Short-term signals from the gastrointestinal (GI) tract control hunger and satiety, which affect the size and number of meals over a time course of minutes to hours. In the absence of food intake (between meals), the stomach produces ghrelin, an orexigenic (appetite-stimulating) hormone that drives hunger. As food is consumed, GI hormones, including cholecystokinin and peptide YY, among others, induce satiety (an anorexigenic effect), thereby terminating eating, through actions on gastric emptying and neural signals to the hypothalamus. Within the hypothalamus, neuropeptides (such as orexigenic neuropeptide Y [NPY] and anorexigenic α-melanocyte–stimulating hormone [α-MSH]) and neurotransmitters (such as anorexigenic serotonin and dopamine) are important in regulating hunger and satiety. Long-term and short-term signals interact, insofar as leptin increases secretion of α-MSH and decreases secretion of NPY. Thus, there are many complex regulatory loops that control the size and number of meals in relationship to the status of body fat stores. [Note: α-MSH, a cleavage product of proopiomelanocortin, binds to the melanocortin-4 receptor (MC4R). Loss-of-function mutations to MC4R are associated with early-onset obesity.]
V. METABOLIC EFFECTS
The primary metabolic effects of obesity include dyslipidemias, glucose intolerance, and insulin resistance expressed primarily in the liver, skeletal muscle, and adipose tissue. These metabolic abnormalities reflect molecular signals originating from the increased mass of adipocytes (see Fig. 25.9, p. 343, and Fig. 26.7). [Note: About 30% of obese individuals do not show these metabolic abnormalities.]
A. Metabolic syndrome
Abdominal obesity is associated with a cluster of metabolic abnormalities (hyperglycemia, insulin resistance, hyperinsulinemia, dyslipidemia [low levels of high-density lipoprotein (HDL) and elevated TAG], and hypertension) that is referred to as the metabolic syndrome (Fig. 26.8). It is a risk factor for CVD and T2D. The low-grade, chronic, systemic inflammation seen with obesity contributes to the pathogenesis of insulin resistance and T2D and likely plays a role in metabolic syndrome. In obesity, adipocytes release proinflammatory mediators such as IL-6 and TNF-α. Additionally, levels of adiponectin, which normally dampens inflammation and sensitizes tissues to insulin, are low.
B. Nonalcoholic liver disease
Obesity is associated with ectopic deposition of TAG in the liver (hepatic steatosis) and results in increased risk for nonalcoholic fatty liver disease ([NAFLD], see p. 343).
VI. OBESITY AND HEALTH
Obesity is correlated with an increased risk of death (Fig. 26.9) and is a risk factor for a number of chronic conditions, including T2D, dyslipidemias, hypertension, CVD, some cancers, gallstones, arthritis, gout, pelvic floor disorders (for example, urinary incontinence), NAFLD, and sleep apnea. The relationship between obesity and associated morbidities is stronger among individuals age <55 years. After age 74 years, there is no longer an association between increased BMI and mortality. [Note: Obesity also has social consequences (for example, stigmatization and discrimination).] Weight loss in obese individuals leads to decreased blood pressure, plasma TAG, and blood glucose levels. HDL increase.
VII. WEIGHT REDUCTION