Mutations: Rare, single gene mutations can cause human obesity. For example, mutations in the gene for leptin (causing decreased production) or its receptor (decreased function) result in hyperphagia (increased appetite for and consumption of food) and severe obesity (Fig. 26.6), underscoring the importance of the leptin system in regulating human body weight (see IV below). [Note: Most obese humans have elevated leptin levels but are resistant to the appetite-regulating effects of this hormone.]
B. Environmental and behavioral contributions
The epidemic of obesity occurring over the last several decades cannot be simply explained by changes in genetic factors, which are stable on this short time scale. Clearly, environmental factors, such as the ready availability of palatable, energy-dense foods, play a role. Furthermore, sedentary lifestyles decrease physical activity and enhance the tendency to gain weight. Eating behaviors, such as portion size, variety of foods consumed, an individual’s food preferences, and the number of people present during eating, also influence food consumption. However, it is important to note that many individuals in this same environment do not become obese. The susceptibility to obesity appears to be explained, at least in part, by an interaction of an individual’s genes and his or her environment and can be influenced by additional factors such as maternal under-or overnutrition that may “set” the body regulatory systems to defend a higher or lower level of body fat. Thus, epigenetic changes (see p.
476) likely influence the risk for obesity.
IV. MOLECULAR INFLUENCES
The cause of obesity can be summarized in a deceptively simple application of the first law of thermodynamics: Obesity results when energy (caloric) intake exceeds energy expenditure. However, the mechanism underlying this imbalance involves a complex interaction of biochemical, neurologic, environmental, and psychologic factors. The basic neural and humoral pathways that regulate appetite, energy expenditure, and body weight involve systems that regulate short-term food intake (meal to meal), and signals for the long-term (day to day, week to week, year to year) regulation of body weight (Fig. 26.7).
and overnourished (B) states. CCK = cholecystokinin; PYY = peptide YY.
A.
Long-term signals reflect the status of fat (TAG) stores.
1.
Leptin: Leptin is an adipocyte peptide hormone that is made and secreted in proportion to the size of fat stores. It acts on the brain to regulate food intake and energy expenditure. When we consume more calories than we need, body fat increases, and leptin production by adipocytes increases. The body adapts by increasing energy use (increasing activity) and decreasing appetite (an anorexigenic effect). When body fat decreases, the opposite effects occur. Unfortunately, most obese individuals are leptin resistant, and the leptin system may be better at preventing weight loss than preventing weight gain. [Note: Leptin’s effects are mediated through binding to receptors in the arcuate nucleus of the hypothalamus.] 2.
Insulin: Obese individuals are also hyperinsulinemic. Like leptin, insulin acts on hypothalamic neurons to dampen appetite. (See Chapter 23 for the effects of insulin on metabolism.) [Note: Obesity is associated with insulin resistance (see p. 342).]
B. Short-term signals