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The prevalence of obesity has increased dramatically in recent decades. Increased body habitus correlates with enhanced availability of low-cost, high-calorie foods. A mismatch in caloric intake and energy expenditure leads to excess body fat accumulation. There are, however, interindividual differences in susceptibility to obesity with exposure to the same obesogenic environment. It is likely that this variability in metabolism, energy storage, or neural hormonal components affecting behavior has genetic, epigenetic, or genomic components.

Gregor Johann Mendel discovered the laws of heredity that bear his name1 by combining diligent observation, prudent choice of experimental organism, and mental discipline. These allowed him to discern and then explain patterns consistent with unitary particulate determinative factors governing discrete phenotypic traits (genes). This insight is an example of Pascal’s dictum that “chance favors the prepared mind.”2 Unitary genetic traits such as sickle cell disease are the delight of educators, who employ them to convey foundational concepts in biology with elegant simplicity: one gene, one protein, one phenotype. This, of course, allows for oversimplification. By contrast, complex traits such as intelligence involve the interaction of multiple genes with various environmental influences. Readers of this text will likely have encountered Mendelian genetics. However, anyone whose genetics learning occurred more than a decade ago may reference and update their vocabulary of new concepts in genomics by referencing various genetics textbooks.3,4


The first single-gene mutation associated with obesity was identified in 1994 by positional cloning of the ob/ob mouse strain. The mutation was mapped to the leptin (lep) gene, which encodes a 16-kDa secreted hormone produced primarily by white adipose tissue.5 Subsequently, a mutation in the leptin receptor gene (lepr) was identified in another obese strain of mice. The leptin receptor is primarily expressed in the hypothalamus, and this hormonal signaling pathway plays an important role in regulation of food intake in both strains of mice. As it eventually became clear, the same is true in humans. Rare homozygous mutations and polymorphisms in both the LEP and LEPR genes have been identified in patients with severe forms of early-onset obesity and hyperphagia6 (see Sidebar 1-1). Leptin deficiency also manifests with reduced insulinlike growth factor 1 (IGF-1) levels, elevated insulin levels, hypothalamic hypothyroidism, impaired growth hormone secretion, and hypogonadotropic hypogonadism. Replacement of leptin by administration of the exogenous peptide has shown remarkable reversal of obesity in patients with homozygous mutations in LEP.7

SIDEBAR 1-1 Leptin Insufficiency

Hassan, the first child of healthy first cousins, was born at term weighing 3680 g. He presented to the clinic at 2.5 years of age weighing 34 kg (>99.9th percentile) with a height of 93.5 cm (69th percentile) and a BMI of 38.6 (>99.9th percentile). The parents reported food-seeking behavior and hyperphagia. Given the high clinical suspicion of a disturbance in the satiety signal in ...

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