Metabolism

Glucagon Signaling

Binds to plasma membrane receptors that are connected to G protein. This leads to a stimulation of adenelyl cyclase and cAMP. Through a signal transduction pathway, this leads to activation of specific enzymes and inactivation of specific enzymes that lead to glycogenolysis and lipolysis.

Neuroendocrine Control

increase in Epi to liver, adipocytes and skeletal muscle and Sympathetic nerves to the liver and adipose tissue increase glycogenolysis in skeletal muscle, glycogenolysis and gluconeogenesis in liver and lipolysis in the adipose tissue. End goal: increase plasma glucose, fatty acids, glycerol.

Summary of Nutrient Metabolism During Post-absorbative State

-Net breakdown of glycogen, fat, and protein occurs. -Glucose is formed in the liver from glycogen stored there and by gluconeogenesis from lactate, pyruvate, glycerol, and amino acids. The kidneys also perform gluconeogenesis. -The glucose produced by the liver and kidneys is used by neural tissues -Lipolysis releases fatty acids from adipose tissues into the blood and the oxidative of these fatty acids by cells and of ketones produces from them by the liver provides most of the body's energy supply. -the brain continues to use glucose but also starts using ketones as they build up in the blood.

Two functional states of the body

1. Absorptive state 2. Post-absorptive state

Stress and Metabolism (Effects of Cortisol)

1. Basal concentrations are permissive for stimulation of gluconeogenesis and lipolysis in postabsorptive state 2. Increased plasma concentrations cause -increased protein catabolism -increased gluconeogenesis -decreased glucose uptake by muscle cells and adipose-tissue cells -increased triglyceride breakdown Net result: increased plasma conc of aa, glucose and free fatty acids

Summary of Nutrient Metabolism During Absorptive State

1. Energy is provided primarily by absorbed carbs in a typical meal. 2. There is a net uptake of glucose by the liver. 3. Some carbs are stored as glycogen in liver and muscle but most carbs and excess fats are stored as fat in adipose tissue 4. There is some synthesis of body proteins from absorbed amino acids. The remaining amino acids are used for energy or converted to fats.

Sources of Blood Glucose

1. Glycogenolysis: hydrolysis of glycogen stores to monomers of glucose-6-phosphate occurs in the liver. Glucose-6-phosphate is enzymatically converted to glucose and enters the blood. Sympathetic nervous system stimulation can cause glycogenolysis. This the first line of defense in maintaining the plasma glucose concentration within a homeostatic range. The amount of glucose available from the liver depletes after several hours. Glycogenolysis also occurs in the muscle. Muscles do not contain the enzyme necessary to form glucose from glucose-6-phosphate, so it is not a good source of blood glucose. Instead glucose-6-phosphate undergoes glycolysis within the muscle cells to yield ATP, pyruvate, and lactate. ATP and pyruvate are used directly by the muscle cell. Some of the lactate enters the blood, circulates to the liver, and is used to synthesize glucose, which can then leave the liver cells and enter the blood. The muscle glycogen contributes to the blood glucose indirectly via the liver's processing of lactate. 2. Catabolism (lipolysis) of triglycerides in adipose tissues yields glycerol and fatty acids then enter the blood by diffusion. The glycerol reaching the liver is used to synthesize glucose. 3. Gluconeogenesis: synthesis of glucose from precursors as amino acids and glycerol. A few hours into the postabsorptive state, proteins become another source of blood glucose. Large quantities of proteins in muscle and other tissues can be catabolized (to a certain limit). The amino acids enter the blood are taken up by the liver, where some can be metabolized via alpha keto acid pathway to glucose. the glucose is then released into the blood.

Role of Leptin

Adipose-derived hormone that acts within the brain to decrease appetite and increase metabolism.

Cholesterol Balance

Cholesterol is not a metabolic energy source but instead is a component of plasma membranes and a precursor for bile salts and steroid hormones. Excess cholesterol can contribute to disease (atherosclerosis). Two sources of cholesterol: dietary (animal sources: egg yolk; excess if excreted) and synthesis within the body (most rely on cholesterol from the blood). Consequently, most cells remove cholesterol from the blood. In contrast, the liver and small intestine can produce large amounts of cholesterol, most of which enters the blood for use elsewhere. Some of the plasma cholesterol is taken up by liver cells and secreted into the bile, which carries it to the gallbladder and from there and from there to the lumen of the small intestine. Here, it is treated much like ingested cholesterol (some absorbed and excess excreted in the feces). Second much of the cholesterol taken up by the liver cells is metabolized into bile salts and flow through the bile duct into the small intestine. Many of these bile salts are then reclaimed by absorption back into the blood across the epithelium of small intestine. The liver is the major organ that controls cholesterol homeostasis: synthesizes, removes and secretes cholesterol. Liver synthesis is inhibited whenever dietary cholesterol is increased vice versa.

Absorbed Carbohydrates

Glucose is the body's major energy source during the absorptive state. Most glucose enters the cell and is catabolized to CO2 and H2O and the energy is used to make ATP. Skeletal muscle is the consumer of glucose. Three fates of absorbed glucose: 1. Adipose tissue: convert glucose to fatty acids and glycerol to make triglycerides and are stored in the cell 2. Liver: during the absorptive state there is a net uptake of glucose into the liver. Glucose is either stored as glycogen or converted to fatty acids and glycerol to make triglycerides. Most of the triglycerides synthesized in the liver are packaged along with specific proteins into molecular aggregates of lipids and proteins called lipoproteins. These aggregates are secreted by liver cells and enter the blood as very-low-density lipoproteins (VLDL)- because they contain more fat than protein and fat is less dense than protein. Because of the large size, VLDLs in the blood do not penetrate capillary walls. Instead their triglycerides are hydrolyzed to monoglycerides and fatty acids by lipoprotein lipase. The fatty acids from VLDL triglycerides originally synthesized in glucose by the liver end up being stored in triglycerides in adipose tissues. The monoglycerides are taken up into adipocytes, where enzymes can reattach fatty acids to the two available carbons of the monoglyceride to form a triglyceride. Some monoglycerides travel via the blood to the liver where are metabolized. 3. Muscle: stored as glycogen.

Response of Target Cells to Insulin

In muscle cells, insulin favors glycogen formation and storage by: -increasing glucose transport into the cell -stimulating key enzymes (glycogen synthase) -inhibiting key enzyme (glycogen phosphorylase that catalyzes glycogen catabolism. Insulin also favors protein synthesis by: -increasing number of active plasma membrane transporters for amino acids -stimulates the ribosomal enzymes that mediate the synthesis of protein from amino acids -inhibiting enzymes that mediate protein catabolism In adipose tissue, insulin favors triglyceride formation In liver cells, insulin favors glycogen formation

Absorptive State

Ingested nutrients enter the blood from the GI tract. Some ingested nutrients provide immediate energy while the remainder is added to the body's energy store to be called upon during the body's post-absorptive state. A typical meal contains three of the main energy supplying food groups: carbohydrates, proteins, and fats

Insulin Signaling

Like all polypeptide hormones, insulin induces its effects by binding to specific receptors on the plasma membranes of its target cells. The binding triggers signal transduction pathways that influence the plasma membrane transport proteins and intracellular enzymes of the target cell. Specifically, GLUT fuse with the plasma membrane. This causes a greater rate of glucose diffusion from extracellular fluid into the cells by facilitated diffusion. Cells in the brain express a non-insulin dependent GLUT that is always present in their plasma membrane. This ensures that even if plasma insulin conc is low, cells of the brain continue to take up glucose from the blood to maintain their function.

Plasma Cholesterol

Like most other lipids, cholesterol circulates in the plasma as part of various lipoprotein complexes. these include: chylomicrons, LDLs and HDLs. Each are distinguished by their relative amount of fat and protein. LDLs are the main cholesterol carriers, they deliver cholesterol to cells throughout the body. LDLs bind to plasma membrane receptors, specific for a protein component of the LDLs and are taken up by the cells of endocytosis. HDLs remove excess cholesterol from blood and tissue including cholesterol loaded cells and atherosclerotic plaques. They then deliver this cholesterol to the liver. Along with LDLs, HDLs deliver cholesterol to steroid producing endocrine cells. Uptake of HDLs by the liver and endocrine cells is facilitated by the presence in their plasma membranes of large receptors specific to HDLs, which bind to the receptors and then are taken into the cells. LDL cholesterol is bad cholesterol because a high plasma concentration can be associated with increased deposition of cholesterol in arterial walls and a higher incidence of heart attacks. HDL cholesterol is good cholesterol. The ratio of LDL toHDL is an important indicator of atherosclerotic disease. The lower the ratio, the lower the risk.

Insulin

Main function: promote glucose uptake and inhibit the breakdown of fat and glucose and ketone production in the liver (gluconeogenesis). The secretion of insulin is increased during the absorptive state.

Absorbed Lipids

Many absorbed lipids are packaged into chylomicrons that enter the lymph vessels and from there, the circulation. The fatty acids of the plasma chylomicrons are released, mainly within adipose tissue capillaries by endothelial lipoprotein lipase. The released fatty acids diffuse into adipocytes and combine with glycerol (synthesized in the adipocytes from glucose) to form triglycerides. Glucose is IMPORTANT for triglyceride synthesis.

Glucose Sparing (Fat Utilization)

Most organs and tissues, other than the NS, significantly decrease their glucose catabolism and increase their fat utilization, the latter becoming the major energy source. Glucose sparing, spares the glucose produced by the liver is used by the NS. The essential step in this adjustment is lipolysis, the catabolism of adipose-tissue triglyceride (liberation of glycerol and fatty acids into the blood). Provides glycerol to the liver as a substrate for the synthesis of glucose. The free fatty acids (FFAs) are taken up and metabolized by almost all tissues (excluding the nervous system). They provide energy in 2 ways: -they undergo beta oxidation to yield hydrogen atoms that take part in oxidative phosphorylation and acetyl coA. -the acetyl CoA enetrs the Krebs cycle and is catabolized to Co2 and H2O In the liver, most of the acetyl CoA formed from fatty acids during post-abs does not enter the Krebs cycle but is processed into 3 compounds collectively called -ketone/ketone bodies. Ketones are released into the blood and provide an imp. energy source during prolonged fasting for many tissues including NS tissues (capable of oxidizing then via Krebs cycle).

Postabsorptive State

No glucose is absorbed from the GI tract during the postabsorptive state, yet the plasma glucose conc must be homeostatically maintained because the nervous system only uses glucose for energy. The events that maintain plasma glucose conc are: 1. reactions that provide sources of blood glucose. 2. cellular utilization of fat for energy thereby sparing glucose

Control of Insulin Secretion

The major controlling factor for insulin secretion is plasma glucose conc. An increase in plasma glucose conc occurs after a meal containing carb. Beta cells stimulate insulin secretion whereas a decrease in plasma glucose removes the stimulus for insulin secretion. Increase in plasma glucose -> increase insulin secretion -> increase in plasma insulin -> increase glucose uptake by adipocytes, liver and muscle. -> restoration of plasma glucose to normal. Other factors that control insulin secretion: 1. Sympathetic activity (Epi) inhibits 2. Parasympathetic activity stimulates 3. Incretins stimultes 4. Increase in plasma amino acids stimulates

Endocrine Pancreas

The most important controls of these transitions from feasting to fasting and vice versa are two pancreatic hormones insulin and glucagon. These hormones are secreted by the islets of Langerhans. The beta cells secrete insulin and the alpha cells secrete glucagon.

Transition between Two States

The term absorptive state could be replaced with actions of insulin and term postabsorptive state results from decreased insulin.

Absorbed Amino Acids

Two fates of absorbed amino acids: 1. Taken up by liver cells and used to synthesize a variety of proteins (liver enzymes and plasma proteins) or they converted to carbohydrate-like intermediates known as alpha-keto acids by removal of amino group (deamination). The amino groups are used to synthesize urea in the liver, which enter the blood and is excreted by the kidneys. The alpha-keto acids can enter the Krebs cycle and can be catabolized to provide energy for the liver cells. They can also be used to synthesize fatty acids, thereby participating in fat synthesis by the liver. 2. Enter other cells, where they are used to synthesize proteins. All cells require a constant supply of amino acids for protein synthesis and participate in protein metabolism. There's a net synthesis of proteins during the absorptive state. Excess protein is converted to carbs and fats.

Glucagon

decrease in plasma glucose-> increase in glucagon by alpha cells -> increase in glucagon -> increase in glycogenlysis, gluconeogenesis, and ketone synthesis by liver and lipolysis in adpicytes-> increase in plasma glucose and ketones. the secretion of glucagon like that of insulin is controlled by plasma conc of glucose but also aa and by nueral and hormonal inputs to the islets. Glucagon is part of the fight or flight responses.

How Insulin is made

preproinsulin -> proinsulin ->insulin and C peptide. half life of insulin: 5 minutes half life of C peptide: 30 minutes