MCAT Biochemistry Review
Chapter 12: Bioenergetics and Regulation of Metabolism
12.5 Hormonal Regulation of Metabolism
If each cell were acting independently of one another, metabolism would be a random process that could not be coordinated with outside events like meals or exertion. In order to make the most efficient use of the resources available, metabolism must be regulated across the entire organism. This regulation is accomplished best through hormonal means. Water-soluble peptide hormones, like insulin, are able to rapidly adjust the metabolic processes of cells via second messenger cascades, while certain fat-soluble amino acid-derivative hormones, like thyroid hormones, enact longer-range effects by exerting regulatory actions at the transcriptional level. Hormone levels are regulated by feedback loops with other endocrine structures, such as the hypothalamic–pituitary axis, or by the biomolecule upon which they act; for example, insulin causes a decrease in blood glucose, which removes the trigger for continued insulin release. Next, we'll examine the specific actions of several hormones involved in the regulation of metabolism and in maintaining homeostasis, including insulin and glucagon, epinephrine, glucocorticoids, and thyroid hormones.
INSULIN AND GLUCAGON
Insulin is a peptide hormone secreted by the β-cells of the pancreatic islets of Langerhans, as shown in Figure 12.4. It is a key player in the uptake and storage of glucose. Glucose is absorbed by peripheral tissues via facilitated transport mechanisms that utilize glucose transporters located in the cell membrane. The tissues that require insulin for effective uptake of glucose are adipose tissue and resting skeletal muscle. Tissues in which glucose uptake is not affected by insulin include:
· Nervous tissue
· Kidney tubules
· Intestinal mucosa
· Red blood cells (erythrocytes)
· β-cells of the pancreas
Figure 12.4. Insulin (light brown) in Pancreatic β-Cells
Take note of the differences between these types of tissues. Some tissues that require insulin actively store glucose when it is present in high concentrations, while other tissues that do not require insulin must still be able to absorb glucose even when the glucose concentration is low.
Insulin impacts the metabolism of the different nutrient classes in different ways. For carbohydrates, insulin increases the uptake of glucose and increases carbohydrate metabolism in muscle and fat. Increased glucose in muscle can be used as additional fuel to burn during exercise, or can be stored as glycogen. Insulin also increases glycogen synthesis in the liver by increasing the activity of glucokinase and glycogen synthase, while decreasing the activity of enzymes that promote glycogen breakdown (glycogen phosphorylase and glucose-6-phosphatase).
While the primary effects of insulin are on carbohydrate metabolism, it also changes the way that the body processes other macromolecules. For instance, insulin increases amino acid uptake by muscle cells, thereby increasing levels of protein synthesis and decreasing breakdown of essential proteins. Insulin also exhibits a significant impact on the metabolism of fats, especially in the liver and adipocytes. The effects of insulin on the metabolism of fats are described below.
· Glucose and triglyceride uptake by fat cells
· Lipoprotein lipase activity, which clears VLDL and chylomicrons from the blood
· Triacylglycerol synthesis (lipogenesis) in adipose tissue and the liver from acetyl-CoA
· Triacylglycerol breakdown (lipolysis) in adipose tissue
· Formation of ketone bodies by the liver
The most important controller of insulin secretion is plasma glucose. Above a threshold of , or about 5.6 mM glucose, insulin secretion is directly proportional to plasma glucose. For glucose to promote insulin secretion, it must not only enter the β-cell but also be metabolized, increasing intracellular ATP concentration. Increased ATP promotes exocytosis of insulin through several ion- and voltage-gated channels. Insulin secretion is also affected by signaling initiated by other hormones, such as glucagon and somatostatin.
Glucagon is a peptide hormone secreted by the α-cells of the pancreatic islets of Langerhans, as shown in Figure 12.5. The primary target for glucagon action is the hepatocyte. Glucagon acts through second messengers to cause the following effects:
· Increased liver glycogenolysis. Glucagon activates glycogen phosphorylase and inactivates glycogen synthase
· Increased liver gluconeogenesis. Glucagon promotes the conversion of pyruvate to phosphoenolpyruvate by pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK). Glucagon increases the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate by fructose-1,6-bisphosphatase
· Increased liver ketogenesis and decreased lipogenesis
· Increased lipolysis in the liver. Glucagon activates hormone-sensitive lipase in the liver. Because the action is on the liver and not the adipocyte, glucagon is not considered a major fat-mobilizing hormone
Figure 12.5. Glucagon (dark brown) in Pancreatic α-Cells
Low plasma glucose (hypoglycemia) is the most important physiological promoter of glucagon secretion, and elevated plasma glucose (hyperglycemia) is the most important inhibitor. Amino acids, especially basic amino acids (arginine, lysine, histidine), also promote the secretion of glucagon. Thus, glucagon is secreted in response to the ingestion of a meal rich in proteins.
Patients with type 1 diabetes mellitus are incapable of synthesizing insulin, but still synthesize glucagon. This combination increases blood sugar much more than if an individual were to lose all pancreatic function or to develop insulin insensitivity.
Functional Relationship of Glucagon and Insulin
Insulin, associated with a well-fed, absorptive metabolic state, and glucagon, associated with a postabsorptive metabolic state, usually oppose each other with respect to pathways of energy metabolism. Enzymes that are phosphorylated by glucagon are generally dephosphorylated by insulin; enzymes that are phosphorylated by insulin are generally dephosphorylated by glucagon. Figure 12.6 displays a feedback diagram of the interaction of insulin and glucagon on plasma glucose concentration, as well as fat and protein metabolism.
Figure 12.6. Relationship of Glucagon and Insulin in Metabolism
Glucocorticoids from the adrenal cortex are responsible for part of the stress response. In order to make a getaway in the “fight-or-flight” response, glucose must be rapidly mobilized from the liver in order to fuel actively contracting muscle cells while fatty acids are released from adipocytes. Glucocorticoids, especially cortisol, are secreted with many forms of stress, including exercise, cold, and emotional stress. Cortisol, shown in Figure 12.7, is a steroid hormone that promotes the mobilization of energy stores through the degradation and increased delivery of amino acids and increased lipolysis. Cortisol also elevates blood glucose levels, increasing glucose availability for nervous tissue through two mechanisms. First, cortisol inhibits glucose uptake in most tissues (muscle, lymphoid, and fat) and increases hepatic output of glucose via gluconeogenesis, particularly from amino acids. Second, cortisol has a permissive function that enhances the activity of glucagon, epinephrine, and other catecholamines. Long-term exposure to glucocorticoids may be required clinically, but causes persistent hyperglycemia, which stimulates insulin. This actually promotes fat storage in the adipose tissue, rather than lipolysis.
Figure 12.7. Structure of Cortisol
The endocrine system, discussed in Chapter 5 of MCAT Biology Review, is a major regulator of homeostasis. Like the glucocorticoids and catecholamines, mineralocorticoids and sex hormones are also synthesized by the adrenal gland and play a more minor role in metabolism.
An enlarged adrenal gland (with a tumor of the adrenal cortex) is shown in Figure 12.8. While the adrenal cortex produces steroid hormones (glucocorticoids, mineralocorticoids, and sex hormones), the adrenal medulla produces catecholamines.
Figure 12.8. Adrenal Gland (Enlarged) Adrenal cortex (yellow) and adrenal medulla (brown interior) visible on both slices.
Catecholamines are secreted by the adrenal medulla and include epinephrine and norepinephrine, also known as adrenaline and noradrenaline. The structures of these hormones are shown in Figure 12.9. Catecholamines increase the activity of liver and muscle glycogen phosphorylase, thus promoting glycogenolysis. This increases glucose output by the liver. Glycogenolysis also increases in skeletal muscle, but because muscle lacks glucose-6-phosphatase, glucose cannot be released by skeletal muscle into the bloodstream; instead, it is metabolized by the muscle tissue itself. Catecholamines act on adipose tissue to increase lipolysis by increasing the activity of hormone-sensitive lipase. Glycerol from triacylglycerol breakdown is a minor substrate for gluconeogenesis. Epinephrine also acts directly on target organs like the heart to increase the basal metabolic rate through the sympathetic nervous system. This increase in metabolic function is often associated with an adrenaline rush.
Figure 12.9. Structures of Adrenal Catecholamines (a) Epinephrine; (b) Norepinephrine.
Thyroid hormone activity is largely permissive. In other words, thyroid hormone levels are kept more or less constant, rather than undulating with changes in metabolic state. Thyroid hormones increase the basal metabolic rate, as evidenced by increased O2 consumption and heat production when they are secreted. The increase in metabolic rate produced by a dose of thyroxine (T4) occurs after a latency of several hours but may last for several days, while triiodothyronine (T3) produces a more rapid increase in metabolic rate and has a shorter duration of activity. The subscript numbers refer to the number of iodine atoms in the hormone; iodine atoms are represented by purple spheres in the structures shown in Figure 12.10. T4 can be thought of as the precursor to T3; deiodonases (enzymes that remove iodine from a molecule) are located in target tissues and convert T4 to T3. Thyroid hormones have their primary effects in lipid and carbohydrate metabolism. They accelerate cholesterol clearance from the plasma and increase the rate of glucose absorption from the small intestine. Epinephrine requires thyroid hormones to have a significant metabolic effect.
Figure 12.10. Structures of Thyroid Hormones (a) Triiodothyronine (T3); (b) Thyroxine (T4).
While thyroid hormones are not responsible for day-to-day adjustments in metabolism, insuffi cient thyroid hormone levels (hypothyroidism) can cause symptoms including cold intolerance, fatigue, weight gain, and depression as metabolism suffers. Excessive thyroid hormone levels (hyperthyroidism) can cause rapid weight loss, anxiety, jitteriness, and fever.
MCAT Concept Check 12.5:
Before you move on, assess your understanding of the material with these questions.
1. Describe the primary metabolic function of each of the following hormones:
· Thyroid hormones (T3 / T4):
2. Thyroid storm is a potentially lethal state of extreme hyperthyroidism in which T3 and T4 levels are significantly above normal limits. What vital sign abnormalities might be expected in a patient with thyroid storm?