Two hormones, leptin and insulin, are responsible for long-term regulation of body weight.
The discovery of the leptin (ob) gene, which encodes a fat-specific messenger RNA (mRNA) for leptin, has given some insight into the mechanism of energy homeostasis. In experimental animal models, the addition of recombinant leptin to obese, leptin-deficient ob/ob mice causes them to reduce their food intake and lose about 30% of their total body weight after 2 weeks of treatment. Unlike mutant mice, in most obese humans, levels of leptin mRNA in adipose tissue as well as serum levels of leptin are elevated. This was observed in all types of obesity, regardless of whether it is caused by genetic factors, hypothalamic lesions, or increased efficiency of food utilization. For unknown reasons, adipocytes in these obese individuals are resistant to leptin’s action, and administration of leptin does not reduce the amount of adipose tissue. Conversely, studies of individuals who have lost weight and those with anorexia nervosa show that leptin mRNA levels in their adipose tissue and serum levels of leptin are significantly reduced. Recent clinical findings indicate that leptin most likely protects the body against weight loss in times of food deprivation.
Insulin, the pancreatic hormone that regulates blood glucose levels, is also involved in regulation of adipose tissue metabolism. It enhances the conversion of glucose into
FIGURE 9.3 • Electron micrograph showing portions of two adjacent adipose cells. The cytoplasm of the adipose cells reveals mitochondria (M) and glycogen (the latter appears as the very dark particles). 15,000. Upper inset. Attenuated cytoplasm (Cy) of two adjoining adipose cells. Each cell is separated by a narrow space containing external (basal) lamina and an extremely attenuated process of a fibroblast. 65,000. Lower inset. The external (basal) lamina (BL) of the adipose cells appears as a discrete layer by which the cells are adequately separated from one another. F, fibroblast processes. 30,000.
the triglycerides of the lipid droplet by the adipocyte. Like leptin, insulin regulates weight by acting on brain centers in the hypothalamus. In contrast to leptin, insulin is required for the accumulation of adipose tissue. Antiobesity drug research is currently focusing on substances that can inhibit insulin and leptin signaling in the hypothalamus.
Deposition and mobilization of lipid are influenced by neural and hormonal factors.
One of the major metabolic functions of adipose tissue involves the uptake of fatty acids from the blood and their conversion to triglyceride within the adipocyte. Triglyceride is then stored within the cell’s lipid droplet. When adipose tissue is stimulated by neural or hormonal mechanisms, triglycerides are broken down into glycerol and fatty acids, a process called mobilization. The fatty acids pass through the adipocyte cell membrane to enter a capillary. Here they are bound to the carrier protein albumin and transported to other cells, which use fatty acids as metabolic fuel.
Neural mobilization is particularly important during periods of fasting and exposure to severe cold. During the early stages of experimental starvation in rodents, adipose cells in a denervated fat pad continue to deposit fat. Adipose cells in the intact contralateral fat pad mobilize fat. It is now known that norepinephrine (which is liberated by the endings of nerve cells of the sympathetic nervous system) initiates a series of metabolic steps that lead to the activation of lipase. This enzyme splits triglycerides, which constitute more than 90% of the lipids stored in the adipocyte. This enzymatic activity is an early step in the mobilization of lipids.