), each with modest effects, which interact with each other (gene–gene interactions) and/or with obesigenic environmental factors (gene–environment interactions) to increase body weight. Obesity resulting from mutations in a single gene (monogenic obesity) is comparatively uncommon, but has increased our understanding of the complex pathways that regulate appetite and body weight homeostasis in humans. Much of the research in this area has concentrated on the leptin-melanocortin pathway, the components of which are important determinants of energy balance in animals and humans.

The Leptin-Melanocortin Pathway

Leptin is a fat-derived hormone, or adipokine, the circulating levels of which correlate with the degree of adiposity. Activation of proopiomelanocortin (POMC) neurones in the hypothalamic arcuate nucleus by leptin (and insulin) results in the proteolytic cleavage of POMC by prohormone convertase-1 (PC-1), yielding the anorectic peptide α-melanocyte stimulating hormone, an endogenous ligand at melanocortin 4 receptors (MC4R) in the paraventricular nucleus. Concurrently, leptin inhibits the release of the orexigenic neuropeptide Y. Activation of MC4R has a number of downstream effects, culminating in inhibition of food intake. Humans with monogenic forms of obesity because of mutations in a number of components of this pathway have been identified over the last decade or so, highlighting the importance of the leptin-melanocortin pathway in mediating energy balance and appetite regulation in humans. With the exception of MC4R deficiency, only a small number [Page 469]of humans with mutations in leptin, leptin receptor, POMC, and PC-1 have been identified. Other genetic syndromes, in which obesity is one of many characteristic features, such as Bardet-Biedl, Prader-Willi, and Alstrom syndromes, will not be discussed further in this entry.

Mutations in Leptin and Leptin-Receptor

Following their initial description of two severely obese Pakistani cousins from a consanguineous family, who were homozygous for a frameshift mutation in the leptin gene, Farooqi and O'Rahilly have identified a number of other individuals homozygous for the same mutation. Congenital leptin deficiency results in extreme and early-onset hyperphagia and obesity. Affected individuals exhibit marked increases in body fat (body fat around 57 percent of weight), delayed puberty with hypogonadotrophic hypogonadism and abnormalities in T-cell number and function, with increased rates of childhood infection and mortality.

The Cambridge group has also reported that treatment of leptin-deficient individuals with subcutaneous leptin therapy led to a significant reduction in body weight (almost entirely due to a reduction in body fat), associated with a reversal of hyperphagia. Furthermore, treatment with leptin led to the onset of appropriately timed puberty and an improvement in abnormalities of immune function.

Homozygous and compound heterozygous mutations in the leptin receptor have also recently been described in severely obese individuals. Although humans with leptin receptor-deficiency exhibit similar features to those with congenital leptin deficiency, there is some recent evidence to suggest that the clinical phenotype may be less severe.

...