Metabolism 4.1 Energy Storage: Carbohydrates and Lipids

Energy stores in the body (major and practical values)

• Approximate energy stores in a healthy 70 kg man

  • Triacylglycerol (adipose tissue): ~$3.0 \times 10^{6} \text{ kJ}$ (about 80 kg of adipose-equivalent energy storage).

  • Liver glycogen: ~$1.0 \times 10^{3} \text{ kJ}$ (≈ 1,000 kJ).

  • Muscle glycogen: ~$3.0 \times 10^{3} \text{ kJ}$ (≈ 3,000 kJ).

  • Muscle protein: ~$1.0 \times 10^{5} \text{ kJ}$.

• Energy stores in an obese 135 kg man

  • Adipose triglyceride stores remain the dominant energy reserve (~$3.0 \times 10^{6} \text{ kJ}$).

  • Liver and muscle glycogen and muscle protein amounts are similar in order of magnitude to the lean case.

• Ethical and practical characteristics of Triacylglycerols (TAGs)

  • TAGs are hydrophobic and stored in an anhydrous form in white adipose tissue.

  • This allows a very high energy density per unit mass.

Glucose, glycogen, and energy regulation: overview

• Tissues with an absolute requirement for glucose as an energy source

  • Erythrocytes (RBCs), leukocytes (WBCs), testes, kidney medulla, lens and cornea of the eye.

• Importance of stable blood glucose levels

  • Essential for normal brain function.

• Glucose as a preferred fuel

  • It is the preferred fuel in several tissues (RBCs, WBCs, etc.).

Glucose utilization over time (physiological timeline)

• Glucose from dietary intake

  • Active for ~$2 \text{ hours}$ after food consumption.

• Glycogenolysis (glycogen breakdown)

  • Maintains glucose for up to ~$8{-}10 \text{ hours}$ post-meal.

• Gluconeogenesis (de novo glucose synthesis)

  • Becomes prominent ~$8{-}10 \text{ hours}$ after fasting and continues during prolonged fasting.

• Body's strategy for glucose storage

  • Stores glucose as glycogen to keep blood glucose at required levels.

  • Glycogen acts as a fast-access store.

• Conceptual timeline summary

  • Glucose from food → glycogenolysis → gluconeogenesis as fasting extends.

Glycogen: structure and localization

• Glycogen's polymer structure

  • Composed of glucose residues.

  • Glucose units linked by $\alpha-1,4$ glycosidic bonds with branch points formed by $\alpha-1,6$ glycosidic bonds every ~$8{-}10$ residues.

• Core primer of glycogen structure

  • Glycogenin, a protein, acts as the primer at the core.

• Storage locations of glycogen

  • Stored as granules in the liver (within hepatocytes).

  • Stored as intra- and intermyofibrillar glycogen granules in muscle.

• Local use of glycogen during muscle contraction

  • Glycogen is locally used to maintain blood glucose homeostasis.

Glycogenesis (glycogen synthesis) – key steps and enzymes

• Overall concept of glycogenesis

  • Glucose is stored as glycogen using UDP-glucose as a donor.

• Stepwise pathway (schematic)

  • Glucose + ATP → Glucose-6-phosphate + ADP.

  • Enzymes: hexokinase (most cells) or glucokinase (in liver).

  • $\text{Glucose} + \text{ATP} \rightarrow \text{Glucose-6-P} + \text{ADP}$.

  • Glucose-6-phosphate ⇄ Glucose-1-phosphate.

  • Enzyme: phosphoglucomutase.

  • $\text{Glc-6-P} \rightleftharpoons \text{Glc-1-P}$.

  • Glucose-1-phosphate + UTP → UDP-glucose + 2 Pi.

  • Enzyme: UDP-glucose pyrophosphorylase.

  • $\text{Glc-1-P} + \text{UTP} \rightarrow \text{UDP-Glc} + 2 \text{Pi}$.

  • UDP-glucose + glycogen (n residues) → glycogen (n+1 residues) + UDP.

  • Enzyme: glycogen synthase (adds $\alpha-1,4$ links).

  • Branching:

  • Forms $\alpha-1,6$ branches via branching enzyme.

  • Net polymer growth and branching establish a highly branched polymer.

• Energetics of glycogenesis

  • Requires energy; the process uses UTP and ATP.

• Net result of glycogenesis

  • Glycogen (n residues) synthesized to glycogen (n+1 residues).

Glycogenolysis (glycogen breakdown) – key steps and enzymes

• Core idea of glycogen degradation

  • Not a simple reversal of glycogenesis; parallel enzymes allow coordinated control.

• Stepwise pathway (schematic)

  • Glycogen (n residues) + Pi → Glucose-1-phosphate + glycogen (n−1 residues).

  • Enzyme: glycogen phosphorylase.

  • Linkage: cleaves $\alpha-1,4$ bonds up to a branch point.

  • Glucose-1-phosphate ⇄ Glucose-6-phosphate.

  • Enzyme: phosphoglucomutase.

  • In liver:

  • Glucose-6-phosphate is dephosphorylated to glucose and exported to blood (via glucose-6-phosphatase).

  • Enzyme: glucose-6-phosphatase.

  • In muscle:

  • Glucose-6-phosphate enters glycolysis for energy production (muscle lacks glucose-6-phosphatase).

• Handling of branch points ( $\alpha-1,4$ vs $\alpha-1,6$ ) during degradation

  • Debranching enzymes assist in mobilization.

• Regulation of glycogenolysis

  • Can be reciprocally regulated with glycogenesis, enabling selective pathway activation/inhibition.

Functional distinctions: liver vs. muscle glycogen

• Role of liver glycogen

  • Supports maintenance of blood glucose.

  • Glucose-6-phosphate can be converted to glucose and released into the bloodstream.

• Role of muscle glycogen

  • Primarily supplies muscle energy during contraction.

  • Maintains local energy supply.

  • Muscle tissue lacks glucose-6-phosphatase, so G-6-P does not contribute to blood glucose.

• Key concept

  • Glycogen stores serve different functions in the liver and muscle.

Regulation of glycogen metabolism (reciprocal control)

• Rate-limiting enzymes

  • Glycogen synthesis: glycogen synthase.

  • Glycogen degradation: glycogen phosphorylase.

• Hormonal control and mechanism

  • Glucagon and adrenaline (epinephrine):

  • Promote glycogen breakdown via phosphorylation.

  • Decrease glycogen synthase activity and increase glycogen phosphorylase activity.

  • Insulin:

  • Promotes glycogen storage via dephosphorylation.

  • Increases glycogen synthase activity and decreases glycogen phosphorylase activity.

• Muscle-specific note on regulation

  • In muscle, glucagon has no effect.

  • AMP activates glycogen degradation in muscle.

Gluconeogenesis (de novo glucose synthesis) – overview

• Rationale for gluconeogenesis

  • After extended fasting (>$8{-}10 \text{ h}$), liver glycogen is depleted.

  • Gluconeogenesis provides a continuous glucose supply.

• Primary sites of gluconeogenesis

  • Liver; to a lesser extent kidney cortex.

• Major precursors

  • Lactate, glycerol, pyruvate, glucogenic amino acids (notably alanine), galactose and fructose.

• Closed-loop concept: Cori cycle

  • Describes glucose-lactate cycling between muscle and liver.

  • Muscle produces lactate during anaerobic glycolysis; lactate travels to the liver and is converted back to glucose for export to blood.

• Cellular localization

  • Gluconeogenesis can be active alongside glycolysis in different tissues or cellular compartments.

  • Bypasses exist where reactions are not simply reversible.

Key enzymes in gluconeogenesis (major control points)

• Three non-reversible steps (not simply the reverse of glycolysis)

  • Pyruvate → Phosphoenolpyruvate (PEP) via Pyruvate Carboxykinase (PEPCK).

  • Fructose-1,6-bisphosphate → Fructose-6-phosphate via Fructose-1,6-bisphosphatase.

  • Glucose-6-phosphate → Glucose via Glucose-6-phosphatase.

• Start/end points in gluconeogenesis

  • Highlight starting substrates and products (e.g., lactate to pyruvate, then to PEP, etc.).

Hormonal regulation of gluconeogenesis (control of PEPCK and FBPase)

• Hormones and effects on key enzymes

  • Glucagon, cortisol, adrenaline:

  • Increase PEPCK and fructose-1,6-bisphosphatase activity and amount.

  • Stimulate gluconeogenesis.

  • Insulin:

  • Decreases PEPCK level and activity.

  • Inhibits gluconeogenesis.

• Summary of hormonal state shifts

  • Hormonal state shifts balance toward gluconeogenesis during fasting or stress.

  • Insulin shifts away from gluconeogenesis after feeding.

Lipid storage and regulation: triacylglycerol (TG) metabolism

• Role of triacylglycerols as efficient energy stores

  • They are the highly efficient energy stores in adipose tissue.

• TG storage characteristics

  • Highly hydrophobic; stored in an anhydrous form in white adipose tissue.

  • Energy content per gram exceeds that of carbohydrate or protein.

• Functional roles of TGs

  • Used during prolonged exercise, stress, starvation, during pregnancy.

  • Mobilization and storage are hormonally controlled.

White adipocytes: structure and capacity

• Typical adipocyte diameter

  • ~0.1 mm.

• Average adult adipocyte count and total adipose mass

  • ~30 billion cells; total adipose mass ~15 kg.

• Capacity for expansion

  • Adipocytes can enlarge up to ~x4 in size during weight gain before increasing total cell number.

• Cytoplasmic organization

  • Large lipid droplet (TAGs and cholesterol esters) pushes cytoplasm and organelles to the periphery.

Lipoprotein lipase (LPL) and TG metabolism

• Pathway overview

  • Dietary TGs are transported as TG within lipoproteins (e.g., chylomicrons).

  • They are hydrolyzed by LPL on capillary endothelium to release fatty acids and glycerol for uptake by tissues.

  • Reassembled in tissues as TG in adipose and muscle for storage or use.

• Involvement of tissues

  • Not all cells can utilize fatty acids (e.g., RBCs lack mitochondria; brain has limited FA uptake due to BBB).

• Regulation and tissue-specific roles

  • In adipose tissue, LPL activity is stimulated by insulin, promoting TG storage.

  • In other tissues, LPL helps provide fatty acids for oxidation during energy-demanding states.

Lipolysis: mobilization of stored TGs

• Lipolysis products

  • Free fatty acids (FFAs) and glycerol are released from TGs.

  • FFAs travel bound to albumin to tissues for energy.

  • Glycerol can be used for gluconeogenesis in the liver.

• Hormonal regulation

  • Glucagon and adrenaline:

  • Stimulate phosphorylation and activation of Hormone-Sensitive Lipase (HSL) and Adipose TG Lipase (ATGL).

  • Insulin:

  • Promotes dephosphorylation and inhibition of HSL/ATGL.

• Transport and fate

  • FFAs travel in blood bound to albumin; used by muscle and other tissues via $\beta$-oxidation.

  • Glycerol transported to the liver for gluconeogenesis or glycolysis depending on energy state.

• Adipose tissue as a dynamic reservoir

  • Serves for energy supply during fasting or stress.

Fatty acid synthesis and its regulation (lipogenesis) – hepatic focus

• Overview

  • Fatty acid synthesis occurs primarily in the liver.

  • Glucose is a major carbon source.

• General pathway

  • Pyruvate → Acetyl-CoA in mitochondria; acetyl-CoA + oxaloacetate → citrate via citrate synthase.

  • Citrate exported to cytosol; citrate → acetyl-CoA + oxaloacetate via ATP-citrate lyase.

  • Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA (rate-limiting step).

  • Fatty acid synthase (FAS) complex elongates fatty acids by sequential two-carbon additions (from malonyl-CoA) to form long-chain fatty acids.

  • Malonyl-CoA also inhibits CPT1, limiting entry of fatty acids into mitochondria for oxidation.

  • Glycerol-3-phosphate provides the glycerol backbone; fatty acids and glycerol combine to form TGs.

• Regulation of ACC and overall lipogenesis

  • Activators: insulin (covalent dephosphorylation) and citrate (allosteric).

  • Inhibitors: glucagon, adrenaline (covalent phosphorylation) and AMP (allosteric inhibition).

• Energy and co-factors

  • Requires ATP and NADPH (PPP provides NADPH and G6P input; cytosolic processes).

  • NADPH source is primarily the pentose phosphate pathway; ongoing facilitation by liver metabolism.

• Outcome

  • Synthesis of TGs and their storage in liver and adipose tissue;

  • Buildup of fatty acid products is regulated to prevent overaccumulation.

Fatty acid synthesis: additional regulatory details

• Localization and energy demands

  • Involved enzymes: ACC, GPAT, DGAT, among others.

  • Requires energy input (ATP) and reducing equivalents (NADPH).

• Feedback and inhibition

  • Accumulation of end products or their intermediates can feedback-inhibit steps.

  • High citrate increases ACC activity; high AMP decreases it.

AMP-activated protein kinase (AMPK) – a cellular energy sensor

• Activation and signals

  • Activated by high AMP levels (low energy state).

  • Expressed in multiple tissues including liver and skeletal muscle.

• Functional role

  • Promotes ATP production by activating catabolic pathways and inhibiting anabolic pathways.

  • Increases fatty acid oxidation, glucose uptake, and glycolysis.

  • Decreases cholesterol synthesis.

• Clinical/metabolic relevance

  • A key molecular target for the actions of metformin (in diabetes management).

Glycogen storage diseases (GSDs)

• Concept of GSDs

  • Excess glycogen storage or defective glycogen breakdown can lead to tissue damage or reduced exercise tolerance.

• Examples of GSDs

  • Von Gierke disease: glucose-6-phosphatase deficiency → hypoglycemia, enlarged liver.

  • McArdle disease: muscle glycogen phosphorylase deficiency → exercise-induced muscle pain and cramps.

• Epidemiology and genetics

  • Genetic or acquired; rare (roughly ~1 in 20,000 to ~1 in 1,000,000 depending on type).

  • >15 distinct GSD types described.

• Implications of understanding GSDs

  • It informs glycogen metabolism regulation and tissue-specific differences.

Gluconeogenesis regulation: hormonal and substrate control (summary)

• Substrate availability driving gluconeogenesis

  • Lactate, glycerol, alanine, pyruvate, galactose, fructose.

• Hormonal control

  • Glucagon, cortisol, adrenaline: upregulate PEPCK and fructose-1,6-bisphosphatase to stimulate gluconeogenesis.

  • Insulin: downregulates PEPCK and fructose-1,6-bisphosphatase to inhibit gluconeogenesis.

Connections to physiology and real-world relevance

• Energy storage strategies mirroring environment and diet

  • Large lipid stores enable survival during prolonged fasting or starvation.

  • Glycogen provides rapid glucose for short-term needs.

• Tissue-specific metabolism

  • Liver acts as glucose reservoir and regulator.

  • Muscle prioritizes local energy needs during activity.

• Hormonal regulation linking nutrient status to metabolic pathways

  • Insulin signals fed-state storage.

  • Glucagon/adrenaline signal starvation or stress responses.

• AMPK integrating energy status with multiple pathways

  • Integrates glycolysis, FA oxidation, cholesterol metabolism.

  • It is a target of therapeutics like metformin.

Notable numerical references and formulas (for quick recall)

• Glycogen branching density

  • Branch points every $8{-}10$ glucose residues.

• Energy content estimates (illustrative)

  • Adipose triglyceride stores: $E_{\text{TG}} \approx 3.0 \times 10^{6} \text{ kJ}$.

  • Liver glycogen: $E_{\text{liver}} \approx 1.0 \times 10^{3} \text{ kJ}$.

  • Muscle glycogen: $E_{\text{muscle}} \approx 3.0 \times 10^{3} \text{ kJ}$.

  • Muscle protein: $E_{\text{protein}} \approx 1.0 \times 10^{5} \text{ kJ}$.

• Core glycolysis-to-gluconeogenesis bypasses (key points)

  • Pyruvate → PEP via PEPCK.

  • F-1,6-BP → F6P via Fructose-1,6-bisphosphatase.

  • G-6-P → Glucose via Glucose-6-phosphatase.

Summary takeaways

• Energy storage distribution

  • Across carbohydrate (glycogen) and lipid (TG) stores with tissue-specific roles.

• Glycogen metabolism regulation

  • Regulated in a reciprocal fashion by hormones to support rapid changes in energy demand.

• Gluconeogenesis

  • Provides a sustained glucose supply during prolonged fasting, regulated by hormonal and substrate availability.

• Lipid synthesis and storage

  • Tightly regulated by hormonal signals and energy state.

  • AMPK serves as a central energy sensor integrating multiple pathways.

• Understanding these pathways

  • Helps explain responses to feeding, fasting, exercise, and metabolic diseases (e.g., GSDs and diabetes therapies).