Bioenergetics and Regulation of Metabolism

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Thermodynamics and Bioenergetics

Biological Systems

• Considered open systems since they can exchange both heat and matter with their environment
  • Energy is exchanged in the form of mechanical work or as heat energy
  • Material is exchanged through food consumption and elimination, as well as respiration
• The cellular and subcellular level of an organism is considered to be closed: no exchange of matter with the environment
  • Internal energy (sum of all different interactions between and within the atoms in a system) can only be changed through work or heat
    • Work is the change in pressure and volume, however, this is usually constant in a living system, so only contributing factor to internal energy is heat.

Enthalpy, Entropy and Free Energy

• Bioenergetics: used to describe energy states in biological systems
• Free energy (DG): provides information about chemical reactions and can predict whether a chemical reaction is favorable and will occur
• Enthalpy and entropy changes are what determines whether a chemical reaction
  • Enthalpy: measures the overall change in heat of a system during a reaction
    • Equal to the heat exchange when pressure and volume are held constant
  • Entropy: measures the degree of disorder or energy dispersion in a system
• Gibb’s Equation relates these three quantities:
  • • • • 
  • Above equation can determine whether or not a spontaneous reaction will occur.
  • Spontaneous reaction proceeds in the forward direction exhibit a net loss of energy and has a negative free energy
  • Non-spontaneous are opposite of spontaneous and would be considered spontaneous in the reverse direction
  • Free energy approaches zero as a reaction reaches equilibrium

Physiological conditions

• Standard free energy (DG°) is the energy changing occurring at standard conditions of 1 M, pressure of 1 atm and temperature of 25°C
  • • • • • 
• Modified Standard State: takes into account that a 1 M concentration of protons would result in a highly acidic solution, so the standard proton concentration for these conditions is assumed to be: [H⁺] = 10^-7 M (pH of 7)
• This condition is specified by DG°^’
• There is a general trend that reactions with more products than reactants have a more negative free energy, vice versa is also true.

The Role of ATP

• Fats are more energy-rich than carbohydrates, proteins or ketones
  • Combustion of a fat results in 9 kcal/g while only 4 kcal/g for the others
  • This is the reason that fat is preferred for long term storage
• End goal of all energy sources is to have as much readily available energy as possible (ATP is this readily available form)

ATP as an Energy Carrier

• A mid-level energy carrier that is formed from substrate-level phosphorylation and from oxidative phosphorylation
• ATP is a mid-level carrier to minimize any wasted energy.
  • If the ATP energy release is greater than required, the added energy is not regained
• Most ATP is produced by mitochondrial ATP synthase, but some is also produced in glycolysis and from the citric acid cycle (indirectly through GTP)
• Consists of an adenosine molecule attached to three phosphate groups
  • Generated from ADP and P_i along with energy input
• ATP is consumed through hydrolysis or through the transfer of a phosphate group to another molecule
  • ATP, ADP & AMP are continuously recycled more than 1000 times per day
• High energy phosphate bonds are what makes ATP such an adept energy carrier
  • Negative charges on each group makes the molecule experience repulsive forces
  • ADP is more stable due to resonance of losing a phosphate group
  • ATP and ADP have similar DG values since they both still experience repulsion, however, AMP has a much smaller free energy value (-30.6 kJ/mol vs -9.5 kJ/mol)

Hydrolysis and Coupling

• ATP hydrolysis will usually occur within a coupled reaction
  • These reactions use ATP as an energy source
  • E.g. – Movement of sodium and potassium against their gradients
• ATP cleavage: transfer of high-energy phosphate groups from ATP to another molecule
  • Generally, activates or inactivates the target molecule
  • Also known as phosphoryl group transfers. Overall free energy of the reaction will be determined by taking the sum of the free energies of the individual reactions

Phosphoryl Group Transfers

• ATP is able to provide a phosphate group as a reactant
  • E.g. – during glycolysis, ATP donates a phosphate group to glucose to form glucose 6-phosphate

Biological Oxidation and Reduction

Half-Reactions

• Should be able to break down all relevant reactions into their half-reactions
• Helps determine the number of electrons that are being transferred
• Spontaneous reactions have a negative free energy and a positive electromotive force

Electron Carriers

• Several molecules act as high-energy electron carriers in the cytoplasm.
  • E.g. – NADH, NADPH, FADH₂, ubiquinone, cytochromes, and glutathione
    • All are soluble
• Some are used in electron transport chain and subsequently leads to oxidative phosphorylation of ADP to ATP
  • Electrons are passed down the transport chain. They end up giving off their free energy to form a proton-motive force across the inner mitochondrial membrane
• There are also membrane-bound electron carriers that are embedded within the inner mitochondrial membrane
  • E.g. – Flavin mononucleotide (FMN): This gets bonded to complex I of the ETC and also acts as a soluble electron carrier
• Proteins with prosthetic groups that contain iron-sulfur clusters are particularly well suited for the transport of electrons

Flavoproteins

• Contain a modified vitamin B₂ (riboflavin)
• These are nucleic acid derivatives and the two common ones are:
  • Flavin adenine dinucleotide (FAD) & Flavin mononucleotide (FMN)
• Most notable for their presence in the mitochondria and chloroplasts as electron carriers
  • Also involved in the modification of other B vitamins to their active forms
  • Also function as coenzymes for enzymes in:
    • the oxidation of fatty acids
    • decarboxylation of pyruvate
    • reduction of flutathione

Metabolic States

• Equilibrium is not desired in biochemistry, instead homeostasis is.
  • Homeostasis: physiological tendency toward a relatively stable state that is maintained and adjusted, usually with the expenditure of energy
    • Allows us to store potential energy, state is different from equilibrium
    • E.g. – storing sodium at a high concentration on one side of the cell allows for the storage of potential energy

Postprandial (Absorptive or Well-Fed) State

• Occurs shortly after eating and is characterized by greater anabolism/fuel storage than catabolism
  • Anabolism is the synthesis of biomolecules
  • Catabolism is the breakdown of biomolecules for energy
• Nutrients make their way through the digestive system, where they are absorbed by the hepatic portal vein and into the liver
  • In the liver, the nutrients can be stored or distributed to other tissues
• This state generally lasts 3-5 hours after eating
• Blood glucose levels rise after eating and stimulate the release of insulin
  • Promotes glycogen synthesis in the liver and muscle
  • Once the glycogen stores are filled, the liver converts excess glucose to fatty acids and triacylglycerols
    • Promotes triglyceride synthesis in adipose tissue and protein synthesis in muscle
      • Also promotes glucose entry into both of these tissues
  • Energy needs of the liver are met by the oxidation of excess amino acids
  • Nervous tissue and red blood cells are not affected by insulin
    • Nervous tissue needs a continuous supply of glucose regardless, all energy is derived from oxidizing glucose to CO₂ and water
      • Unless in prolonged fasting state
    • RBC’s only use glucose anaerobically for all of their energy needs

Postabsorptive (Fasting) State

• Counterregulatory Hormones: hormones that oppose the actions of insulin
  • Glucagon, cortisol, epinephrine, norepinephrine and growth hormone
  • Stimulate glycogen degradation in the liver and stimulates the release of glucose into the blood
  • Glucagon also stimulates Hepatic Glycogenolysis
    • This is a much slower response to the almost instantaneous Glycogenolysis process.
• Epinephrine increase and insulin decrease stimulates the release of amino acids from the skeletal muscle and fatty acids
  • These provide the necessary carbon skeletons and energy required for gluconeogenesis

Prolonged Fasting (Starvation)

• Glucagon and epinephrine levels are highly elevated
• Increased level of glucagon as compared to insulin results in the rapid degradation of glycogen stores in the liver
• As glycogen stores are depleted, gluconeogenic activity is consistently occurring.
  • After 24 hours, this is the predominant source of glucose for the body
• Fats begin breaking down (Lipolysis) relatively quickly
  • Results in excess Acetyl-CoA, which can be used in the synthesis of ketone bodies
• Once levels of fatty acids and ketones is high enough in the blood, muscle tissue will utilize fatty tissue as its main source of energy. The brain will also adapt to using ketones for energy (after a long period of time).
  • Brain derivers approximately 2/3 of energy from ketones and 1/3 from glucose after several weeks of fasting
  • Shift from glucose to ketones allows gluconeogenesis to be slowed
    • This reduced the quantity of amino acids that must be degraded to support gluconeogenesis
      • This spares proteins which are vital for living function
• Cells that do not have mitochondria (e.g. – RBCs) continue to be dependent on glucose

Hormonal Regulation of Metabolism

• Metabolism is regulated across the entire organism, which is best organized by hormones
• Peptide hormones: water-soluble and are able to rapidly adjust the metabolic process of cells by using second messenger cascades
  • E.g. – Insulin
• Amino Acid-Derivative & Steroid Hormones: fat-soluble and enact a longer-range effect through the exertion of regulatory actions at the transcriptional level
  • E.g. – Amino acid derivative: thyroid hormones; Steroids: cortisol
• Hormones are regulated by feedback loops with other endocrine structures

Insulin and Glucagon

Insulin

• Peptide hormone that is secreted by the beta-cells of the pancreatic islets of Langerhans
• Glucose is absorbed by peripheral tissue via facilitated transport mechanisms
  • Utilize glucose transporters that are located in the cell membrane
• Resting skeletal muscle and adipose tissue require insulin for the effective uptake of glucose
  • These tissues store glucose when it is in high concentrations
• Nervous tissue, kidney tubules, intestinal mucosa, RBCs, Pancreatic b-cells have a glucose uptake that is not affected by insulin.
  • These tissues must be able to absorb glucose, even when its concentrations are low
• In carbohydrates, insulin increases the uptake of glucose and increases carbohydrate metabolism in muscles and fats
  • Increase of glucose in muscle can be used as additional fuel or can be stored as glycogen
  • Increases glycogen synthesis in the liver by increasing the activity of glucokinase and glycogen synthase and decreasing the activity of enzymes that promote the breakdown of glycogen
• Amino acid uptake by muscle cells is increased by insulin
  • This increases the levels of protein synthesis and decreases the breakdown of essential proteins
• In fats, Insulin:
  • Increases glucose and triacylglycerol uptake by fat cells
  • Increases Lipoprotein lipase activity: clears VLDL and chylomicrons from blood
  • Increases triacylglycerol synthesis (lipogenesis)
  • Decreases triacylglycerol breakdown (lipolysis) in adipose tissue
  • Formation of ketone bodies by the liver
• Insulin secretion is controlled by plasma glucose levels
  • Above 5.6 mM glucose levels, insulin secretion is directly proportional to plasma glucose
  • Glucose does not directly affect insulin secretion
    • It must first enter the beta-cell and then be metabolized
    • This will lead to an increase in ATP concentration
    • Increased ATP leads to calcium release in the cell
    • Increased calcium concentration is what stimulates the exocytosis of preformed insulin through vesicles

Glucagon

• Peptide hormone that is secreted by the alpha cells of the pancreatic islets of Langerhans
• Primary target for glucagon action is the hepatocyte (liver cell)
• Glucagon acts through second messengers to cause the following effects:
  • Liver Glycogenolysis is increased: Glucagon activates glycogen phosphorylase and inactivates glycogen synthase
  • Increased Liver Gluconeogenesis: promotes the conversion of pyruvate to phosphoenolpyruvate by the enzymes pyruvate carboxylase and phosphoenolpyruvate carboxykinase (PEPCK)
    • Does this by increasing the conversion of fructose 1,6-biphosphate to fructose 6-phosphate by using fructose 1,6-bisphosphatase
  • Increased liver ketogenesis and decreased lipogenesis
  • Increased lipolysis in the liver: Activates hormone-sensitive lipase in the liver.
    • Glucagon is not a major fat-mobilizing hormone since it acts on the liver and not an adipocyte
• Glucagon is secreted in response to low plasma glucose (hypoglycemia) and is inhibited by hyperglycemia.
  • Also promoted by amino acids (especially the basic amino acids: arginine, lysine, histidine)
  • i.e. – glucagon is secreted in when protein is ingested

Functional Relationship of Insulin and Glucagon

• Two hormones are antagonistic: insulin is associated with a well-fed state, while glucagon is associated with a Postabsorptive metabolic state
• Enzymes that are phosphorylated by glucagon are usually dephosphorylated by insulin, and vice versa

Glucocorticoids

• Formed in the adrenal cortex and are responsible for the stress response
• In the “fight or flight” response, glucose must be rapidly mobilized from the liver in order to actively fuel contracting muscle cells
  • Fatty acids are also released from adipocytes.
• Secreted in response to many forms of stress (especially cortisol)
  • Stress like exercise, cold and emotional stress
• Cortisol is a steroid hormone that promotes the mobilization of energy stores through the degradation and increased delivery of amino acids and increased lipolysis
  • Also increases blood glucose levels to increase the glucose uptake ability for nervous tissue
    • Cortisol inhibits glucose uptake in most tissues
    • Increases hepatic output of glucose via gluconeogenesis
  • Cortisol also has a permissive function that enhances the activity of glucagon, epinephrine, and other Catecholamines
• Long term exposure to Glucocorticoids causes persistent hyperglycemia which stimulates insulin
  • Promotes fat storage rather than lipolysis  

Catecholamines

• Secreted by the adrenal medulla
• E.g. – Epinephrine, norepinephrine or adrenaline and noradrenaline
• Increase the activity of liver and muscle glycogen phosphorylase
  • This promotes Glycogenolysis which increases glucose output by the liver
    • In muscles, the glucose is simply used by the muscle since it cannot be released into the bloodstream since muscle cannot produce glucose-6-phosphate
• Act on adipose tissue by increasing lipolysis through stimulating the activity of lipase
  • Glycerol from triacylglycerol breakdown is used in gluconeogenesis
• Epinephrine also acts directly on target organs
  • E.g. – Increases the basal metabolic rate of the heart. “adrenaline rush”

Thyroid Hormones

• These hormones activity are largely permissive, which means that thyroid hormones are kept at a relatively constant level.
• These increase the basal metabolic rate
  • Increased O₂ consumption and heat production when thyroid hormones are secreted
• Thyroxine (T₄): Increases the metabolic rate more slowly, but effects can last for several days
• Triiodothyronine (T₃): more rapid metabolic increase but has shorter term effects.
• Subscripts in two above numbers refers to the number of iodine atoms in the hormone
  • T₄ is like a precursor to T₃ since deoidonases are enzymes that remove iodine from a molecule
• Thyroid hormones have a primary effect on lipid and carbohydrate metabolism
  • Accelerate cholesterol clearance from the plasma
  • Increase the rate of glucose absorption from the small intestine
• Epinephrine requires thyroid hormones to have a significant effect on metabolism.

Tissue Specific Metabolism

• Major sites of metabolic activity are the liver, skeletal/cardiac muscle, brain and adipocytes
• Epithelial cells are the primary secretory cells of the body, so they help in regulating metabolism
  • They along with connective tissue do not require much energy, so they are not significantly involved in metabolism activity.
  • 

Liver

• Two major roles of the liver in fuel metabolism:
  • Maintain a constant level of blood glucose under varying conditions
  • Synthesize ketones when excess fatty acids are being oxidized
• After a meal, the liver extracts excess glucose from the glucose-rich portal blood
  • Uses glucose to replenish its glycogen stores
  • Any remaining glucose is then converted to Acetyl-CoA and used in fatty acid synthesis
• Increase in insulin after a meal stimulates glycogen synthesis and fatty acid synthesis
  • Fatty acids converted to triacylglycerol and released into the blood as VLDL
• In the well-fed state, the liver derives most of its energy from the oxidation of excess amino-acids
• Between meals and during prolonged fast, the liver begins releasing glucose into the blood.
  • Caused by an increase in glucagon which induces both glycogen degradation and gluconeogenesis
  • Lactate from anaerobic metabolism, glycerol from triglycerides, and amino acids provide the carbon skeletons for glucose synthesis.

Adipose Tissue

• Elevated insulin levels stimulate glucose uptake by adipose tissue, after a meal.
  • Also triggers fatty acids to release from VLDL and chylomicrons (carry triglycerides that are absorbed from the digestive tract)
  • Also stimulates lipoprotein lipase
• Fatty acids that are released from lipoproteins are taken up by adipose tissue
  • Are then re-esterified to triacylglycerols for storage
    • Glycerol phosphate that is required for this is provided by glucose metabolism in adipocytes
• Insulin also suppresses the release of fatty acids from adipose tissue
• In fasting state: decreased insulin levels and increased epinephrine activate hormone-sensitive lipase in fat cells
  • This allows fatty acids to be released into circulation.

Skeletal Muscle

Resting Muscle

• Major fuels are glucose and fatty acids and skeletal muscle is the major consumer of fuel
• Insulin promotes glucose uptake in skeletal muscle
  • This replenishes glycogen stores and amino acids that are used in protein synthesis
    • These excess amino acids and glucose molecules can also be oxidized for energy
• In fasting state, resting muscle uses fatty acids that are derived from free fatty acids that are circulating in the bloodstream
  • Ketone bodies are also used in states of prolonged fasting

Active Muscle

• Primary fuel source in muscle depends on the magnitude and duration of exercise, and the major fibers that are involved.
• Creatine Phosphate: short-lived (2-7 seconds) source of energy
  • Transfers a phosphate group to ADP to form ATP
• Also use stores of glycogen and triacylglycerols
  • Can also use glucose or free fatty acids
• Short bursts of high intensity exercise can be supported by anaerobic glycolysis that draw on the stored glycogen.
• Moderately high intensity (continuous exercise), oxidation of glucose and fatty acids are needed
  • Stored of glycogen become depleted after 1-3 hours.
    • Intensity of exercise declines to a rate that can be supported by oxidation of fatty acids.

Cardiac Muscle

• Cardiac myocytes prefer fatty acid as their major source of fuel
• Use ketones in prolonged states of fasting
• Cardiac myocytes act like skeletal muscle that is used during extended periods of exercise
• Patients with cardiac hypertrophy (thickening of heart muscle): glucose oxidation increases and beta-oxidation decreases (reverses the process)

Brain

• 2% of body weight, but receives 15% of cardiac output, uses 20% of O₂, and consumes 25% of the total glucose
• Glucose is the brains primary food
  • This is why blood glucose levels are so tightly regulated, so that a sufficient glucose supply to the brain can be maintained
• Normal function depends on continuous glucose supply from the blood stream
  • If brain becomes hypoglycemic (<70 mg/dL), then the hypothalamic center of the brain releases glucagon and epinephrine to combat the reduced glucose level
• Fatty acids cannot cross the blood-brain barrier, so they are not used at all in the brain.
• Between meals, the brain relies on blood glucose that is to be supplied through hepatic Glycogenolysis and gluconeogenesis
• Brain adapts to use ketone bodies after prolonged states of starvation (only uses a maximum of up to two-thirds)

Integrative Metabolism

Analysis of Metabolism

• Levels of glucose, thyroid hormones, and thyroid-stimulating hormone, insulin, glucagon, oxygen, and carbon dioxide can all be measured in the blood
  • These substrates have a predictable effect on metabolism, so they can be used as indicators

Respirometry

• allows for accurate measurement of the respiratory quotients
  • This quotient depends on the fuels used by the organism:
    • • • 
• Complete combustion of the fuel source is different for each nutrient:
  • Carbohydrates need an RQ of 1.0
  • Lipids need a RQ of 0.7
• RQ is generally around 0.8 in resting state, but can change under conditions of high stress, starvation, and exercise

Calorimeters

• Measures the basal metabolic rate (BMR)
  • Based on heat exchange with the environment
• Requires the use of large insulated chambers that have specialized heat sinks
  • Expensive and not practical, so BMR is estimated by age, weight, height and sex

Regulation of Body Mass

• Body mass is determined by several factors such as water, carbohydrates, proteins, and lipids
  • Nucleic acids do not contribute significantly to body mass maintenance
  • Overall mass of carbs and proteins does not change unless put through a state of prolonged starvation or by muscle-building activities
  • Water is adjusted quickly by the endocrine system and the kidneys.
    • Does not play a major factor in weight regulation or obesity.
    • Primary source of the frequent minor weight changes
  • Lipids are the primary factor in a gradual change of body mass over time
• Maintaining weight means that the same amount of energy is consumed as it spent on the average day.
  • If calories consumed is greater than calories expended, then weight is gained
• Individuals who increase their mass, also increase their basal metabolic rate which increases their energy expenditure.
  • This is done until equilibrium is reached between the new basal metabolic rate and the existing intake
  • However, there is a threshold value for this effect
• Small adjustments in intake are partially or fully compensated by changes in energy expenditure. Small changes in activity (energy expenditure) can also be compensated by changes in hunger.
  • For actual body mass changes to occur, the threshold value must be overcome
  • Threshold has a larger negative energy balance than positive energy balance
    • i.e. – larger changes are needed to lose weight as compared to gain it.
• Weight control involves many factors such as diet, exercise, genetics, socioeconomic status and geography. Also controlled by hormones such as thyroid hormones, cortisol, epinephrine, glucagon and insulin. However, there are also hormones that control hunger and satiety:
  • Ghrelin: secreted by the stomach in response to signals for an impending meal
    • Involves sight, sound taste and smell
    • Increases appetite and stimulates secretion of orexin
  • Orexin: increases appetite and involved in alertness and involved in the sleep-wake cycle.
    • Triggered by hypoglycemia and ghrelin
  • Leptin: hormone secreted by fat cells that decrease appetite by suppressing orexin production. Variations in this have implications in obesity
• Body mass can be measured using the body mass index (BMI):
  • • • • • • • 
• Normal: 18.5-25, Above 30 is obese.