Genetics vs Lifestyle

The relative contribution of genes versus lifestyle and environment in the development of obesity has not been precisely delineated. A child's risk of adulthood obesity is three times greater if one parent is obese and 10 times greater if both are obese. Indeed, for children younger than 3 years, parental weight is a greater determinant of risk of obesity than the child's own weight (Whitaker et al., 1997). However, the influence of parental weight does not reflect only genetic predisposition, because family members also share the same environment. A correlation in adult weight between identical twins is seen, even when they have been raised apart. Among adoptees, weight correlates with the weight of their biologic parents, but the correlation is not as strong as in twin studies. In summary, genetic makeup plays a permissive role, with adult weight being determined by interaction with the environment. Overall, genetic factors are estimated to be responsible for 30% to 40% of the variability in adult weight.

Genetic Factors

Most of the genetic influence on obesity is polygenic. More than 250 genes and chromosomal regions are associated with phenotypic obesity (Larsen et al., 2003). In some cases, the genes code specifically for visceral as opposed to subcutaneous obesity. Although specific genetic factors to explain common obesity have not been identified, several singlegene defects cause obesity in animals, with some correlates in humans.

Single-gene mutations related to obesity often involve leptin and melanocortin. Leptin is a protein produced in adipose tissue that provides negative feedback to appetite control centers. Obesity may reflect lack of hormone production or a lack of leptin receptors. There are leptin-deficient animal models, and rarely, this deficiency has been identified in humans. In leptin-deficient people, weight loss results when leptin is replaced. Leptin supplementation in non-leptin-deficient obese subjects does not result in weight loss (Bray, 2002).

Rare defects in melanocortin receptors in the adrenals have also been associated with obesity. Most often, a person must be homozygous for the abnormal gene for the trait to be expressed. A defect in the melanocortin-4 receptor is the most common single-gene mutation associated with severe obesity but still accounts for only about 5% of this population. Other single-gene mutations have been found in animal models as well as humans, but all are extremely rare. Recently identified genes include the FTO (fat mass and obesity-associated) gene. Each of these genes seems to be associated with a modest increase in weight.

There are a number of congenital syndromes in which obesity is part of the phenotype. The best known, Prader-Willi syndrome, results from a defect in the long arm of chromosome 15 and causes poor muscle tone in the newborn period, with hyperphagia, hypogonadism, behavioral problems, and developmental delay noted later. As with other medical causes of childhood obesity, linear growth is poor while growth in weight is excessive. Although the exact mechanisms by which the genetic abnormalities lead to obesity are unclear, patients with Prader-Willi syndrome have elevated levels of ghrelin, a peptide produced in the stomach and duodenum that stimulates eating.

Modulation of Appetite

Many hormonal factors are involved in appetite, as well as in the absorption, storage, and use of calories. Factors providing input to the brain include leptin levels, vagal afferent activity, and fluctuation in plasma glucose levels. Neuropeptides and monoamine neurotransmitters are also involved in appetite control. Some weight loss medications exert their influence through modulation of neurotransmitter levels, which may affect appetite or satiety.

Influences on Central Obesity

Central obesity suggests increased visceral fat deposits, likely caused by increased production of peptides and other metabolic messengers. Hormonal influences most likely play a role in the distribution of fat. Central obesity is believed to result partly from increased androgenic effects, which is why men have a greater tendency for central obesity. Central obesity is also associated with hyperandrogenic states in women, such as polycystic ovary syndrome (PCOS). The increase in visceral deposition of fat that can occur after menopause in women may be related to a decrease in growth hormone and estrogen production (see Chapter 35).

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