Endocrine Biochemical Aspects PDF

Endocrine biochemical aspects The biochemical basis of the following conditions Condition Biochemical basis ❖ cAMP affects transcription via cAMP response element binding protein (CREB protein): cAMP affects When CREB pro...

Endocrine biochemical aspects The biochemical basis of the following conditions Condition Biochemical basis ❖ cAMP affects transcription via cAMP response element binding protein (CREB protein): cAMP affects When CREB protein is phosphorylated by PKA, it binds the CREB-binding transcription protein (CBP) and becomes a highly potent transcription factor led to activation of transcription. 1-GTPase activity of α subunit that converts GTP into GDP with re-association of the How is hormonal three subunits to return to the resting state. action terminated? 2- Phosphodiesterase that convert cAMP into 5-AMP. 3-Phosphatases remove phosphate from phosphorylated proteins, reversing the effects of PKA, and thus terminate the hormonal action. Bacterial toxin that are enzymes catalyze ADP ribosylation of α subunit of Gs of intestinal cells thus Blocking GTPase activity and Continuous activation of Adenylyl cyclase of intestinal cells leading to increased Cholera cAMP. Continuous secretion of CL-, HCO3 and water, Diarrhea & dehydration Pertussis toxins are enzymes catalyze ADP ribosylation of α subunit of Gi thus Preventing displacement of GDP by GTP and blocking inhibition of adenylyl cyclase by Whooping cough Gi, Since Gαi normally inhibits adenylyl cyclase, its inactivation removes this inhibition, resulting in increased cAMP, and increased mucus secretion causing Whooping cough symptoms. Mutation of RAS protooncogene has been implicated in point mutation of RAS protooncogene the development of Mutant RAS protein is with very low GTPase activity various types of So, RAS protein will be permanently in the active state. cancers (i.e., Cell responds as if high levels of hormone were present, leading to pancreatic, colon, increased cell proliferation. endometrial, and thyroid cancers). 1  Definition: A cluster of metabolic abnormalities associated with abdominal visceral obesity - It includes: § glucose intolerance Biochemical basis and § insulin resistance, components of § hyperinsulinemia, metabolic syndrome § dyslipidemia (low levels of high-density lipoprotein and elevated TAGs), and hypertension. - The metabolic syndrome is also associated with a state of low- grade, chronic, systemic inflammation that contributes to the pathogenesis of insulin resistance and atherosclerosis. Autoimmune disease: caused by the autoimmune destruction of insulin- producing beta cells in the pancreas due to: 1. 1. Genetic predisposition Type I DM etiology 2. Environmental factors: viral infection (e.g. mumps, rubella and coxsackie B viruses) that trigger the autoimmune process in genetically predisposed individuals. - A complex metabolic disorder involves an interplay of genetic, environmental, and lifestyle factors: Etiology of type 2 DM 1. Genetic predisposition 2. Environmental: Sedentary lifestyle and dietary habits, obesity associated with insulin resistance § Increase rate of lipolysis with increases level of FFAs. § Excess FFAs leads to: Some of the putative o They are potent inhibitors of insulin signaling and result in an acquired pathways leading to insulin resistance state. insulin resistance in o Excess FFAs lead to secretion of the cytokine interleukin IL-1β. Type 2 DM o IL-1β mediates the secretion of additional pro- inflammatory cytokines promoting insulin resistance. o The consequences of this abnormal inflammatory microenvironment are beta cell dysfunction. The main goal of insulin is to decrease glucose level It increases: How can insulin decrease the -Glucose uptake -Glycolysis -Glycogenesis -Lipogenesis blood glucose level? -HMP pathway It decreases: -Gluconeogenesis -Glycogenolysis 2  Decreased insulin activity leads to: Decrease the activity of lipoprotein lipase within endothelial cells, leading to Hypertriglyceridemia in increased TAG in blood, also increased lipolysis and mobilization of FFA to diabetes mellitus the liver will lead leading to increased release of VLDL from liver which will further increase blood TAGs besides Chylomicron from intestinal TAG (absorbed from diet). § It results from increased mobilization of fatty acids from adipose tissue. Ketosis in uncontrolled diabetes § FAs are oxidized in the liver producing excess acetyl Co-A that forms ketone bodies. Hyperglycemia causes increased formation of AGEs. AGEs are formed because of nonenzymatic reactions between intracellular glucose with the amino groups of both intracellular and extracellular proteins. Mechanism by which AGEs produce cellular damage: § Receptor mediated effect: o AGEs bind to a specific receptor (RAGE), which is expressed on inflammatory cells (macrophages and T cells) and in endothelium and vascular smooth muscle. Role of Advanced glycation o It leads to: end products (AGEs) in the pathogenesis of chronic - Release of proinflammatory cytokines and growth factors from intimal diabetic complications macrophages. - Generation of reactive oxygen species in endothelial cells. § AGEs can directly cross- link extracellular matrix proteins: o AGEs cross link with Collagen, producing leaker basement membrane. o Low- density lipoprotein (LDL) gets trapped within AGE-modified large vessel walls, accelerating atherosclerosis. o Albumin can get trapped within capillaries, causing basement membrane thickening that is characteristic of diabetic microangiopathy. 3  Diabetes leads to an increase in intracellular glucose that is then metabolized by the enzyme aldose reductase to sorbitol, a polyol, in a reaction that uses NADPH as a cofactor. Activation aldose reductase pathway causes: Increased Osmotic damage: Sorbitol, which accumulates inside cells, is poorly permeable across cell membranes, leading to osmotic stress. Disturbance in polyol This causes cellular swelling and damage, particularly in tissues that are pathway role in insulin-independent for glucose uptake, such as the lens, nerves, kidneys pathogenesis of chronic and blood vessels. diabetic complications Oxidative Stress: The conversion of glucose to sorbitol depletes NADPH, which is essential for regenerating reduced glutathione (GSH), a major cellular antioxidant. Reduced levels of GSH lead to increased oxidative stress and cellular damage. blood vessels. ❖ Compare between lipophilic hormones and hydrophilic hormones Aspect Hydrophilic Hormones Lipophilic Hormones Peptide hormones (e.g., insulin, Steroid hormones (e.g., cortisol, estrogen, Examples glucagon), catecholamines (e.g., testosterone), thyroid hormones. epinephrine, norepinephrine) Solubility Soluble in water Insoluble in water, soluble in lipids Transport in Freely transported in plasma, No carrier Bound to specific carrier proteins (e.g., Blood protein albumin, SHBG, CBG, TBG) Short, Less stable, rapidly degraded by Longer, More stable, protected from Half-Life enzymes degradation by carrier proteins Receptor Cell surface receptors Intracellular receptors (cytoplasm or Location nucleus) Signal Often involves secondary messengers Directly influences gene transcription and Transduction (e.g., cAMP, IP3, DAG) protein synthesis - They can’t enter target cells. - They diffuse through cell membrane of - They deliver message to the cell target cells. surface receptors. - The receptors for them are present in Mechanism - The message is carried through nucleus and cytoplasm. of Action cascade of protein-protein interactions. H+ R HR Complex H-R complex is translocated to hormone H+R HR Complex response element (HRE) on DNA 4  Increased second messagers mRNA production synthesis of Cellular response. structural, enzymatic, carrier or receptor proteins. ❖ Compare between G protein different complexes as regards effector enzymes and second messengers G protein Coupled to Second Coupled to complex effector 1 messenger effector 2 Gαs Adenyl cyclase cAMP PKA phosphorylates target proteins Gαi Adenyl cyclase Inhibits cAMP Inhibits PKA Gαq Phospholipase C DAG, IP3, Ca Activate PKC Regulates Ca- binding proteins ❖ Compare between different states of G protein Trimeric G proteins alternate between Active state with bound guanosine Inactive (trimeric)state with bound triphosphate (GTP) guanosine diphosphate (GDP) 5  ❖ Compare between metabolic functions of ant insulin hormones. - Comparison between Diabetic Ketoacidosis (DKA) and Hyperglycemic Hyperosmolar State (HHS): Feature Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar State (HHS) Commonly Type 1 Diabetes Type 2 Diabetes Associated With Cause Severe insulin deficiency, Relative insulin deficiency, severe ketogenesis, acidosis hyperglycemia, hyperosmolarity Precipitating Infection, missed insulin, stress, Infection, dehydration, poor Factors dehydration glucose control, stress Blood glucose Typically above 250 mg/dL Often even higher than DKA, Levels exceeding 600 mg/dL Ketones Present and elevated in the Usually absent or very low blood and urine Acidosis Present due to ketone buildup, Absent, blood pH remains normal causing a decrease in blood pH Breathing Often rapid and deep, fruity Normal or rapid, no fruity odor odor may be present Dehydration Common More severe than DKA 6 ❖ Compare between macronutrients and micronutrients Feature Macronutrients Micronutrients Definition Needed in large amounts Needed in small amounts Primary Provide energy, support Regulate biochemical processes Functions growth/repair Types Carbohydrates, Proteins, Fats Vitamins, Minerals Energy Yes No Production Daily Grams Milligrams or Micrograms Requirements Sources Bread, meat, oils, dairy Fruits, vegetables, dairy, meat, nuts Storage in Body Stored (e.g., glycogen, fat) Limited storage; regular intake needed ❖ Dietary components represent a balanced diet include: 70% CHO, 20% fat & 10% protein ❖ Compare between kwashiorkor and marasmus: Aspect Kwashiorkor Marasmus A severe form of malnutrition A severe form of malnutrition Definition characterized by protein characterized by overall deficiency. energy deficiency. Inadequate protein intake despite Inadequate caloric intake Main Cause sufficient caloric intake. leading to energy deficiency. Edematous (swollen appearance) Emaciated (wasting Appearance appearance) Often appears normal or slightly Significantly underweight due Body Weight overweight due to edema. to severe wasting. - Muscle atrophy and fat § Severe muscle and fat loss. retention due to edema. § Absent edema - Edema Present (commonly in § Dry, loose, and wrinkled legs and face) skin. - Dry, flaky skin with possible § Severe growth retardation Symptoms& lesions and signs § Good appetite, but lack of hyperpigmentation. food - Stunted growth - Poor appetite § Alert and irritable - Apathy, irritability, and lethargy 7  Common Age Typically seen in children 1-3 Typically seen in infants under Group years old 1 year old Immune Severely impaired Severely impaired Function Compare and contrast the long-term signals of body weight regulation Long term signals (hours to days) Insulin Leptin adiponectin Insulin Site of synthesis: Site of synthesis: It is produced from ß cell of It is produced mainly from adipocytes produced in adipose tissue islets of Langerhans in adipose tissue, placenta, skeletal muscle, pancreas. stomach, liver, bone marrow, and mammary glands. Blood level: Function Insulin acts on Leptin varies with fat mass; Reduces levels of blood free hypothalamic increased fat mass stimulates leptin fatty acids. neurons to decrease secretion. Improved lipid profiles: appetite. A meal or overeating increases increase HDL cholesterol, Obese individuals are also leptin. That decreases appetite and decrease LDL cholesterol, hyperinsulinemic. prevents overconsumption of decrease triglycerides calories. Increase insulin sensitivity: Function of leptin: better glycemic control Decrease appetite and metabolism Anti-inflammatory Reduce Increase energy expenditure inflammation Leptin can affect the sensitivity of hypothalamic neurons to CCK ❖ Compare and contrast the short-term signals of body weight regulation: I- Long-term signals: - Long-term signals are involved in the regulation of body weight over a more extended period and are related to the body's energy stores, primarily fat mass. - Leptin is an adipocyte peptide hormone that is secreted in proportion to the size of fat stores. Leptin - It increases with fat gain and decreases with fat loss. - Functions: § Regulation of Appetite: Leptin reduces food intake by 8  suppressing appetite. § Increase energy expenditure - Leptin Resistance: § In obesity, despite elevated leptin levels, the body often exhibits leptin resistance, characterized by reduced sensitivity to the hormone. § This condition leads to continued overeating and decreased energy expenditure, contributing to further weight gain. - Like leptin, insulin acts on hypothalamic neurons to decrease Insulin: appetite. - Obese individuals are also hyperinsulinemic § Adiponectin is secreted by adipocytes, but unlike leptin, its levels are inversely related to body fat. - Functions: § Increase insulin sensitivity: better glycemic control § Fatty Acid Oxidation: It promotes the oxidation of fatty acids, reducing the storage of fat in tissues. § Cardiovascular Protection: improves lipid profiles; increases Adeponectin HDL cholesterol, decreases LDL cholesterol, decreases triglycerides § Anti-inflammatory: reduces inflammation - Adiponectin Deficiency: - Low levels of adiponectin are associated with obesity, type 2 diabetes, metabolic syndrome, and cardiovascular diseases. 9  II- Short term signals - Short-term signals are involved in the regulation of hunger and satiety on a meal-to-meal basis. - These signals primarily come from the gastrointestinal tract and related organs and affect the initiation and cessation of eating. § Short-term signals from the gastrointestinal tract control hunger and satiety, which affect the size and number of meals over a time course of minutes to hours. o In the absence of food intake (between meals), the stomach produces ghrelin, an orexigenic (appetite- stimulating) 1- Stomach hormone that drives hunger. (CCK, PYY) o As food is consumed, gut hormones, including cholecystokinin (CCK) and peptide YY, among others, induce satiety (an anorexigenic effect), thereby terminating eating, through actions on gastric emptying and neural signals to the hypothalamus. § Within the hypothalamus: o neuropeptides such as neuropeptide Y (orexigenic) and α- melanocyte–stimulating hormone (α-MSH), which is 2- Hypothalamus anorexigenic, and o neurotransmitters, such as serotonin and dopamine, are important in regulating hunger and satiety. ❖ Compare between visceral and subcutaneous adipose tissue 10  List ❖ Types of protein kinases: Protein Kinase A (cAMP) Protein Kinase C (DAG) Ca-calmodulin dependent protein kinase (Ca-calmodulin) Protein kinase B (Insulin and insulin receptor substrate 1 (IRS) ❖ Types of hormonal receptors: Cell surface receptors ▪ Serpentine receptors coupled to G protein e.g., glucagon and epinephrine receptors. ▪ Receptors with enzyme activity e.g., insulin hormone receptor. ▪ Receptors that interact with cytosolic protein kinase (Jaks) e.g., Growth hormone receptor. Intracellular receptors ▪ Cytoplasmic as steroid hormones receptors ▪ Nuclear as thyroid hormone receptors 11  ❖ List structure of G protein coupled receptor. Identify its domains. GPCRs are monomeric proteins (i.e., single polypeptide chain) containing seven transmembrane a-helices (serpentine) a) Extracellular domain contains hormone-binding site b) Trans membrane domain c) Cytosolic domain interacts with trimeric G protein consisting of three subunits (α, β and γ) ❖ List different transporters required for glucose uptake and identify their site. Transporter Name Site GLUT-1 Brain, Red Blood Cells GLUT-2 Liver, Pancreas, Small Intestine, Kidneys GLUT-3 Brain, Kidney, Placenta GLUT-4 Skeletal Muscle, Adipose Tissue, Heart Insulin-dependent glucose uptake SGLT-1 Small Intestine, Kidneys ❖ List the different hormones implicated in blood glucose level regulation Insulin Anti-insulin hormones as: Glucagon, epinephrine, cortisol (secreted by suprarenal cortex), anterior pituitary hormones (Growth hormone). ❖ List the different metabolic actions of insulin hormone: Organ Metabolic Changes Liver - Increased Glycolysis: by inducing glucokinase, PFK1, PK - Stimulates glycogenesis: through stimulation of glycogen synthase - Inhibits gluconeogenesis through inhibition of the four regulatory key enzymes - Increased lipogenesis Adipose Tissue - Increased lipogenesis Skeletal Muscle - Stimulates glycogenesis by stimulation of glycogen synthase - Increased protein synthesis as insulin is an anabolic hormone ❖ List the different metabolic actions of glucagon hormone - Glucagon is produced by alpha cells in the pancreas in response to low blood glucose level. - In liver: o It stimulates Glycogenolysis. o It stimulates gluconeogenesis by: § inducing the synthesis of key enzymes of gluconeogenesis. 12  § increasing protein breakdown to supply glucogenic amino acids. o It inhibits glycolysis and glycogenesis List causes of hypoglycemia 1- Insulin-induced hypoglycemia: in patients with diabetes who are receiving insulin overdose. 2- Postprandial hypoglycemia: § This is the second most common form of hypoglycemia. § It is caused by an exaggerated insulin release following a meal, prompting transient hypoglycemia with mild adrenergic symptoms. § The plasma glucose level returns to normal even if the patient is not fed. 3- Fasting hypoglycemia: § Reduction in the rate of glucose production by hepatic glycogenolysis or gluconeogenesis in cases of: o Hepatocellular damage o Renal Failure o Adrenal insufficiency 4- Alcohol-related hypoglycemia: List the different metabolic changes occurring in Diabetes Mellitus - Metabolic changes in DM are due to decreases insulin/anti-insulin ratio that causes the following changes: 1- Changes in carbohydrate metabolism: - Hyperglycemia, due to: § Decreased glucose uptake by GLUT4 in muscle and adipose tissues. § Decreased glucose utilization (oxidation& glycogenesis). § Increased Glycogenolysis and gluconeogenesis in the Liver. 2- Changes in lipid metabolism: - Increased lipolysis and decreased lipogenesis - Hypertriacylglyceridemia: § Decreased insulin activity will: o Decrease the activity of lipoprotein lipase within endothelial cells, leading to increased TAG in blood, also increased lipolysis and mobilization of FFA to the liver will lead leading to increased release of VLDL from liver which will further increase blood TAGs besides Chylomicron from intestinal TAG (absorbed from diet). - Ketosis: § It results from increased mobilization of fatty acids from adipose tissue. § FAs are oxidized in the liver producing excess acetyl Co-A that forms ketone bodies. § Ketosis is usually minimal or absent in type 2. 3- Changes in protein metabolism: 13 - Increased protein breakdown due to accelerated gluconeogenesis - Decreased antibody formation leads to recurrent infection. ❖ List the acute complications occurring in uncontrolled Diabetes Mellitus A- Diabetic Ketoacidosis (DKA): More common in Type 1 diabetes. B- Hyperosmolar Hyperglycemic State: More common in Type 2 diabetes. C- Hypoglycemic coma. ❖ List the chronic (late) complications occurring in uncontrolled Diabetes Mellitus due to hyperglycemia: A- Macrovascular Complications: Increased risk of cardiovascular diseases such as coronary artery disease, stroke, and peripheral artery disease. B- Microvascular Complications: Includes retinopathy, nephropathy and neuropathy. List causes of different types of nitrogen balance 1. Positive nitrogen balance: § This occurs when nitrogen intake exceeds nitrogen excretion. § It is observed during situations in which tissue growth occurs: o Growing children o Pregnant women o Athletes in building muscle o People recovering from illness or injury 2. Negative nitrogen balance: § This occurs when nitrogen loss is greater than nitrogen intake. § Causes: o Decrease intake (starvation, malnutrition, malabsorption) o Increase loss (chronic hemorrhage) o Increase tissue breakdown (DM, fever, cancer, hyperthyroidism) 3. Nitrogen equilibrium: § This occurs when the amount of nitrogen intake equals the amount of nitrogen excreted. § This is the normal state for most healthy adults. List Complications of Obesity § Cardiovascular Diseases: Hypertension, Coronary Artery Disease, Heart Failure, Stroke § Metabolic Disorders: Type 2 Diabetes, Dyslipidemia, Metabolic Syndrome § Respiratory Issues: Sleep Apnea, Asthma 14  § Musculoskeletal Problems: Osteoarthritis, Back Pain § Gastrointestinal and Liver Conditions: GERD, NAFLD § Reproductive and Hormonal Problems: Infertility, PCOS § Psychological and Social Issues: Depression and Anxiety, Social Isolation List the different ways for assessment of obesity Body mass Index Anatomical differences in fat deposition: Waist to hip ratio Mention the caloric content obtained from oxidation of each type of food Carbohydrate Oxidation of 1 gm of CHO gives 4 Kcal (4 Kcal/g) Fat Oxidation of 1 gm of fat gives 9 Kcal (9 Kcal/g) Protein Oxidation of 1 gm of protein gives 4 Kcal (4 Kcal/g) Mention the daily caloric needs according to the different patterns of lifestyle Sedentary adults require 30 Kcal/Kg/day e.g If man has weight 70Kg the daily caloric needs=30x70=2100Kcal Moderately active adult requires 35 Kcal/Kg/day E.g. If man has weight 70Kg the daily caloric needs=35x70=2450Kcal A very active adult requires 40 Kcal/Kg/day E,g. If man has weight 70Kg the daily caloric needs=40x70=2800Kcal Case A 70 Kg, moderately active man takes, 275 g CHO, 75 g protein & 65 g lipid. Estimate the following: A. Total caloric intake. B. Normal daily caloric requirements. C. This person: 1. is losing weight 2. is gaining weight 3. No weight change Answer: A. Total caloric intake: 275 X4 CHO + 75 X4 protein + 65X9 Fat = 1985 Kcal/day B. Normal daily caloric requirements: 35 X 70 = 2450 Kcal/day. C. This subject is losing weight. Define the Body mass Index and describe how weight is classified according to Body mass index. It means weight (kg) / height (m2.) WHO classified the weight according to body mass index (BMI) into: 15  -Underweight :< 18.5 -Normal weight :18.5-24.9 -Overweight: 25.0-29.9 -Obesity class I: 30.0-34.9 -Obesity class II:35.0-39.9 -Obesity class III: ≥ 40.0 o A 49 –year- old married woman has 158 cm tall and weighing 108 Kg, calculate BMI and comment? BMI= weight (kg) / height (m2) =108 /(1.58²) = 43,37 Comment: obesity class III Hormone signaling pathways ❖ Cyclic AMP (cAMP) pathway -Receptors for glucagon, epinephrine (b receptors), and other hormones coupled to Gs protein transmit a hormonal signal by means of the second messenger cAMP. - Hormone binding to the appropriate receptor causes a conformational change in the intracellular domain, Leading to activation of Gs protein - The released α subunit-GTP complex activates adenylate cyclase enzyme that leads to increased synthesis of cAMP cAMP activates protein kinase A which phosphorylates intracellular proteins. Phosphorylation leads to either activation or inhibition of key enzymes. ❖ Phosphoinositide pathway Receptors coupled to Gq protein transmit signals from hormones such as oxytocin, angiotensin II, and vasopressin (V1 receptor) by means of several second messenger. - Hormone binding to the appropriate receptor causes activation of Gq α subunit 2. Active Gq α subunit stimulates phospholipase C (similar to stimulation PLC cleaves phosphatidyl inositol 4,5-bisphosphate (PIP2) to yield two lipids derived second messengers: a. IP3 can diffuse in the cytosol. b. DAG remains associated with the plasma membrane. IP3, a second messenger in the phosphoinositide pathway, causes a rapid release of Ca2 from the endoplasmic reticulum (ER) by opening Ca2 channels in the ER membrane. a. Calmodulin binds cytosolic Ca2, forming the Ca2 -calmodulin complex that activates Ca2 -calmodulin-dependent protein kinases. 16  c. Ca2 -calmodulin complex activates myosin light-chain (MLC) kinase led to smooth muscle contraction. c. DAG activates protein kinase C, which regulates various target proteins by phosphorylation. ❖ Insulin signaling Hormone-binding (e.g., insulin) activates tyrosine kinase activity, leading to autophosphorylation of the receptor. ❖ The phosphorylated insulin receptor phosphorylates insulin receptor substrate 1(IRS 1). Insulin receptor uses insulin receptor substrate 1 (IRS-1) to transduce the insulin signal by two pathways: a. RAS-dependent pathway involved in cell growth, proliferation, and differentiation through a particular cascade. This pathway is often referred to as the mitogenic pathway. b. RAS-independent pathway, regulates metabolic processes such as glucose uptake, glycogen synthesis, protein synthesis, and cell survival. This pathway is often referred to as a metabolic pathway. ❖ Major organs that play dominant role in fuel metabolism: Well-fed state Fasting state (Insulin) (Glucagon / epinephrine) LIVER 17 Carbohydrate metabolism: Carbohydrate metabolism: 1-↑ glycolysis Increase Glycogenolysis (glycogen exhausted 2-↑ glycogen synthesis 10-18 h)) 3-↑ HMP activity Increase Gluconeogenesis (Begins 4–6 hours 4-↑lipogenesis after the last meal and becomes fully active as 5-↓ gluconeogenesis stores of liver glycogen are depleted.) lipid metabolism: ↓ HMP activity 1-↑ fatty acid synthesis (Availability of Acetyl CoA and NADPH lipid metabolism: from HMP----Activated Acetyl CoA Increase FA oxidation (The oxidation of FAs carboxylase obtained from lipolysis in adipose tissue is the 2-↑ TAG synthesis (Lipogenesis) major source of energy in the liver. Fatty acids (de novo synthesis and TAG Increase Ketogenesis (Excess acetyl-CoA is hydrolysis of chylomicron---Glycerol 3 p converted into ketone bodies.), Liver is only (from glycolysis) organ for synthesis and release) 3-VLDL Secretion Newly synthesized triglycerides are packaged into very low-density lipoproteins (VLDL) and released into the bloodstream. Protein metabolism: 1- Protein synthesis: There is an increase in amino acid uptake and protein synthesis. Amino acid degradation: Excess amino acids are deaminated in the liver. The resulting carbon skeletons are converted to pyruvate, acetyl CoA, or TCA cycle intermediates. Adipose tissue Adipose Tissue is Carbohydrate metabolism: second only to the liver in its ability to distribute fuel molecules. ↓insulin → ↓ glucose uptake and utilization → ↓ lipogenesis from glucose. Carbohydrate metabolism: Increase glucose uptake: insulin increases glucose transport into the adipose tissue cells lipid metabolism: by GLUT4. ↑ Increased lipolysis that releases: Increase glycolysis: Glycolysis supply 1-FA are transported to various tissues for energy glycerol-3-P and acetyl-CoA for TAG production. synthesis. 2- Glycerol: is transported to the liver for Increase activity of HMP: provides NADPH gluconeogenesis. for fatty acids synthesis. 18  lipid metabolism: Increase synthesis of FA: from acetyl-CoA Increase TAG synthesis from FA (lipogenesis)(provided from hydrolysis of TAG in chylomicron and VLDL&Glycerol-3- P (supplied by glycolysis) Decrease TAG degradation(lipolysis): High insulin / glucagon ratio inhibits lipolysis. Brain Carbohydrate metabolism: During 1st days of fasting, Brain continues to Glycolysis: the brain exclusively uses glucose use glucose as a fuel, completely oxidizing approximately Prolonged fasting, plasma ketone bodies 140 g/day to CO2 and H2O. markedly increase, replacing use of glucose lipid metabolism: and ↓ proteolysis for gluconeogenesis. The brain lacks significant stores of TAG, and the FAs circulating in the blood make little contribution to energy production because FAs bound to albumin do not efficiently cross the BBB. Skeletal muscle Carbohydrate metabolism: Carbohydrate metabolism: Increase glucose uptake (glycolysis) ↓ insulin → ↓ glucose uptake and ↓ glucose Increase glycogen synthesis metabolism lipid metabolism: lipid metabolism: Fatty acids are of secondary importance as a Fatty acids released from adipose tissue are fuel for muscles in the well-fed state in which used as a primary energy source. glucose is the primary source. The first 2 weeks of fasting muscle uses FA from Adipose tissue and ketones from liver Protein metabolism: After about 3 weeks of fasting, muscle decreases its use of ketone bodies (thus Increase protein synthesis sparing them for brain) and oxidizes FA Increase uptake of Branched Chain Amino Acids exclusively. Protein metabolism: 19  1st few ds of fasting, rapid break down of ms protein provide AA for gluconeogenesis (alanine and glutamine) Several Ws, ↓ rate of Ms proteolysis due to ↓ need of glucose by brain and depending on ketones. Kidney in long-term fasting Kidney is important as fasting continues to early starvation Express enzymes of gluconeogenesis including glucose 6 phosphatase Compensation for the acidosis associated with the increase of ketones Uptake Glutamine released from muscle → renal glutaminase and glutamate dehydrogenase act on it → produce α ketoglutarate (TCA) and ammonia Ammonia picks up H+ from ketone body dissociation, exerted in urine as NH4+ and ↓load of acidity 20