For many years obesity in rodents has been known to be caused by a number of distinct mutations distributed through the genome. Most of these singlegene mutations cause both hyperphagia and diminished energy expenditure, suggesting a physiologic link between these two parameters of energy homeostasis. Identification of the ob gene mutation in genetically obese (ob/ob) mice represented a major breakthrough in the field. The ob/ob mouse develops severe obesity, insulin resistance, and hyperphagia, as well as efficient metabolism (., it gets fat even when ingesting the same number of calories as lean litter mates). The product of the. | Chapter 074. Biology of Obesity Part 4 SPECIFIC GENETIC SYNDROMES For many years obesity in rodents has been known to be caused by a number of distinct mutations distributed through the genome. Most of these singlegene mutations cause both hyperphagia and diminished energy expenditure suggesting a physiologic link between these two parameters of energy homeostasis. Identification of the ob gene mutation in genetically obese ob ob mice represented a major breakthrough in the field. The ob ob mouse develops severe obesity insulin resistance and hyperphagia as well as efficient metabolism . it gets fat even when ingesting the same number of calories as lean litter mates . The product of the ob gene is the peptide leptin a name derived from the Greek root leptos meaning thin. Leptin is secreted by adipose cells and acts primarily through the hypothalamus. Its level of production provides an index of adipose energy stores Fig. 74-4 . High leptin levels decrease food intake and increase energy expenditure. Another mouse mutant db db which is resistant to leptin has a mutation in the leptin receptor and develops a similar syndrome. The OB gene is present in humans and expressed in fat. Several families with morbid early-onset obesity caused by inactivating mutations in either leptin or the leptin receptor have been described thus demonstrating the biologic relevance of leptin in humans. The obesity in these individuals begins shortly after birth is severe and is accompanied by neuroendocrine abnormalities. The most prominent of these is hypogonadotropic hypogonadism which is reversed by leptin replacement. Central hypothyroidism and growth retardation are seen in the mouse model but their occurrence in leptin-deficient humans is less clear. To date there is no evidence to suggest that mutations or polymorphisms in the leptin or leptin receptor genes play a prominent role in common forms of obesity. Figure 74-4 Glucose arid lipid metabolism Httnger satieiy Tharmogonssis
