A Anatomic Characteristics of Adipose Tissue and Fat Distribution
Obesity is a disease whose pathology lies in the increased size and number of fat cells. An anatomic classification of obesity from which a pathologic classification arises is based on the number of adipocytes, on the regional distribution of body fat, or on the characteristics of localized fat deposits (1,2).
1 Size and Number of Fat Cells
The number of fat cells can be estimated from the total amount of body fat and the average size of a fat cell (3).
Because fat cells differ in size in different regions of the body, a reliable estimate of the total number of fat cells should be based on the average fat cell size from more than one location. In adults, the upper limits of the total of normal fat cells range from 40 to 60 x 109. The number of fat cells increases most rapidly during late childhood and puberty, but may increase even in adult life. The number of fat cells can increase three- to fivefold when obesity occurs in childhood or adolescence.
a. Hypertrophic Obesity
Enlarged fat cells are the pathologic sine qua non of obesity (3-5). Enlarged fat cells tend to correlate with an android or truncal fat distribution and are often associated with metabolic disorders such as glucose intolerance, dyslipidemia, hypertension, and coronary artery disease. These derangements occur because large fat cells secrete more of the many peptides and metabolites that they make.
b. Hypercellular Obesity
An increased number of fat cells usually occurs when obesity develops in childhood. Whether it begins in early or middle childhood, this type of obesity tends to be severe (6). Increased numbers of fat cells may also occur in adult life and this is to be expected when the body mass index (BMI) is >40 kg/m2 (7).
Measuring fat distribution in subcutaneous versus visceral compartments is important because visceral fat predicts development of health risks better than total body fat. The distribution of body fat can be estimated by a variety of techniques. The ratio of waist circumference divided by hip circumference waist-hip ratio; (WHR) was used in the pioneering studies that brought scientific recognition in the 1980s to the relationship of centrally located fat to the risk of developing heart disease, diabetes, and other chronic problems associated with obesity (8-10). This concept was originally suggested by Vague in 1948 (11) and is now widely accepted. The subscapular skinfold has also been valuable in estimating central fat in epidemiologic studies (12). The sagittal diameter, measured as the distance between the surface of the midabdominal skin and the table beneath a recumbent subject, has been used as an index of central fat (13). The only truly reliable estimates of visceral fat, however, are made by computed tomography (CT) (14) or magnetic resonance imaging (MRI). Using this technique and its association with dyslipide-mia, Pouliot et al. (15) and Lean et al. (16) showed that waist circumference was as good as or better than WHR or sagittal diameter in estimating visceral fat. For practical purposes, waist circumference alone and/or WHR are used as one criterion for evaluating the contribution of fat distribution to the health risk from obesity.
b. The Metabolic Syndrome
Central adiposity is one diagnostic criterion for the metabolic syndrome. This syndrome is a complex of traits that enhance the risk of cardiovascular disease and is discussed in more detail later in this chapter (17,18). The diagnosis requires three of the following five features: central obesity, hypertension, insulin resistance, dyslipidemia, or diabetes mellitus (17).
Table 1 Types of Lipodystrophy
Type of lipodystrophy
Generalized congenital lipodystrophy Partial lipodystrophy Acquired lipodystrophy Acquired peripheral lipodystrophy
Localized fat accumulations include single lipomas, multiple lipomas, liposarcomas, and lipodystrophy (2). Lipomas vary in size from 1 cm to >15 cm. They can occur in any body region, and represent encapsulated accumulations of fat. Multiple lipomatosis is an inherited disease transmitted as an autosomal-dominant trait. Von Recklinghausen's syndrome, Maffucci's syndrome, and Madelung's deformity are lipomatous syndromes.
Liposarcomas are relatively rare, representing <1% of lipomas. They tend to affect the lower extremities and consist of four types: well-differentiated myxoid; poorly differentiated myxoid; round cell or adenoid; and mixed (2).
Weber-Christian disease and Dercum's disease are idiopathic accumulations of fat. Dercum's disease, also called adiposis dolorosa, is named after the painful nodules in the subcutaneous fat of middle-aged women. Weber-Christian disease, on the other hand, is a relapsing febrile disease occurring in younger women. All of these forms of localized fat deposits are relatively rare (2).
Lipodystrophy is a loss of body fat in one or more regions of the body (19). It can have genetic causes or it can be acquired. Table 1 shows the various types of lipodystrophy. The clinical features include regional or general decrease in adipose tissue, severe insulin resistance, often with diabetes, markedly elevated triglycerides, and fatty liver. Acanthosis nigricans is also common. Animals with no body fat (20) show similarly marked insulin resistance that can be relieved when small amounts of fat are transplanted into the fat-deficient animals.
Familial partial lipodystrophy is a genetic defect due to an alternation in the laminin A/C gene. The protein
Berardinelli-Seip syndrome Dunnigan's syndrome Lawrence syndrome AIDS or protease lipodystrophy normally produced by this gene is thought to be involved in the entry of molecules into the nucleus. When the aberrant base substitution in the DNA is in one end of the molecule, the disease manifests itself as muscular dystrophy or congestive heart failure. When the molecular substitution is at the other end of the molecule, lipodystrophy is the result.
Drug-induced lipodystrophies appeared when patients with human immunodeficiency virus (HIV) disease were treated with proteases. The proteases reduce the viral burden, but also cause a central distribution of body fat. The mechanism for this central location of fat is currently under intense study.
B Etiologic Classification surgery in the posterior fossa, or increased intracranial pressure (22). The symptoms usually present in one or more of three patterns: (1) headache, vomiting and diminished vision due to increased intracranial pressure; (2) impaired endocrine function affecting the reproductive system with amenorrhea or impotence, diabetes insipidus, and thyroid or adrenal insufficiency; or (3) neurologic and physiologic derangements, including convulsions, coma, somnolence, and hypothermia or hyperthermia (Table 2). The clinical presentation of one patient is shown in Figure 1. Weight gain occurred in the third year after the appearance of several endocrine and hypothalamic changes. The patient died with multiple tuberculomas in the hypothalamus despite triple-antibiotic therapy.
A number of specific etiologies that cause obesity are described below.
Hypothalamic obesity is rare in humans (21). It can be regularly produced in animals by injuring the ven-tromedial or paraventricular region of the hypothalamus or the amygdala (22). These brain regions are responsible for integrating metabolic information on nutrient stores provided by leptin with afferent sensory information on food availability. When the ventrome-dial hypothalamus is damaged, hyperphagia develops, the response to leptin is eliminated, and obesity follows. Hypothalamic obesity in humans may be caused by trauma, tumor, inflammatory disease (22) (Table 2),
Table 2 Hypothalamic Obesity
Lesions causing hypothalamic obesity tumors inflammation trauma
Clinical features of hypothalamic obesity
1. Endocrine disturbances amenorrhea/impotence impaired growth diabetes insipidus thyroid/adrenal insufficiency
2. Intracranial pressure papilledema vomiting
3. Neurologic disturbances thrist somnolence b. Cushing's Syndrome
Obesity is one of the cardinal features of Cushing's syndrome (Table 3) (23). Thus, the differential diagnosis of obesity from Cushing's syndrome and pseudo-Cush-ing's syndrome is clinically important for therapeutic decisions (23,24). Pseudo-Cushing's is a name used for a variety of conditions that distort the dynamics of the hypothalamic-pituitary-adrenal axis and can confuse the interpretations of biochemical tests for Cushing's syndrome. Pseudo-Cushing's includes such things as depression, anxiety disorder, obsessive-compulsive disorder, poorly controlled diabetes mellitus, and alcoholism. Four different biochemical tests can be used to separate these entities. The first is a urinary free cortisol, which is the initial screening test, and is considered abnormal if it is more than two times the upper limit of normal (25,26). Patients with pseudo-Cushing's syndrome can have values that are elevated by fourfold, so other tests may be needed. The next test is the overnight suppression of cortisol at 8 am with a 1-mg dose of dexamethasone given orally at midnight. The dividing line is 3.6 Ag/dL, but the lower the value the more likely it is to exclude Cushing's syndrome. If the overnight dexamethasone test is equivocal, a nighttime cortisol level may be drawn. This distinguishes Cushing's syndrome from pseudo-Cushing's syndrome with 95% accuracy if the value is <7.5 Ag/dL. The final test is a dexamethasone-CRH test. This test can be helpful, but is also cumbersome to perform because of the timing. If tests are equivocal, then they may be repeated, but it may be advisable to wait for a few weeks in case the patient is an individual with intermittent Cushing's syndrome. For the differential diagnosis and treatment of Cushing's syndrome, the reader is referred elsewhere (24-26).
Onset 6 12 18 24 30 36
Duration of illness (months)
Figure 1 Symptomatic course of a patient with tuberculomas and hypothalamic obesity. Numerous symptoms developed in the first 2 years, followed by rapid weight gain in the third year.
Table 3 Clinical Findings with Cushing's Syndrome
Patients with hypothyroidism frequently gain weight because of a generalized slowing of metabolic activity. Some of this gain is fat. However, the weight gain is usually modest, and marked obesity is uncommon. Hy-pothyroidism is common, particularly in older women. In this group, measurement of thyroid-stimulating hormone (TSH) is a valuable diagnostic tool (27).
The definition of the polycystic ovary syndrome (PCOS) is based on a conference held at the National Institutes of health in April of 1990 and includes menstrual irregularity plus hyperandrogenism, excluding other pathology such as congenital adrenal hy-perplasia and androgen-secreting tumors (28). The presence of these other diseases can be suspected from measurements of TSH, prolactin, follicle-stimulating hormone (FSH), plasma testosterone, dehydroepian-drosterone-sulfate (DHEA-S), and a morning 17-hydroxyprogesterone.
The features of the syndrome are summarized in Table 4. Obesity, particularly central obesity, is common in this syndrome. Similarly, insulin resistance is
Percent of 70 patients
Decreased libido (men/women)
Obesity or weight gain
Dodrsal fat pad
Recurrent infections Abdominal pain Acne
100% 97% 94% 88% 84% 81% 74% 62% 62% 56% 56% 55% 54% 50% 50% 50% 47% 43% 25% 21% 21% 13%
Table 4 Features of the Polycystic Ovary Syndrome
Clinical and metabolic components of the polycystic ovary syndrome
Hypothalamic-pituitary abnormalities Metabolic abnormalities
Amenorrhea or oligomenorrhea
Increase risk of miscarriage Dysfunctional bleeding Hirsutism
Seborrhea and acne Male pattern of balding Elevated plasma androgens Increased LH or LH/FSH ratio Increased prolactin Obesity (10-80%)
Insulin resistance, even in nonobese women Acanthosis nigricans present, even when obesity is minimal. The basis for the association of the hypothalamic-adrenal-gonadal problem and the obesity is unclear. Luteinizing hormone (LH) is usually increased, and the ovary is the source for the increased amounts of testosterone, possibly through stimulation by insulinlike growth factor-1 (IGF-1).
More than 50% of women with PCOS are obese (29). The cardinal features of this syndrome are oligomenor-rhea, hirsutism, and polycystic ovaries. Although obesity is not always present, it occurs more often than not. Insulin resistance is present in both normal and overweight women with PCOS. LH is usually increased, and ovarian overproduction of testosterone, probably through ovarian stimulation by IGF-1, is amain source of the elevated testosterone. The factors responsible for this association are not understood.
Lean body mass is decreased and fat mass is increased in adults and children who are deficient in growth hormone (GH), compared with those who have normal GH secretion. However, the increase in fat does not produce clinically significant obesity. Growth hormone replacement reduces body fat and visceral fat (30). Acromegaly produces the opposite effects with reduced body fat and particularly visceral fat. Treatment of acromegaly, which lowers GH, increases body fat and visceral fat. Growth hormone selectively decreases visceral fat. The gradual decline in GH with age may be one reason for the increase in visceral fat with age.
2 Drug-Induced Weight Gain
Several drugs can cause weight gain, including a variety of psychoactive agents (31) and hormones (Table 5).
The degree of weight gain is generally not sufficient to cause true obesity, except occasionally in patients treated with high-dose corticosteroid, some psycho-active drugs, or valproate.
Most antipsychotics (phenothiazines and butyrophe-nones) cause weight gain. One study found that men hospitalized for mental illness, many of whom were treated with phenothiazines, gained an average of 3.2 kg over a stay of 35 months. Phenothiazines and the ''atypical'' antipsychotics are particularly prominent in this weight gain. Antidepressants are a second group of drugs that can cause obesity. The tricyclic antidepres-sant amitriptyline (Elavil) is particularly likely to cause weight gain and to increase the preference for carbohydrates. Lithium also has been implicated in weight gain. Valproate (Depakote®) is an antiepileptic drug that acts on the NMDA (glutamate) receptor. It causes weight gain in up to 50% of patients. Glucocorticoids cause fat accumulation in particular areas, similar to that of Cushing's syndrome. These changes occur mostly in patients taking >10 mg/d of prednisone. Megestrol acetate (Megace) is a progestin used in women with breast cancer and in patients with AIDS to increase appetite and induce weight gain (32). The increase in weight is fat. The serotonin antagonist cyproheptadine (Periactin) is associated with weight gain. Insulin probably produces weight gain by stimulating appetite, with intermittent hypoglycemia as the most likely mechanism. Weight gain occurs in diabetic patients treated with insulin; with sulfonylureas, which enhance endogenous insulin release; and with thiazolidinediones, which act on the PPAR-g receptor. In contrast, weight gain is not a problem with metformin (Glucophage). In the large UKPDS Trial diabetics treated conventionally or with metformin gained the same amount of weight
Table 5 Drugs That Produce Weight Gain and Alternatives
Drugs that cause weight gain
Monoamine oxidase inhibitors Selective serotonin reuptake inhibitors Anticonvulsants
Adrenergic blockers Adrenergic blockers Steroid hormones
Thioridazine; olanzepine; quetiapine; resperidone; clozapine
Amitriptyline; nortriptyline imipramine; mitrazapine; paroxetine
gabapentin Insulin Sulfonylureas Thiazolidinediones Pizotifen Cyproheptidine Propranolol Terazosin Contraceptives
Glucocorticoids Progestational steroids
Molindone; haloperidol; ziprasodone
Protriptyline Bupropion; nefazadone
Fluoxetine; sertraline Topiramate; lamotrigine; zonisamide
Miglitol; sibutramine Metformin; orlistat
Inhalers; decongestants ACE inhibitors; calcium channel blockers Barrier methods Nonsteroidal anti-inflammatory agents
(3.1 kg in 10 years). Patients treated with chlorpropamide gained 5.7 kg, patients treated with glibenclamide gained 4.8 kg, and patients treated with insulin gained 7.1 kg (33). The effect of insulin was dose dependent. In the Diabetes Control and Complications Trial, the mean increase in weight in patients with insulin-dependent diabetes was 5.1 kg with intensive insulin therapy and 2.4 kg with conventional therapy (34).
Weight gain is very common when people stop smoking and is at least partly mediated by nicotine withdrawal. Weight gain of 1-2 kg in the first few weeks is often followed by an additional 2- to 3-kg weight gain over the next 4-6 months. Average weight gain is 4-5 kg, but can be much greater (35). Researchers have estimated that smoking cessation increases the odds ratio of obesity 2.4-fold in men and 2.0-fold in women, compared with nonsmokers.
The effects of smoking and smoking cessation on body weight have also been evaluated by comparing pairs of identical twins to control for genetic and certain environmental factors. Light, moderate, and heavy-smoking twins were an average of 3.2, 2.4, and 4.0 kg lighter than their nonsmoking twin. On the other hand, past smokers had a significantly higher incidence of obesity (27%) than their currently smoking siblings.
Because of the substantial predictability of weight gain after smoking cessation, an exercise program and decreased caloric intake and the possible use of bupropion (Zyban) are recommended for all patients who plan to stop smoking.
A sedentary lifestyle lowers energy expenditure and promotes weight gain in both animals and humans. Restriction of physical activity in rats causes weight gain, and animals in zoos tend to be heavier than those in the wild. In an affluent society, energy-sparing devices in the workplace and at home reduce energy expenditure and may enhance the tendency to gain weight (36). In children there is a graded increase in BMI as the number of hours of television watching increases (37). "g
A number of additional observations illustrate the I importance of decreased energy expenditure in the pathogenesis of weight gain. The highest frequency of -a overweight occurs in men in sedentary occupations. Estimates of energy intake and energy expenditure in « Great Britain suggest that reduced energy expenditure | is more important than increased food intake in causing obesity (36). A study of middle-aged men in the | Netherlands found that the decline in energy expenditure accounted for almost all the weight gain (38). According to the Surgeon General's Report on Phys- I
ical Activity (39), the percentage of adult Americans participating in physical activity decreases steadily with age, and reduced energy expenditure in adults and children predicts weight gain. In the United States, and possibly other countries, the amount of time spent watching television is related to the degree of obesity in children; the number of automobiles is related to the degree of obesity in adults. Finally, the fatness of men in several affluent countries (the Seven Countries Study) was inversely related to levels of physical activity (40).
The amount of energy intake relative to energy expenditure is the central reason for the development of obesity. However, diet composition also may be variably important in its pathogenesis. Dietary factors become important in a variety of settings.
Several recent papers have suggested that breastfeeding may reduce the prevalence of obesity in later life. In a large German study of more than 11,000 children, Von Kries et al. (41) showed that the duration of breastfeeding as the sole source of nutrition was inversely related to the incidence of obesity, defined as a weight above the 95th centile, when children entered the first grade. In this study, the incidence was 4.8% in children with no breastfeeding, falling in a graded fashion to 0.8% in children were were solely fed from the breast for 12 months or more. A second large report (42) also showed that breastfeeding reduced the incidence of overweight, but not obese, adolescents. The third report, with fewer subjects and more ethnic heterogeneity, failed to show this effect (43). However, the potential that breastfeeding can reduce the future risk of obesity is another reason to recommend breastfeeding for at least 6-12 months.
Voluntary overeating (repeated ingestion of energy exceeding daily energy needs) can increase body weight in normal-weight men and women. When these subjects stop overeating, they invariably lose most or all of the excess weight. The use of overeating protocols to study the consequences of food ingestion has shown the importance of genetic factors in the pattern of weight gain (44).
Progressive hyperphagic obesity is one clinical form of overeating (2). A small number of patients begin to be overweight in childhood and then have unrelenting weight gain, usually surpassing 140 kg (300 lb) by 30 years of age. The recent death of a 13-year-old weighing 310 kg (680 lb) illustrates a nearly maximal rate of weight gain of 25 kg/year. These patients gain about the same amount of weight year after year. Because ~ 22 kcal/kg is required to maintain an extra kilogram of body weight in an obese individual, the energy requirements in these patients must increase year by year, with the weight gain being driven by excess energy intake.
Japanese sumo wrestlers who eat large quantities of food twice a day for many years, and who have a very active training schedule, have low visceral fat relative to total weight during training. When their active career ends, however, the wrestlers tend to remain overweight and have a high probability of developing diabetes mellitus (45).
c. Dietary Fat Intake
Epidemiologic data suggest that a high-fat diet is associated with obesity. The relative weight in several populations, for example, is directly related to the percentage of dietary fat in the diet (46-48). A high-fat diet introduces palatable, often high-fat foods into the diet, with a corresponding increase in energy density (i.e., lesser weight of food for the same number of calories). This makes overconsumption more likely. Differences in the storage capacity for various macronutrients may also be involved. The capacity to store glucose as glycogen in liver and muscle is limited, and needs to be replenished frequently. This contrasts with fat stores, which are more than 100 times the daily intake of fat. This difference in storage capacity makes eating carbohydrates a more important physiologic need that may lead to overeating when dietary carbohydrate is limited and carbohydrate oxidation cannot be reduced sufficiently.
d. Dietary Carbohydrate and Fiber
When the consumption of sugar and body weight are g examined there is usually an inverse relationship. However, there are recent data to suggest that the consumption of sugar-sweetened beverages in children may enhance the risk of more rapid weight gain. Both the baseline consumption and the change in consumption over 2 years were positively related to the increase in BMI over 2 years. That is, children who drank more sugar-sweetened beverages gained more weight, and those who increased their beverage consumption had an even greater increase (49).
A second relationship between obesity and carbohydrate intake may be through the glycemic index. In a review of six studies, Roberts documented that the consumption of higher glycemic index foods was associated with higher energy intake than when the foods had a lower glycemic index. This means that the higherfiber foods that release carbohydrate more slowly stimulate food intake less than the food in which the glucose is rapidly released, as it is in the high glycemic index foods (50).
The glycemic index is a way of describing the ease with which starches are digested in the intestine with the release of glucose that can be readily absorbed (53). A high glycemic index food is one that is readily digested and produces a large and rapid rise in plasma glucose. A low glycemic index food, on the other hand, is more slowly digested and is associated with a slower and lower rise in glucose. Comparative studies show that feeding high-glycemic index food suppresses food intake less than low-glycemic index foods. The low-gly-cemic foods are the fruits and vegetables that tend to have fiber. Potatoes, white rice, and white bread are high-glycemic foods. Legumes, whole wheat, etc., are low-glycemic foods.
In addition to the relation of energy intake and gly-cemic index, there are recent data to support the idea that diets with higher fiber intake are associated with lower weight. The Seven Countries Study initiated by Keys and associates more than 20 years ago has been a fertile source for epidemiologic data (40). A recent reexamination of this group has shown that the fiber intake within each of the participating countries was inversely related to the body weight. Men eating more fiber had lower body weight. Epidemiological data suggest that countries that have a higher fiber consumption have a lower prevalence of obesity (40). Fiber intake may also be inversely related to the development of heart disease (51) and diabetes (52).
e. Dietary Calcium
Nearly 20 years ago, McCarron et al. (54) reported that there was a negative relationship between BMI and dietary calcium intake in the data collected by the National Center for Health Statistics. More recently, Zemel et al. (55) found that there was a strong inverse relationship between calcium intake and the risk of being in the highest quartile of BMI. These studies have prompted a reevaluation of studies measuring calcium intake or giving calcium orally. In the prospective trials, subjects receiving calcium had a greater weight loss than those who were receiving placebos. Increasing calcium from 0 to nearly 2000 g/d was associated with a reduction in BMI of ~ 5 BMI units (56). These data might suggest that low calcium intake is playing a role in the current epidemic of obesity.
f. Frequency of Eating
The relationship between the frequency of meals and the development of obesity is unsettled. Many anecdotal reports argue that overweight persons eat less often than normal-weight persons, but documentation is scanty. However, frequency of eating does change lipid and glucose metabolism. When normal subjects eat several small meals a day, serum cholesterol concentrations are lower than when they eat a few large meals a day. Similarly, mean blood glucose concentrations are lower when meals are frequent (57). One explanation for the effects of frequent small meals compared with a few large meals could be the greater insulin secretion associated with larger meals.
g. Restrained Eating
A pattern of conscious limitation of food intake is called ''restrained'' eating (58). It is common in many, if not most, middle-aged women of ''normal weight.'' It also may account for the inverse relationship of body weight to social class; women of upper socioeconomic status often use restrained eating to maintain their weight. In a weight loss clinic, higher restraint scores were associated with lower body weights (59). Weight loss was associated with a significant increase in restraint, indicating that higher levels of conscious control maintain lower weight. Greater increases in restraint correlate with greater weight loss, but also with higher risk of''lapse'' or loss of control and overeating.
h. Binge-Eating Disorder
Binge-eating disorder is a psychiatric illness characterized by uncontrolled episodes of eating, usually in the evening (60). The patient may respond to treatment with | drugs that modulate serotonin.
i. Night-Eating Syndrome cj
The night-eating syndrome is the consumption of at least 25% (and usually >50%) of daily energy intake | between the evening meal and the next morning (61,62). 5 It is one pattern of disturbed eating in the obese. It is related to sleep disturbances and may be a component of sleep apnea, in which daytime somnolence and nocturnal wakefulness are often found.
Psychological factors in the development of obesity are widely recognized, although attempts to define a specific personality type that causes obesity have been unsuccessful. One condition linked to weight gain is seasonal affective disorder (SAD), which refers to the depression that occurs during the winter season in some people living in the North, where days are short. These patients tend to increase body weight in winter. This can be effectively treated by providing higher-intensity artificial lighting in the winter (63).
Obesity is more prevalent in lower socioeconomic groups in the United States and elsewhere. The inverse relationship of socioeconomic status (SES) and overweight is found in both adults and children. In the Minnesota Heart Study (64), for example, the SES and BMI were inversely related. People of higher SES were more concerned with healthy weight control practices, including exercise, and tended to eat less fat. In the National Heart, Lung and Blood Institute Growth and Health Study (65), SES and overweight were strongly associated in Caucasian 9- and 10-year-old girls and their mothers, but not in African-American girls. The association of SES and overweight is much stronger in Caucasian women than in African-American women. African-American women of all ages are more obese than are Caucasian women. African-American men are less obese than white men, and socioeconomic factors are much less evident in men. The prevalence of obesity in Hispanic men and women is higher than in Caucasians. The basis for these ethnic differences is unclear. In men, the socioeconomic effects of obesity are weak or absent. This gender difference, and the higher prevalence of overweight in women, suggests important interactions of gender with many factors that influence body fat and fat distribution. The reason for this association is not known.
Discovery of the basis for the five single-gene defects that produce obesity in animals was followed by the recognition that these same defects, though rare, also produce human obesity. Table 6 summarizes the clinical features of 25 cases caused by seven genetic defects.
The rare humans with leptin deficiency correspond to the obese (ob/ob) mouse animal model (66-68). Leptin is a 167-amino acid protein produced in adipose tissue, the placenta, and possibly other tissues that signals the brain through leptin receptors about the size of adipose stores. In three families, consanguineous marriages led to expression of the recessive leptin-deficient state. These very fat children are hypogonadal, but are not hypothermic or endocrine deficient. They lose weight when treated with leptin. A defect in the leptin receptor
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