Feed/fast cycle ENDO 412

Objectives 1- Identifying hormones that promote influx & efflux of glucose, fat & protein (nutrients) into & out of energy storage pools. 2- Describing the mechanisms involved in the control of flow intermediates in the metabolic pathways. 3-Describing the organ map that traces the movement of metabolites between tissues. 4- Understanding the alterations in the metabolism of the liver, adipose tissue, muscles & brain in the absorptive state. 5-Understanding the motion of exchange of substrates among liver, adipose tissue, muscle & brain to maintain adequate glucose blood level in case of fasting. 6-Creating an expanded & clinically useful vision of the whole body metabolism.

Absorptive (fed) state Overview of the absorptive (fed) state The absorptive state is the 2 – 4 hours period after ingestion of a normal meal. During this interval, transient increase in plasma glucose, amino acids & triacylglycerols (main nutrients) occur. As a result of elevated glucose & amino acids, insulin secretion is increased from the pancreas & glucagon secretion is decreased. Elevated insulin/glucagon ration & ready availability of circulating substrates cause increased synthesis of triacylglycerol & glycogen to be stored (anabolic period). During the absorptive period, all tissues use glucose as a fuel. During the absorptive period, metabolic responses of the body is dominated by alterations of the metabolism of 4 organs , liver, adipose tissue, muscle & brain.

Enzyme changes in the fed state Flow of intermediates through metabolic pathways is controlled by: 1- Availability of substrates (within minutes) 2- Allosteric regulation of enzymes (within minutes) 3- Covalent modification of enzymes (within minutes to hours) 4- Induction-repression of enzyme synthesis (within hours to days) Each mechanism operates on a different time-scale (i.e. response occurs within minutes, minutes to hours or hours to days) In fed state, these regulatory mechanisms ensure that available nutrients of food (in abundance) are directed to be stored as glycogen, triacylglycerol & protein

Liver: nutrient distribution center Venous drainage of gut & pancreas passes through the hepatic portal vein (to liver cells) before entry into the general circulation Thus, after a meal, liver receives blood containing absorbed nutrients (mainly glucose, amino acids & fatty acids) & elevated levels of insulin secreted by the pancreas During the absorptive period, the liver takes up nutrients which are carbohydrates, lipids & most amino acids. These nutrients are metabolized or: stored or: routed to other tissues

Liver: nutrient distribution center Carbohydrate metabolism: After a meal containing carbohydrate, liver consumes about 60% of glucose from portal circulation. Increased entry of glucose is not insulin dependent: as GLUT-2 of liver is not influenced by insulin. Liver metabolism of glucose is increased by: 1- Increased phosphorylation of glucose (i.e. glucose 6-phosphate by glukokinase) 2- Increased glycolysis of glucose (with production of acetyl CoA fatty acids) 3- Increased glycogen synthesis glucose stored or: energy 4- Increased activity of pentose phosphate pathway of glucose (to provide NADPH) 5-Decreased gluconeogenesis (synthesis of glucose from non-carbohydrate sources)

Liver: nutrient distribution center Fat metabolism: 1- Increased fatty acid synthesis: Favored by : - Availability of substrates (acetyl CoA & NADPH from glucose metabolism) - Activation of acetyl CoA carboxylase (enzyme of the rate-limiting step in fatty acid synthesis) 2- Increased triacylglycerol (TAG) synthesis: Favored by: - Fatty acid is provided from de novo synthesis from acetyl CoA & chylomicron remnants taken by the liver. - Glycerol 3-phosphate is provided by glucose metabolism (glycolysis). Liver packages TAG into very-low density lipoproteins (VLDL) that are secreted into blood for use by extrahepatic tissues (particularly adipose & muscle).

Liver: nutrient distribution center Amino acid metabolism: 1- Increased protein synthesis: Increase in synthesis of liver proteins to replace any degraded proteins during fast period. No store of extra protein or amino acids. 1- Increased amino acid degradation: In the absorptive state, more amino acids are present than the liver can use for synthesis of proteins (i.e. more than liver capacity to synthesize proteins) Excess amino acids are not stored in any form BUT, they are released to blood to other tissues for protein synthesis or, deaminated in liver into carbon skeleton & ammonia Carbon skeleton can be catabolized for energy production or used for fatty acid synthesis. Liver can synthesize proteins from abundant diet amino acids to a certain limit after which excess amino acids are either released to other tissues or degraded.

Liver: nutrient distribution center in the absorptive state

Adipose tissue: energy storage depot Carbohydrate metabolism: 1- Increased glucose transport: GLUT-4 of adipocytes are insulin-sensitive. In the absorptive state, insulin conc. is elevated resulting in increased influx of glucose into adipocytes. 2- Increased glycolysis: due to increased intracellular levels of glucose Glycolysis provides glycerol 3-phosphate for triacylglycerol synthesis. 3- Increased activity of pentose phosphate pathway (PPP) Increased PPP results in increased formation of NADPH essential for fatty acid synthesis.

Adipose tissue: energy storage depot Fat metabolism: 1- Increased synthesis of fatty acids (NOT A MAJOR PATHWAY): Fatty acid synthesis in adipose tissue is not a major pathway. Instead, most fatty acids added to adipose tissues are provided by diet fat (in chylomicrons) with a lesser amount supplied by VLDL of liver. 2- Increased triacylglycerol synthesis: Exogenous fatty acids (from diet fat: chylomicrons & liver fat: VLDL) & glycerol 3 phosphate (from glycolysis of glucose) are used for synthesis of triacylglycerol in adipose tissue. Thus, in well-fed state (absorptive state), storage of triacylglycerol (fat) in adipose tissue is favored

Adipose tissue: energy storage depot in the absorptive state

Resting skeletal muscle Overview: Skeletal muscle is able to respond to changes in demand for ATP that accompanies muscle contraction. At rest, muscle account for about 30% of oxygen consumption of the body During vigorous exercise, muscles account for up to 90% of total oxygen consumption. Skeletal muscle depends on anaerobic & anaerobic glycolysis metabolism for getting energy (while heart muscle depends on aerobic metabolism only). Skeletal muscles have stores for energy in the form of glycogen & lipids, (while heart muscle does not have these stores).

Resting skeletal muscle Carbohydrate metabolism: 1- Increased glucose transport: GLUT-4 of skeletal muscles cells are insulin-sensitive. In the absorptive state (after a carbohydrate rich meal), insulin conc. is elevated resulting in increased influx of glucose into skeletal muscle cells. Glucose provides energy to muscles during the fed state (in contrast to the fasting state in which ketone bodies & fatty acids are the major fuels of resting muscles. 1- Increased glycogen synthesis: During absorptive period, glucose (which is abundant after a carbohydrate rich meal), is stored in the form of glycogen in skeletal muscles.

Resting skeletal muscle Amino acid metabolism: 1- Increased protein synthesis: During the absorptive period, amino acid uptake & protein synthesis is increased to replace degraded protein since the previous meal. 2- Increased uptake of branched-chain amino acids (leucine, isoleucine & valine) These amino acids escape metabolism by the liver & are taken up by muscle.

Resting skeletal muscle Skeletal muscles in the absorptive state

Brain Overview: Brain accounts for 20% of basal oxygen consumption of body at rest (although it is only 2% of adult weight). Brain uses energy at a constant rate. Brain is vital for proper functioning of all organs of the body & so, special priority is given to its energy needs. Glucose normally serves as the primary fuel as the concentration of ketone bodies in the fed state is too low to serve as an alternate energy source. If blood glucose falls to below 30 mg/100 ml (Normal: 70 – 90 mg/100 ml), cerebral functions are impaired. If hypoglycemia occurs for even a short time, severe & irreversible brain damage may occur. N.B. During fast, ketone bodies play a significant roles.

Brain Carbohydrate metabolism: In the fed (absorptive) state, the brain uses glucose exclusively as a fuel. (140 grams/day is oxidized to carbon dioxide & water) Excess glucose is not stored (no glycogen stores). Accordingly, the brain is completely dependant on availability of blood glucose.

Organ map during the absorptive state showing intertissue relationship

Fasting Overview of fasting Fasting may result from: - Ramadan fasting for Muslims - Inability to obtain food - Desire to lose weight rapidly - Clinical situations in which an individual cannot eat (trauma, surgery , etc..) In absence of food, plasma levels of glucose, amino acids & triacylglycerol (main nutrients) fall with a resulting decline in insulin secretion & increase in glucagon release. The decreased insulin/glucagon ratio & decreased availability of circulating substrates, favors a catabolic period in which degradation of triacylglycerol, glycogen & protein is characteristic. Exchange of substrates between liver, adipose tissue, muscle & brain is guided by two priorities: 1- Need to maintain adequate plasma levels of glucose to secure energy metabolism to brain, RBCs & other tissues utilizing glucose as sole fuel. 2- Need to mobilize fatty acids from adipose tissue, synthesis & release of ketone bodies to supply energy to other tissues.

Fuel stores at the beginning of fasting For a normal 70 kg man at the beginning of a fast: N.B. Only 1/3 of body`s protein can be used for energy production without fatally compromising vital function.

Enzymatic changes in fasting Flow of intermediates through metabolic pathways is controlled by: 1- Availability of substrates (within minutes) 2- Allosteric regulation of enzymes (within minutes) 3- Covalent modification of enzymes (within minutes to hours) 4- Induction-repression of enzyme synthesis (within hours to days) The metabolic changes in fasting are generally opposite to those in fed state. In fasting, substrates are not provided by diet, but are available from the breakdown of tissues stores (e.g. lipolysis: with release of fatty acids & glycerol from adipose tissue & proteolysis with release of amino acids from muscles.

Liver in fasting Overview The primary role of liver in energy metabolism during fasting is maintaining of blood glucose through production & release of energy molecules for use by other organs.

Liver in fasting Carbohydrate metabolism: In liver during fasting, glycogen is degraded first (10-18 hrs of fasting) & then gluconeogenesis (after 18 hrs to secure glucose to brain & other tissues utilizing glucose as a sole fuel). 1- Increased glycogen degradation (glycogenlysis) to produce glucose to blood: exhausted after 10 – 18 hours of fasting (early fasting). 2- Increased gluconeogenesis: Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources: amino acids & lactate from muscles & glycerol from adipose fat. Gluconeogenesis plays an essential role during overnight & prolonged fasting. Gluconeogenesis begins 4 - 6 hours after the last meal & becomes fully active when stores of glycogen are depleted (after about 18 hours).

Liver in fasting Fat metabolism: 1- Increased fatty acid oxidation: Fatty acids obtained from adipose tissue is the major source of energy to liver during the fasting state. 2- Increased synthesis of ketone bodies: The liver can synthesize & release ketone bodies from fatty acids to tissues for use as a fuel. (BUT: liver cannot use ketone bodies as a fuel). Ketone bodies formation is favored by the availability of fatty acids obtained from adipose tissue (fatty acids are degraded to acetyl CoA, the precursor of ketone bodies). In this case, acetyl CoA produced from fatty acids exceeds the capacity of citric acid cycle. Significant synthesis of ketone bodies starts during the first days of fasting. Ketone bodies (unlike FA) are water-soluble & appears in blood & urine by the second day of a fast. Ketone bodies in blood during fasting is important as they can be used as fuel for most tissues including the brain tissue (can pass BBB). Accordingly, it reduces the need for gluconeogenesis from amino acids & thus slowing the loss of essential protein. or

Liver in fasting Liver in the fasting state

Adipose tissue in fasting Fat metabolism: 1- Increased degradation of triacylglycerols: Activation of hormone-sensitive lipase with subsequent hydrolysis of stored triacylglycerol are enhanced by elevated catecholamines (epinephrine & norepinephrine) released from sympathetic nerve endings in adipose tissue 2- Increased release of fatty acids from adipose tissue: Fatty acids produced from hydrolysis of triacylglycerol are released to blood & are transported to tissues to be utilized as a source of energy. Fatty acids are also transported to liver to be converted to ketone bodies Glycerol produced from hydrolysis of triacylglycerol in adipose tissue is taken by the liver & is converted to glucose (gluconeogenesis). So, fat is a source of glucose (carbohydrate) in fasting state.

Adipose tissue in fasting

Resting skeletal muscle in fasting Resting muscle uses fatty acids as its major fuel source. By contrast, exercising muscle initially uses its glycogen stores as a source of energy. Carbohydrate metabolism: Because of low levels of insulin, glucose transport & glucose metabolism are depressed. Lipid metabolism: During first 2 weeks of fasting , muscle uses fatty acids from adipose tissues & ketone bodies from liver as sources of energy After 3 weeks, muscles depend only on fatty acids. Protein metabolism: During the first few days of fasting, there is a rapid breakdown of muscle proteins, providing amino acids that are used by the liver for gluconeogenesis. After several weeks of fasting, rate of proteolysis s is decrease as there is a decline in need for glucose as a fuel for the brain (which begins use ketone bodies as a source of energy)

Resting skeletal muscle in fasting

Brain in fasting During the first few days of fasting, the brain continues to use glucose only as a source of energy. In prolonged fasting (more than 2 -3 weeks), plasma ketone bodies reach elevated levels & are used in addition to glucose in as a source of energy the brain. This reduces the need for protein degradation for gluconeogenesis.

Brain in fasting

Organ map during the fasting state showing intertissue relationship