Integration and Regulation of Mammalian Fuel Metabolism

We will discuss:

· What are the specialized cells and tissues involved in fuel metabolism?

· How are these cells and tissues coordinated for maximal efficiency and adaptability?

General Principles

· Even in prokaryotes, metabolic process are coordinated.

o Opposing pathways are not operating simultaneously.

o Respond to changing environmental conditions.

o Meet the demands set by genetically dictated growth, development, and reproduction.

· Task much more complex in multicellular organisms.

o Must coordinate this task among various cell types.

o Task is somewhat simplified by division of metabolic responsibilities among different tissues.

o Animals further enlist the help from neuronal circuits and hormones.

Organ Specialization

· Seven Major Pathways for ATP Generation (See Fig. 21-1)

o Glycolysis

o Gluconeogenesis

o Glycogen degradation and synthesis

o Fatty acid degradation and synthesis

o Citric Acid cycle

o Oxidative phosphorylation

o Amino acid synthesis and degradation

· Pyruvate and Acetyl-CoA are the Two Major Metabolites that connect these pathways.

· Acetyl-CoA is formed from glucose, fatty acids, ketogenic amino acids.

· Acetyl-CoA can be (a) oxidized to CO₂ and H₂O by TCA cycle and Oxi-Pho and (b) used for synthesis of ketone bodies and fatty acids.

· Pyruvate is produced from glycolysis and degradation of glucogenic amino acids.

· Pyruvate can be (a) oxidatively decarboxylated to acetyl-CoA or (b) carboxylated (by pyruvate carboxylase) to oxalloacetate.

· Only a few tissues, such as LIVER, can carry out all 7 pathways.

· Most cells can only carry out a small portion of these pathways in significant rates.

· Organs are connected by the blood stream so information about the state of metabolism is passed through the blood. Consequently, flux of metabolites will vary.

Brain

· ~2% of adult body mass account for ~20% of O₂ consumption in its resting state.

· Major use of ATP is to operate the plasma membrane (Na⁺-K⁺)-ATPase to maintain the membrane potential required for impulse transmission.

3 Na⁺(in) + 2 K⁺(out) + ATP + H₂O ® 3 Na⁺(out) + 2 K⁺(in) + ADP + Pi

· Glucose as the primary fuel under usual conditions, and switches to ketone bodies during extended fast.

· Has very little glycogen storage. Rely on steady supply of glucose by blood.

· Normal blood glucose level 4-8 mM (~5 mM as stated in VVP). <half of the normal level triggers brain dysfunction. Levels much below 50% of the normal level result in coma, permanent brain damage, and even death.

Muscle

· Major fuels as glucose (from glycogen), fatty acids, and ketone bodies.

· Glycogen storage accounts for ~2% of muscle mass at resting state.

· Glycogen can release glucose rapidly, and glucose can be metabolized, when needed such as during heavy exercise, anaerobically to produce ATP.

· In muscle, glycogen à G1P ⇌ G6P. However, muscles do not participate in gluconeogenesis nor export glucose due to a lack of Glu-6-phosphatase.

· Muscle carbohydrate metabolism serves only muscle.

Muscle Contraction

· Powered by ATP hydrolysis, with ATP formed aerobically (TCA and Oxi Pho) and anaerobically (glycolysis and homolactic fermentation).

· Skeletal muscle at rest accounts for ~30% of total O₂ consumption for aerobic generation of ATP.

· Under conditions of maximum exertion, muscles derive ATP from phosphocreatine for a brief period of time (~4 sec).

Phosphocreatine + ADP ⇌ Creatine + ATP

· Then switches to glycolysis of G6P, with much of it converted to lactate anaerobically (last step by lactate dehydrogenase to convert pyruvate to lactate).

· Pyruvate + NADH ⇌ Lactate + NAD⁺

· Muscle fatigue is not caused by glycogen depletion but by acidification due to accumulation of lactate.

Heart

· Relies entirely on aerobic metabolism.

· Rich in mitochondria (occupying ~40% of cytoplasmic space)

· Can utilize fatty acids, ketone bodies, glucose, pyruvate, and lactate.

· Resting state: Primary fuels are fatty acids.

· Heavy work: Increasing consumption of glucose, derived primarily from relatively limited glycogen store.

Adipose Tissue

· To store and release fatty acids as needed.

· Average 70 kg man has 15 kg of fat. Enough fat to sustain energy needs for 3 months. This represents 590,000 kJ of energy or 141,000 calories.

· Gets fatty acids from lipoproteins from circulation.

· Fatty acids are activated to fatty acyl-CoA, which react with Glycerol-3-phosphate to form triglycerides for storage.

· When in need, adipocytes hydrolyze triglycerides to fatty acids and glycerol through hormone-sensitive lipase.

· Fatty acid metabolic fates are regulated by Glucose uptake.

o Glycerol-3-phosphate is formed from dihydroxyacetone phosphate, which is from glucose glycolysis.

o High G à High Glycerol-3-phosphate à react with Fatty Acids to form triglycerides.

o Low G à Low glycerol-3-phosphate à fatty acids released into bloodstream.

Liver

Acts as a blood glucose “buffer”

· Keeping blood glucose concentrations between 4 to 8 mM.

· At high Glucose levels, converts Glucose to G6P by Glucokinase. (Fig. 21-4)

· Hexokinase: K_m for muscle hexokinase is < 0.1 mM; Michaelis-Menten kinetics; inhibited by G6P.

· Liver Glucokinase: K_m is ~5 mM; sigmoidal kinetics (very low activity at glucose levels much lower than 5 mM but activity increases rapidly at [Glu] > normal levels); not inhibited by G6P.

· At low [Glu], liver does not compete with efficient uses of glucose by hexokinase in other tissues.

· At high [Glu], liver glucokinase effectively converts Glu to G6P while still allowing efficient uses of glu by other tissues.

G6P Is at the Crossroads of Carbohydrate Metabolism. (Fig. 21-5)

· Converted to glucose.

Blood [Glu] < 5 mM à causes pancreas to excrete glucagon à binding of glucogon to liver cell surface receptors à activate adenylate cyclase à increase [cAMP] à triggers glycogen breakdown.

· Converted to glycogen for storage when blood glucose is elevated.

· Converted to acetyl-CoA by glycolysis. Acetyl-CoA can produce more ATP by oxidative phosphorylation or used to make fatty acids, phospholipids, and cholesterol.

· Generates, via pentose phosphate pathway, NADPH required for the synthesis of fatty acid and other metabolites and generates pentoses.

Fatty Acid Metabolism by Liver

· Liver lacks 3-ketoacyl-CoA transferase, required for conversion of ketone bodies to acetyl-CoA.

· High metabolic fuel demands:

o FAs degraded to acetyl-CoA à formation of ketone bodies à transport to peripheral tissues.

o Also, FAs rather than glucose or ketone bodies as major acetyl-CoA in liver for energy.

· Low metabolic fuel demands:

o FAs incorporated into phospholipids and triglycerides. The latter are secreted into bloodstream as VLDL for uptake by adipose tissue.

AA Metabolism by Liver

· AA can be metabolized in liver for (a) complete oxidation to CO₂ and H₂O, (b) conversion to glucose, or (c) conversion to ketone bodies.

· AAs are a significant source of energy after a meal.

· During fasting or starvation alanine and glutamine from muscle protein degradation is converted to glucose by the liver.

· Proteins are a significant fuel reserve.