Metabolic Principles: Exam 2

• New material begins in February 2025, the content refers to Exam 2
• Lecture topics include organismal metabolism and metabolic principles/processes

Metabolic Principles

• Topics include:
• Energy Balance
• Fed-State Metabolism
• Fasted-State Metabolism
• Homeostatic Control of Metabolism
• Metabolism
• Learning objectives and additional information are in the slides' Notes feature

Energy Balance

• Total body energy equals energy intake plus energy out plus energy stored
• Energy input factors:
• Diet
• Hunger/appetite
• Satiety
• Social and psychological factors
• Work accounts for roughly 50% of energy output -Transport across membranes -Mechanical work -Movement -Chemical work -Synthesis for growth and maintenance -Energy storage -High-energy phosphate bonds e.g. ATP -Chemical bonds e.g. glycogen, fat
• Heat accounts for roughly 50% of energy output -Unregulated -Thermoregulation
• Most work is unconscious
• Short-term energy storage:
• Long-term energy storage:

Nutrient Pools

• Glucose pool is tightly regulated
• Glycogenesis is the synthesis of glycogen
• Lipogenesis is the synthesis of fat
• Glycogenolysis is the breakdown of glycogen
• Gluconeogenesis is the synthesis of glucose from a non-carbohydrate precursor

Energy Production

• Glucose is the primary substrate for ATP production
• 30% of glucose is metabolized in the liver
• 70% of glucose is in the nutrient pool to give access to the:
• Brain
• Muscles
• Other organs and tissues
• Immediately glucose used in cells for glycolysis and citric acid cycle
• If not immediately used, glucose is stored as glycogen which is a 4-hour supply in the liver
• Amino acids go to tissue for protein synthesis
• The liver synthesizes lipoproteins and plasma proteins
• Other cells use amino acids to create:
• Structural & functional proteins
• Enzymes
• Amine hormones
• Neurotransmitters
• Amino acids can be used for energy
• They're converted to intermediates for use in glycolysis or the citric acid cycle
• Amino acids are deaminated which is a removal of an amino group
• Products of deamination are ammonia and organic acid
• Organic acids include pyruvate, acetyl CoA, and citric acid cycle intermediates
• Intestinal cells assemble the monomers of fats into lipoproteins and chylomicrons
• Chylomicrons consist of triglycerides, cholesterol, phospholipids, and apoproteins
• Triglycerides are converted to free fatty acids and glycerol
• Glycerol feeds into glycolysis
• Fatty acids undergo beta oxidation where 2-carbon acyl units become acyl CoA

Nutrient Fate

• Carbohydrates
• Absorbed as glucose, fructose, and galactose
• Primarily used immediately for energy through aerobic pathways or for lipoprotein synthesis in the liver
• Stored as glycogen in the liver and muscle (glycogenesis)
• Excess is converted to fat and stored in adipose tissue (lipogenesis)
• Proteins
• Absorbed as amino acids and small peptides
• Most go to tissues for protein synthesis primarily
• Some go to the liver to form intermediates for aerobic metabolism via deamination
• Excess is converted to fat and stored in adipose tissue (lipogenesis)
• Fats
• Absorbed as fatty acids, triglycerides, and cholesterol
• Stored as triglycerides primarily in the liver and adipose tissue mainly
• Cholesterol for steroid synthesis or as a membrane component
• Fatty acids used for lipoprotein and eicosanoid synthesis
• During the fasted state
• Glycogen polymers are broken down (glycogenolysis) in the liver and kidney to glucose, or into glucose-6-phosphate for use in glycolysis
• Proteins broken down into amino acids
• Amino acids deaminated in the liver for ATP production or used to make glucose (gluconeogenesis)
• Triglycerides broken down into fatty acids and glycerol (lipolysis)
• Fatty acids used for ATP production through aerobic pathways (β-oxidation)

Fed State Metabolism

• Anabolic pathways synthesize larger molecules from smaller ones
• Energy is stored in fat and glycogen
• Glycogen (glucose polymer) is stored in liver and skeletal muscles for short-term storage of glucose as the primary source of ATP
• Fat is compact and leads to long-term energy storage
• Fats have more than twice the energy content equal to an amount of carbohydrate or protein
• Energy in fats is harder and slower to access
• Amino acids make:
• Structural and functional proteins
• Enzymes
• Amine hormones
• Neurotransmitters
• Excess amino acids are burned as energy or stored as fat

Fasted State Metabolism

• Catabolic pathways break down (lyse) large molecules into smaller ones
• Glycogen converts to glucose via glycogenolysis
• Proteins can be used to make ATP via deamination of amino acids, where ammonia is that byproduct converted to urea
• Lipids store more energy than glucose or protein
• Lipids broken down through lipolysis
• Glycerol feeds into glycolysis
• Fatty acids undergo beta-oxidation (β-oxidation) to produce acetyl CoA
• Excess acetyl CoA becomes ketone bodies (ketones or keto acids)
• Strong metabolic acids lead to ketoacidosis

Homeostatic Control

• Islets of Langerhans are in the pancreas
• Beta cells secrete insulin
• Alpha cells secrete glucagon
• D cells secrete somatostatin
• PP cells (F cells) secrete pancreatic polypeptide
• The insulin-to-glucagon ratio regulates metabolism
• Insulin dominates in the fed state
• Glucagon dominates in the fasting state

Regulation of metabolism

• Enzyme control the direction of metabolism
• Push-pull control regulates metabolism during the fed and fasted states
• Net synthesis of products is under hormonal control
• Insulin regulates enzyme activity in the fed-state to promote the net synthesis of glycogen
• Glucagon regulates enzyme activity in the fasted-state to promote the net synthesis of glucose

Insulin and Glucagon

• The metabolism is controlled by the ratio of insulin to glucagon
• Insulin is the dominant hormone of the fed state and promotes anabolism
• Enhances storage of glucose and fats and the utilization of glucose and amino acids for energy
• Activates insulin-receptor substrates (IRS) to move glucose to the cells and lowers plasma concentration
• Stimulated by increased plasma glucose and amino acids, the feedforward effects of GI hormones, and parasympathetic activity
• Sympathetic activity inhibits insulin secretion releasing adrenal catecholamines like epinephrine and norepinephrine
• Glucagon is dominant in the fasted state and is an antagonist to insulin
• Glucagon prevents hypoglycemia, primarily targeting the liver to stimulate glycogenolysis and gluconeogenesis
• Glucagon release is stimulated by low blood glucose and plasma amino acids

Insulin Secretion

• Stimulated by:
• Distension of GI tract wall
• Presence of carbohydrates in GI lumen
• Nutrients digestion and absorption
• Plasma glucose
• Plasma amino acids

Glucose Transport

• In the fasted state:
• There are no GLUT4 transporters in the membrane in adipose and resting skeletal muscle cells
• Hepatocytes make glucose and transport it out into the blood, using GLUT2 transporters
• In the fed state:
• Insulin signals the insertion of GLUT4 transporters into the membrane, in adipose and resting skeletal muscle cells
• The glucose concentration gradient reverses, and glucose enters the hepatocyte

Diabetes

• Diabetes mellitus (DM) an abnormally elevated plasma glucose or hyperglycemia
• Complications of diabetes affect blood vessels, eyes, kidneys, and nervous system
• Type 1 diabetes: insulin deficiency from autoimmune destruction of beta cells
• Type 2 diabetes: insulin-resistant diabetes
• Diagnosing diabetes:
• Blood glucose after 8 hrs fasting
• Prediabetes: 100 – 125 mg/dL, Diabetes: >125 mg/dL
• Glucose tolerance test (after 2 hrs)
• Prediabetes: 140 – 199 mg/dL, Diabetes: >200 mg/dL
• Type I DM genetic predisposition, sometimes preceded by viral infection in childhood
• Without insulin cells go into the fasted-state metabolism
• Type 1 Diabetics are prone to ketoacidosis
• Protein, Fat, and Glucose Metabolism
• Hyperglycemia
• Brain function affected
• excessive eating known as polyphagia
• Osmotic diuresis and polyuria
• Glucose present in urine, glucosuria resulting in excessive urination, polyuria
• Dehydration occurs resulting in excessive drinking, polydipsia
• Metabolic acidosis present
• Accounts for 90% of all cases of diabetes
• Insulin resistance
• First therapy: exercise and weight loss
• Drugs - stimulate beta-cell secretion of insulin

Energy Use

• Direct calorimetry measures the energy content of food in kilocalories
• Metabolic energy is slightly less because food is not fully digested
• Indirect calorimetry estimates metabolic rate
• Oxygen consumption
• Carbon dioxide production
• Ratio of CO₂ produced to consumed O₂.
• Respiratory quotient (RQ) or Respiratory exchange ratio (RER)
• From a high of 1 for a pure carb diet
• To 0.8 for a pure protein diet
• 0.7 for pure fat
• Average for the American diet is 0.82

Metabolic Rate Factors and Calculation

• Basal metabolic rate (BMR) is an individual's lowest metabolic rate
• Resting metabolic rate (RMR) after 12-hour fast
• Six factors affect metabolic rate:
• Age and sex
• Amount of lean muscle mass
• Activity level
• Diet and diet-induced thermogenesis
• Hormones
• Genetics
• Factors that can be voluntarily changed:
• Only energy intake and level of physical activity
• Strength training increases lean muscle mass:
• Uses additional energy
• Decreases calories going into storage
• Metabolic Rate (kcal/day) = L O₂ consumed/day x kcal/L O2
• A mixed diet with an RQ of 0.8 requires 1 L O₂ for each 4.80 kcal metabolized
• Resting Metabolic Rate = 430 L O₂/day x 4.80 kcal/L O₂ = 2064 kcal/day
• Multiple hormones influence metabolism
• Neuropeptide and hypothalamic hormones involved in hunger/satiety have metabolic effects
• Thyroid hormone and Epinephrine increases MRB
• Hormones of the cortisol pathway decrease MBR
• Growth hormone suppresses glucose uptake and glucose oxidation and stimulates gluconeogenesis, glycogenesis, and lipolysis, along with antagonizing the action of insulin on peripheral tissues and thereby decreasing glucose uptake and increasing glucose production