Key Words

Certain endocrine and metabolic disorders cause mild to moderate weight gain and fat deposition. Excess fat storage in turn can have profound effects on intermediary metabolism and endocrine function. We begin this section with a brief discussion of endocrine disorders that promote excess weight gain. We then review the effects of obesity on linear growth and bone maturation, thyroid function, sexual development, adrenal function, and calcium homeostasis and bone mineralization. Subsequent chapters in this volume discuss the implications of obesity for insulin production and action and the regulation of glucose tolerance, blood pressure, lipid metabolism and atherogenesis, sleep hygiene, and hepatic function.

Metabolic and Hormonal Disorders Causing Excess Fat Deposition

Hormonal disorders commonly associated with weight gain and increases in the ratio of fat to lean body mass include growth hormone (GH) deficiency, hypothyroidism, glucocorticoid excess, and the polycystic ovarian syndrome (PCOS, Table 1). Fat deposition in GH deficiency results from heightened insulin sensitivity, impaired lipolysis, sarcopenia, and induction of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in visceral or abdominal fat, which favors local overproduction of cortisol ( 1 ). Hypothyroidism promotes weight gain by reducing resting energy expenditure, while glucocorticoid excess causes hyperphagia, adipogenesis, and muscle wasting. Ovarian hyperandrogenism/PCOS is associated with insulin resistance and hyperinsulinemia; given the ability of insulin to stimulate ovarian androgen production (see below), it may be a consequence as well as a cause of obesity.

Table 1 Mechanisms of Weight Gain in Hormonal Disorders
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Hypothalamic damage or disease can cause insatiable appetite and progressive weight gain. Reductions in basal metabolic rate and physical activity contribute to hypothalamic obesity (see Chapter 2 by Lustig). Deficiencies of GH, thyroid hormone, and glucocorticoids are common in this setting and some patients have precocious puberty, which can promote fat deposition, particularly in girls. The insatiable appetite and obesity probably result from central leptin resistance and heightened vagal tone with hyperinsulinemia. The use of high-dose glucocorticoids around the time of surgery facilitates weight gain; hyperprolactinemia, which has been associated with weight gain in adults and children ( 2 , 3 ), may also contribute.

GH deficiency, hypothyroidism, glucocorticoid excess, and pseudohypoparathyroidism (which can be accompanied by hypothyroidism as well as GH deficiency) are associated with short stature and/or decreased height velocity. In contrast, stature and height velocity are normal or increased in “exogenous” obesity (see below). Laboratory testing in an obese child is unlikely to reveal an underlying hormonal disorder (other than insulin resistance and glucose intolerance) if the height, growth velocity, pubertal development, and menstrual function are appropriate for age and family history. It should be noted, however, that linear growth and bone maturation may not be reduced in children with adrenal tumors that produce androgens as well as cortisol. Moreover, linear growth may appear normal or even increased in GH-deficient or hypothyroid patients who also have precocious puberty.

Effects of Obesity on Linear Growth and Bone Maturation

Final adult height in otherwise normal obese children generally falls within two standard deviations of target height. However, rates of linear growth and bone maturation are often increased in obese pre- and peri-pubertal children despite marked reductions in basal and stimulated plasma growth hormone (GH) concentrations and a reduction in circulating GH half-life ( 4 ). The reduction in GH secretion in obese children and adults has been ascribed to negative feedback by free fatty acids, a reduction in plasma ghrelin (a GH secretagogue produced by the stomach), and nutrient-stimulated increases in IGF-1 production. Total IGF-1 and IGF binding protein (BP)-3 concentrations in obese subjects are typically normal or only mildly elevated; this may reflect in part the production of IGF-1 and IGF BP-3 by white adipose tissue ( 5 , 6 ) and/or an increase in hepatic GH sensitivity, resulting from induction of hepatic GH receptors by hyperinsulinemia (Fig. 1). Induction of GH receptor expression in obesity is suggested by an increase in levels of GH binding protein ( 7 ), the circulating form of the extracellular GH receptor domain, and by heightened production of IGF-1 following a single dose of GH ( 8 ).

Fig. 1.
figure 1

Mechanisms that may explain the normal or increased rates of growth and bone maturation in pre- and peri-pubertal obese children. IGF, insulin-like growth factor; BP, binding protein. An increase in adrenal androgen production in obese children with precocious adrenarche may also accelerate bone maturation.

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Total IGF-2 concentrations were elevated in obese adults in two studies but were normal in a study of obese adolescents ( 9 ). Many investigations find reductions in serum IGF binding proteins 1 and 2 (IGFBP-1 and BP-2), which correlate inversely with plasma insulin concentrations and liver fat content ( 10 , 11 ). The reductions in IGFBPs 1 and 2 are postulated to increase the bioavailability of IGF-1, which may thereby maintain or increase linear growth in obesity despite diminished GH secretion. “Free” IGF-1 levels have been found to be elevated in some, but not all, studies of obese adults ( 12 , 13 ); however, a recent investigation found that the bioactivity of IGF-1, as assessed by a kinase receptor activation assay, was normal in obese women. The ratio of bioactive IGF-1 to total IGF-1, however, was increased ( 14 ).

Reductions in plasma IGF BP-1 or 2 concentrations in insulin-resistant obese subjects may facilitate weight gain because overexpression of IGFBP-1 or 2 in transgenic mice reduces adipogenesis and prevents diet-induced obesity. Interestingly BP-1 excess reduces insulin sensitivity but BP-2 excess improves glucose tolerance ( 15 , 16 )

The effects of IGF-1 on growth and bone maturation may be potentiated by insulin-induced increases in adrenal androgen production (Fig. 1 and below); bone age may be advanced as much as 1 year in children with precocious adrenarche, which is more common in obese children. The hyperleptinemia of obesity also appears to play a role (Fig. 1). Circulating leptin levels rise in proportion to body (particularly subcutaneous) fat stores and are higher in girls than in boys. Leptin stimulates proliferation of isolated mouse and rat osteoblasts and increases the width of the chondroprogenitor zone of the mouse mandible in vivo. Conversely, leptin deficiency in ob/ob mice reduces cortical bone mass but increases trabecular mass ( 17 ); leptin treatment increases femoral length, bone area, and bone mineral content ( 18 ) and may promote the differentiation of osteoblasts from bone marrow stem cells ( 17 ). The effects of leptin may be exerted in concert with IGF-1 because leptin increases IGF-1 receptor expression in mouse chondrocytes ( 19 ). Nevertheless, linear growth is normal in patients with congenital deficiencies of leptin or the leptin receptor ( 20 , 21 ).

Thyroid Function

Plasma T4 and TSH levels generally fall within the normal range in obese subjects but tri-iodothyronine concentrations are mildly elevated, a consequence of nutrient-dependent T4 to T3 conversion [( 4 ), Fig. 2]. The elevation of T3 increases resting energy expenditure and may thereby limit further weight gain. Caloric restriction and weight loss, on the other hand, decrease total and free T4 and T3 levels, reducing energy expenditure and thereby facilitating weight regain.

Fig. 2.
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Hyperleptinemia and nutrient-dependent conversion of T4 to T3 can increase T3 levels in obesity; fasting reduces T4 and T3 production and increases the conversion of T4 to inactive reverse T3 (rT3).

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The effects of caloric excess and deprivation on thyroid hormone levels are mediated in part by leptin-dependent effects on hypothalamic TRH production (Fig. 2; see also Chapter 28 by Lechan and Fekete). Thyroid hormone levels are variably low in leptin receptor-deficient humans and are reduced in leptin receptor-deficient db/db mice. Leptin treatment reverses the loss of TSH pulsatility that accompanies short-term fasting and normalizes thyroid hormone levels following longer-term caloric restriction. These actions are mediated by direct effects of leptin/STAT-3 signaling on TRH transcription and indirect effects on TRH production mediated by increases in ∝MSH and reductions in agouti-related peptide (AgRP) and neuropeptide Y ( 22 , 23 ).

Gonadal Function and Pubertal Development

A recent study found that obesity in early childhood (age 36–54 months) and excessive weight gain between 3 and 9 years of age increase the risks of precocious thelarche and may reduce the age of menarche ( 24 ). Since leptin promotes gonadotropin secretion and rises transiently before the onset of puberty in normal weight children, it is possible that the hyperleptinemia of obesity promotes early sexual maturation, at least in girls.

More commonly, obese girls and boys develop precocious adrenarche without true puberty, and teenage obese girls are prone to ovarian hyperandrogenism with mild hirsutism, acne, anovulation, and menstrual irregularity. The pathogenesis of precocious adrenarche and ovarian hyperandrogenism remains poorly understood. However, insulin and IGF-1 in excess act in synergy with adrenocorticotrophic hormone (ACTH) and luteinizing hormone (LH) to stimulate the production of androgens from adrenocortical cells and ovarian theca cells, respectively. These effects are mediated through induction of P450c17α hydroxylase activity. The biologic availability of ovarian and adrenal androgens is increased because insulin suppresses hepatic sex hormone binding globulin (SHBG) expression and reduces plasma SHBG concentrations. Free androgens increase the frequency of gonadotropin-releasing hormone (GnRH) pulses and the ratio of LH to follicle-stimulating hormone (FSH), thereby exacerbating thecal androgen production. The increase in free androgens may induce precocious adrenarche in pre-pubertal girls and boys and may cause anovulation and hirsutism in adolescent girls and young women [( 25 , 26 ), Fig. 3; see also Chapter 24 by Franks and Joharatnam].

Fig. 3.
figure 3

Development of ovarian hyperandrogenism and gynecomastia in obese adolescents. IGF, insulin-like growth factor; BP, binding protein; GHBP, growth hormone binding protein; SHBG, sex hormone binding globulin; LH, luteinizing hormone; FSH, follicle-stimulating hormone.

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Free and total testosterone levels are generally normal in obese boys but may decline with dramatic weight gain in association with a fall in gonadotropin levels. These changes can reverse with weight loss. Aromatization of androstenedione in adipose tissue increases plasma estrone concentrations, causing gynecomastia in adolescent boys.

In rare cases the gynecomastia and ovarian hyperandrogenism in obese children are caused by hyperprolactinemia. Prolactin levels are typically normal or low in obese children or adults. However, hyperprolactinemia deriving from a pituitary tumor may be associated with weight gain in children as well as adults ( 2 , 3 ).

Glucocorticoid Production and Turnover

The abdominal weight gain, striae, hirsutism, and menstrual irregularity that may accompany obesity are often confused with Cushing’s syndrome. In contrast to “exogenous” obesity, Cushing’s syndrome is typically associated with linear growth failure and delayed bone maturation (unless a primary adrenal tumor produces excess androgens as well as glucocorticoids) as well as hemorrhagic/violaceous, rather than pink, striae. Basal plasma, salivary, and urinary free cortisol concentrations and basal ACTH levels in obese, non-Cushingoid children generally fall within the normal range, and diurnal variation and the response to dexamethasone are maintained ( 27 ). However, body fat mass correlates with total excretion of glucocorticoid metabolites, suggesting that obesity is accompanied by increased cortisol secretion and turnover.

Changes in tissue glucocorticoid metabolism may modulate fat distribution and peripheral insulin sensitivity ( 28 ). For example, polymorphisms in the glucocorticoid receptor have been associated with obesity, hypertension, and insulin resistance in some studies in adults. Additional investigations suggest that overexpression of 11 beta hydroxysteroid dehydrogenase type 1 (11βHSD1) in visceral adipose tissue may exacerbate weight gain by increasing local production of cortisol from inactive cortisone. In contrast, other studies find lower expression of 11βHSD1 in preadipocytes of obese, non-diabetic adults ( 29 ); the expected reduction in tissue cortisol concentrations is postulated to counteract the insulin resistance and weight gain in obese patients. An increase in 11βHSD1 expression after weight loss may facilitate adipose cortisol production, adipogenesis, and weight rebound.

Calcium Homeostasis, Bone Mineralization, and Fractures

Adolescents and adults with severe obesity, particularly those with dark skin, often have reduced circulating levels of 25-hydroxyvitamin D (25OHD). One study ( 30 ) found that 25OHD levels were less than 20 ng/ml in 78.4% of markedly obese (BMI 43.3) African-American teenage girls (mean age 14 years). The prevalence of vitamin D deficiency is lower in obese whites than in black or Hispanic children ( 31 ): in a total of 127 obese adolescents (mean age 13 years, BMI 36.4), vitamin D deficiency was noted in 43.6% of Hispanics and 48.7% of African-Americans but only 10.2% of Caucasians; levels of 25OHD correlated inversely with serum parathyroid hormone (PTH). A more recent investigation ( 32 ) showed that 17 of 58 obese adolescents (mean 14.9 years, BMI 36, 66% female, 14% black) had 25OHD levels below 20 ng/ml; however, none had elevated (>65 ng/ml) PTH levels, and bone mineral content and density fell within the normal range.

The reductions in 25OH vitamin D levels in obese children may be explained by decreased intake of vitamin D-containing dairy products, decreased cutaneous synthesis of vitamin D3 (in persons of color), and/or reduced bioavailability of vitamin D3 owing to deposition in adipose tissue ( 33 ). 25OHD levels in adults are inversely proportional to visceral and subcutaneous fat stores and measures of insulin sensitivity ( 34 ). Recent evidence suggests that 1,25 diOH vitamin D inhibits expression of peroxisome-proliferator-activated receptor gamma (PPARγ) and c/EBPα, providing a mechanism by which vitamin D deficiency may promote adipogenesis ( 35 ). However, no studies thus far have demonstrated that Vitamin D treatment can prevent or reverse weight gain in obese subjects.

Some studies show variable decreases in bone mineral content in obese subjects; others find that overweight and obese children have normal or increased bone mass compared with lean children. Yet the incidence of extremity fractures appears to be higher in obese than in lean children ( 36 , 37 ); experiments in mice suggests that high-fat feeding increases bone density but reduces bone strength, bending stiffness, and fracture resistance ( 38 ). Overall bone quality appears to reflect a number of genetic and environmental factors including milk intake and sun exposure, consumption of carbonated beverages, and physical activity, which promotes bone accrual and strength ( 39 ).