27.1 Caloric Homeostasis Is a Means of Regulating Body Weight

Many people are able to maintain a near-constant body weight throughout adult life. This ability is a demonstration of caloric homeostasis, a physiological condition in which energy needs match energy intake. When energy intake is greater than energy needs, weight gain results. In the developed world, obesity is at epidemic proportions and is implicated as a contributing factor in a host of pathological conditions.

27.2 The Brain Plays a Key Role in Caloric Homeostasis

Various signal molecules act on the brain to control appetite. Short-term signals such as CCK and GLP-1 relay satiety signals to the brain while eating is in progress. Long-term signals include leptin and insulin. Leptin, secreted by adipose tissue in direct proportion to adipose-tissue mass, is an indication of fat stores. Leptin inhibits eating. Insulin also works in the brain, signaling carbohydrate availability.

Leptin acts by binding to a receptor in brain neurons, which initiates signal-transduction pathways that reduce appetite. Obesity can develop in individuals with normal amounts of leptin and the leptin receptor, suggesting that such individuals are leptin resistant. Suppressors of cytokine signaling may inhibit leptin signaling, leading to leptin resistance and obesity.

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27.3 Diabetes Is a Common Metabolic Disease Often Resulting from Obesity

Diabetes is the most common metabolic disease in the world. Type 1 diabetes results when insulin is absent due to autoimmune destruction of the β cells of the pancreas. Type 2 diabetes is characterized by normal or higher levels of insulin, but the target tissues of insulin, notably muscle, do not respond to the hormone, a condition called insulin resistance. Obesity is a significant predisposing factor for type 2 diabetes.

In muscle, excess fats accumulate in an obese individual. These fats are processed to second messengers that activate signal-transduction pathways that inhibit insulin signaling, leading to insulin resistance. Insulin resistance in target tissues ultimately leads to pancreatic β-cell failure. The pancreas tries to compensate for a lack of insulin action by synthesizing more insulin, resulting in ER stress and subsequent activation of apoptotic pathways that lead to β-cell death.

Type 1 diabetes is due to metabolic derangements resulting in an insufficiency of insulin and an excess of glucagon relative to a person’s needs. The result is an elevated blood-glucose level, the mobilization of triacylglycerols, and excessive ketone-body formation. Accelerated ketone-body formation can lead to acidosis, coma, and death in untreated insulin-dependent diabetics.

27.4 Exercise Beneficially Alters the Biochemistry of Cells

Exercise is a useful prescription for insulin resistance and type 2 diabetes. Muscle activity stimulates mitochondrial biogenesis in a calcium-dependent manner. The increase in the number of mitochondria facilitates fatty acid oxidation in the muscle, resulting in increased insulin sensitivity.

Fuel choice in exercise is determined by the intensity and duration of the bout of exercise. Sprinting and marathon running are powered by different fuels to maximize power output. The 100-meter sprint is powered by stored ATP, creatine phosphate, and anaerobic glycolysis. In contrast, the oxidation of both muscle glycogen and fatty acids derived from adipose tissue is essential in the running of a marathon, a highly aerobic process.

27.5 Food Intake and Starvation Induce Metabolic Changes

Insulin signals the fed state; it stimulates the formation of glycogen and triacylglycerols and the synthesis of proteins. In contrast, glucagon signals a low blood-glucose level; it stimulates glycogen breakdown and gluconeogenesis by the liver and triacylglycerol hydrolysis by adipose tissue. After a meal, the rise in the blood-glucose level leads to an increased secretion of insulin and a decreased secretion of glucagon. Consequently, glycogen is synthesized in muscle and the liver. When the blood-glucose level drops several hours later, glucose is then formed by the degradation of glycogen and by the gluconeogenic pathway, and fatty acids are released by the hydrolysis of triacylglycerols. The liver and muscle then increasingly use fatty acids instead of glucose to meet their own energy needs so that glucose is conserved for use by the brain and the red blood cells.

The metabolic adaptations in starvation serve to minimize protein degradation. Large amounts of ketone bodies are formed by the liver from fatty acids and released into the blood within a few days after the onset of starvation. After several weeks of starvation, ketone bodies become the major fuel of the brain. The diminished need for glucose decreases the rate of muscle breakdown, and so the likelihood of survival is enhanced.

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27.6 Ethanol Alters Energy Metabolism in the Liver

The oxidation of ethanol results in an unregulated overproduction of NADH, which has several consequences. A rise in the blood levels of lactic acid and ketone bodies causes a fall in blood pH, or acidosis. The liver is damaged because the excess NADH causes excessive fat formation as well as the generation of acetaldehyde, a reactive molecule. Severe liver damage can result.