Leptin is secreted by fat cells, and its output is regulated by the adequacy of fat stores. BMI and body fat stores are directly related to leptin secretion. With abundant adipose tissue, leptin secretion is stimulated, and the hormone crosses the blood–brain barrier and travels to the hypothalamus, where it reduces food intake by stimulating POMC/ CART neurons and inhibiting NPY/AgRP neurons. The opposite sequence of events occurs when there are inadequate stores of body fat: Leptin secretion is diminished and food intake is increased. In persons of stable weight, the activities of these pathways are balanced. Leptin also increases energy expenditure by stimulating physical activity, energy expenditure, and thermogenesis, and these may be the most important catabolic effects mediated by leptin through the hypothalamus. Although the effects of leptin on food intake and energy expenditure can be readily demonstrated in nonobese mice and humans, the anorexigenic response of leptin is blunted in states of obesity despite high levels of circulating leptin. Such leptin resistance in obese mice can be bypassed by intraventricular injection of leptin. In keeping with this observation, injections of leptin in obese humans fail to affect food intake and energy expenditure, dashing initial enthusiasm of leptin therapy for obesity.
In rodents and humans, loss-of-function mutations affecting components of the leptin pathway give rise to massive obesity. Mice with mutations that disable the leptin gene or its receptor fail to sense the adequacy of fat stores, so they behave as if they are undernourished, eating ravenously. As in mice, mutations of the leptin gene or receptor in humans, although rare, may cause massive obesity. More common are mutations in the melanocortin receptor-4 gene (MC4R), found in 4% to 5% of patients with massive obesity. As mentioned earlier, MSH sends satiety signals by binding to this receptor. These monogenic traits underscore the importance of the leptin pathway in the control of body weight, and it is possible that more common types of defects in this pathway will be discovered in the obese. In closing it should be mentioned that, like leptin, insulin also exerts anorexigenic responses. However, the mechanism of this effect of insulin is less clear, and most of the evidence suggests the primacy of leptin in the regulation of adiposity.
Adiponectin, produced in the adipose tissue, has been called a “fat-burning molecule” and the “guardian angel against obesity.” It directs fatty acids to muscle for their oxidation. It decreases the influx of fatty acids to the liver and the total hepatic triglyceride content. It also decreases glucose production in the liver, causing an increase in insulin sensitivity and protecting against the metabolic syndrome. In addition to its metabolic effects, adiponectin has anti-diabetic, anti-inflammatory, anti-atherogenic, anti-proliferative, and cardioprotective effects. Its serum levels are lower in obese than in lean individuals. These effects contribute to obesity-associated insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease (Chapter 14), and possibly increased risk of certain cancers, discussed later.