Obese persons generally have hypertriglyceridemia and low HDL cholesterol levels, factors that increase the risk of coronary artery disease. The association between obesity and heart disease is not straightforward, however, and such linkage as there is relates more to the associated diabetes and hypertension than to weight per se.
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Nonalcoholic fatty liver disease is commonly associated with obesity and type 2 diabetes. It can progress to fibrosis and cirrhosis (Chapter 16).
Cholelithiasis (gallstones) is six times more common in obese than in lean subjects. The mechanism is mainly an increase in total body cholesterol, increased cholesterol turnover, and augmented biliary excretion of cholesterol in the bile, which in turn predisposes affected persons to the formation of cholesterol-rich gallstones (Chapter 16).
Hypoventilation syndrome is a constellation of respiratory abnormalities in very obese persons. It has been called the pickwickian syndrome, after the fat lad who was constantly falling asleep in Charles Dickens’ The Pickwick Papers. Hypersomnolence, both at night and during the day, is characteristic and is often associated with apneic pauses during sleep (sleep apnea), polycythemia, and eventual right-sided heart failure.
Marked adiposity is a predisposing factor for the development of degenerative joint disease (osteoarthritis). This form of arthritis, which typically appears in older persons, is attributed in large part to the cumulative effects of wear and tear on joints. The greater the body burden of fat, the greater the trauma to joints with the passage of time.
Markers of inflammation, such as C-reactive protein (CRP) and proinflammatory cytokines like TNF, are often elevated in obese persons. The basis for the inflammation is uncertain; both a direct proinflammatory effect of excess circulating lipids and increased release of cytokines from fat-laden adipocytes have been proposed. Whatever the cause, it is thought that chronic inflammation may contribute to many of the complications of obesity, including insulin resistance, metabolic abnormalities, thrombosis, cardiovascular disease, and cancer.
There is an increased incidence of certain cancers in the overweight, including cancers of the esophagus, thyroid, colon, and kidney in men and cancers of the esophagus, endometrium, gallbladder, and kidney in women. Overall, obesity is associated with approximately 20% of cancer deaths in women and 14% of deaths in men. The underlying mechanisms are unknown and are likely to be multiple.
Elevated insulin levels. Insulin resistance leads to hyperinsulinemia, which includes multiple effects that may directly or indirectly contribute to cancer. For example, hyperinsulinemia causes a rise in levels of free insulin-like growth factor-1 (IGF-1). IGF-1 is a mitogen, and its receptor, IGFR-1, is highly expressed in many human cancers. IGFR-1 activates the RAS and PI3K/AKT pathways, which promote the growth of both normal and neoplastic cells (Chapter 6).
Obesity has effects on steroid hormones that regulate cell growth and differentiation in the breast, uterus, and other tissues. Specifically, obesity increases the synthesis of estrogen from androgen precursors, increases androgen synthesis in ovaries and adrenals, and enhances estrogen availability in obese persons by inhibiting the production of sex-hormone–binding globulin (SHBG) in the liver.
As discussed earlier, adiponectin secretion from adipose tissue is reduced in obese individuals. Adiponectin suppresses cell proliferation and promotes apoptosis. It also counteracts the actions of p53 and p21. In obese individuals these anti-neoplastic actions of adiponectin may be compromised.