In addition to leptin and adiponectin, adipose tissue produces other mediators, such as cytokines, chemokines, and steroid hormones, which allow adipose tissue to function as a link between lipid metabolism, nutrition, and inflammatory responses. The total number of adipocytes is established by the time of adolescence and is higher in people who were obese as children, providing another reason for concern about childhood obesity. Although in adults approximately 10% of adipocytes turn over annually, the number of adipocytes remains constant, regardless of individual body mass. Diets fail in part because the loss of fat from adipocytes causes leptin levels to fall, stimulating the appetite and diminishing energy expenditure.
Gut hormones are rapidly acting initiators and terminators of volitional eating. Prototypical examples are ghrelin and peptide YY (PYY). Ghrelin is produced in the stomach and the arcuate nucleus of the hypothalamus. It increases food intake, acting most likely by stimulating the NPY/AgRP neurons in the hypothalamus. Ghrelin levels normally rise before meals and fall 1 to 2 hours afterward, but this drop is attenuated in obese persons. Ghrelin levels are lower in obese individuals as compared to those with normal weight, and they increase with a reduction in obesity. Interestingly, the rise in ghrelin levels is much reduced in individuals in whom gastric bypass surgery is performed for the treatment of obesity, suggesting that the beneficial effects of such surgery may be in part due to a reduced surface of gastric mucosa that is exposed to food.
PYY is secreted from endocrine cells in the ileum and colon in response to the consumption of food. It decreases appetite and augments a sense of fullness (satiety). It acts, presumably, by stimulating POMC/CART neurons in the hypothalamus, thereby decreasing food intake.
PYY also reduces the rate of gastric emptying and intestinal motility (“ilea brake”), all of which contribute to satiety. PYY levels are reduced with obesity and may be of therapeutic value in the treatment of those who are overweight or obese.
The Role of Gut Microbiome
An interesting series of observations suggest that the gut microbiome may be involved in the development of obesity. In support of this notion is the finding that the profiles of gut microbiota differ between genetically obese mice and their lean littermates. The microbiome of genetically obese mice can harvest much more energy from food as compared to that of lean mice. Colonization of the gut of germfree mice by microbiota from obese mice (but not microbiota from lean mice) is associated with increased body weight. The relevance of these models to human obesity is tantalizing but remains to be proven.
Clinical Consequences of Obesity
Obesity, particularly central obesity, is a known risk factor for a number of conditions, including type 2 diabetes, cardiovascular disease, and cancer. Central obesity also stands at the center of a cluster of alterations known as the metabolic syndrome, characterized by abnormalities of glucose and lipid metabolism coupled with hypertension and evidence of a systemic proinflammatory state. This seems to be caused by the inflammasome response to free fatty acids and excess levels of lipids in cells and tissue. The inflammasome stimulates secretion of IL-1, which induces insulin resistance. The following associations are worthy of note:
Obesity is associated with insulin resistance and hyperinsulinemia, important features of type 2 diabetes (Chapter 20). Excess insulin, in turn, may play a role in the retention of sodium, expansion of blood volume, production of excess norepinephrine, and smooth muscle proliferation that are the hallmarks of hypertension. Whatever the mechanism, the risk of developing hypertension among previously normotensive persons increases proportionately with weight.