Chapter 074. Biology of Obesity (Part 4)

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 (e.g., it gets fat even when ingesting the same number of calories as lean litter mates). The product of the...
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Chapter 074. Biology of Obesity (Part 4) Chapter 074. Biology of Obesity (Part 4) SPECIFIC GENETIC SYNDROMES For many years obesity in rodents has been known to be caused by anumber of distinct mutations distributed through the genome. Most of these single-gene mutations cause both hyperphagia and diminished energy expenditure,suggesting a physiologic link between these two parameters of energyhomeostasis. Identification of the ob gene mutation in genetically obese (ob/ob)mice represented a major breakthrough in the field. The ob/ob mouse developssevere obesity, insulin resistance, and hyperphagia, as well as efficient metabolism(e.g., it gets fat even when ingesting the same number of calories as lean littermates). The product of the ob gene is the peptide leptin, a name derived from theGreek root leptos, meaning thin. Leptin is secreted by adipose cells and actsprimarily through the hypothalamus. Its level of production provides an index ofadipose energy stores (Fig. 74-4). High leptin levels decrease food intake andincrease energy expenditure. Another mouse mutant, db/db, which is resistant toleptin, has a mutation in the leptin receptor and develops a similar syndrome. TheOB 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 leptinreceptor have been described, thus demonstrating the biologic relevance of leptinin humans. The obesity in these individuals begins shortly after birth, is severe,and is accompanied by neuroendocrine abnormalities. The most prominent ofthese is hypogonadotropic hypogonadism, which is reversed by leptinreplacement. Central hypothyroidism and growth retardation are seen in the mousemodel, but their occurrence in leptin-deficient humans is less clear. To date, thereis no evidence to suggest that mutations or polymorphisms in the leptin or leptinreceptor genes play a prominent role in common forms of obesity. Figure 74-4 The physiologic system regulated by leptin. Rising or falling leptin levelsact through the hypothalamus to influence appetite, energy expenditure, andneuroendocrine function and through peripheral sites to influence systems such asthe immune system. Mutations in several other genes cause severe obesity in humans (Table 74-1); each of these syndromes is rare. Mutations in the gene encodingproopiomelanocortin (POMC) cause severe obesity through failure to synthesizeα-MSH, a key neuropeptide that inhibits appetite in the hypothalamus. Theabsence of POMC also causes secondary adrenal insufficiency due to absence ofadrenocorticotropic hormone (ACTH), as well as pale skin and red hair due toabsence of α-MSH. Proenzyme convertase 1 (PC-1) mutations are thought tocause obesity by preventing synthesis of α-MSH from its precursor peptide,POMC. α-MSH binds to the type 4 melanocortin receptor (MC4R), a keyhypothalamic receptor that inhibits eating. Heterozygous loss-of-functionmutations of this receptor account for as much as 5% of severe obesity. These fivegenetic defects define a pathway through which leptin (by stimulating POMC andincreasing α-MSH) restricts food intake and limits weight (Fig. 74-5). Table 74-1 Some Obesity Genes in Humans and Mice Gen Gene Product Mechanism In Ine of Obesity Human Rodent Lep Leptin, a fat- Mutation Y Y(ob) derived hormone prevents leptin es es from delivering satiety signal; brain perceives starvation Lep Leptin receptor Same as Y YR (db) above es es PO Proopiomelanoco Mutation Y YMC rtin, a precursor of prevents synthesis es es several hormones and of melanocyte- neuropeptides stimulating hormone (MSH), a satiety signal MC4 Type 4 receptor Mutation Y YR for MSH prevents reception es es of satiety signal from MSH AgR Agouti-related Overexpress N YP peptide, a neuropeptide ion inhibits signal o es expressed in the through MC4R hypothalamus PC- Prohormone Mutation Y N1 convertase 1, a prevents synthesis es o processing enzyme of neuropeptide, probably MSHFat Carboxypeptidas Same as N Y e E, a processing above o es enzymeTub Tub, a Hypothalam N Y hypothalamic protein of ic dysfunction o es unknown functionTrkB TrkB, a Hyperphagi Y Y neurotrophin receptor a due to es es uncharacterized ...