Obesity and the Regulation of Body Mass:- The Lipostat Theory Predicts the Feedback Regulation of Adipose Tissue
The lipostat theory postulates a mechanism that inhibits eating behavior and increases energy consumption whenever body weight exceeds a certain value (the set point); the inhibition is relieved when body weight drops below the set point (Fig. 1). This theory pre dicts that a feedback signal originating in adipose tissue influences the brain centers that control eating behavior and activity (metabolic and motor). The first such factor, leptin, was discovered in 1994, and several others are now known. Leptin (Greek leptos, “thin”) is a small protein (167 amino acids) that is produced in adipocytes and moves through the blood to the brain, where it acts on receptors in the hypothalamus to curtail appetite. Leptin was first identified as the product of a gene designated OB (obese) in laboratory mice. Mice with two defective copies of this gene (ob/ob genotype; lowercase letters signify a mutant form of the gene) show the behavior and physiology of animals in a constant state of starvation: their serum cortisol levels are elevated; they are unable to stay warm, they grow abnormally, do not re produce, and exhibit unrestrained appetite. As a con sequence of the last effect, they become severely obese, weighing as much as three times more than normal mice (Fig. 2). They also have metabolic disturbances very similar to those of diabetic animals, and they are insulin-resistant. When leptin is injected into ob/ob mice, they lose weight and increase their locomotor activity and thermogenesis. A second mouse gene, designated DB (diabetic), has also been found to have a role in appetite regulation. Mice with two defective copies (db/db) are obese and diabetic. The DB gene encodes the leptin receptor. When the leptin receptor is defective, the signaling function of leptin is lost. The leptin receptor is expressed primarily in regions of the brain known to regulate feeding behavior— neurons of the arcuate nucleus of the hypothalamus . Leptin carries the message that fat reserves are sufficient, and it promotes a reduction in fuel intake and increased expenditure of energy. Leptin receptor interaction in the hypothalamus alters the re lease of neuronal signals to the region of the brain that affects appetite. Leptin also stimulates the sympathetic nervous system, increasing blood pressure, heart rate, and thermogenesis by uncoupling electron transfer from ATP synthesis in the mitochondria of adipocytes . Recall that thermogenin, also called uncoupling protein (UCP), forms a channel in the inner mitochondrial membrane that allows protons to reenter the mitochondrial matrix without passing through the ATP synthase complex . This permits continual oxidation of fuel (fatty acids in an adipocyte) without ATP synthesis, dissipating energy as heat and consuming dietary calories or stored fats in potentially very large amounts.
FIGURE 1 Set-point model for maintaining constant mass. When the mass of adipose tissue increases, released leptin inhibits feeding and fat synthesis and stimulates oxidation of fatty acids. When the mass of adipose tissue decreases, a lowered leptin production favors a greater food intake and less fatty acid oxidation.
FIGURE 2 Hypothalamic regulation of food intake and energy expenditure. (a) Anatomy of the hypothalamus. (b) Interactions between the hypothalamus and an adipocyte, described later in text.
