Energy metabolism Ch 21

Metabolic Pathways and Strategies Organ specialization

Brain, Muscle, Adipose Tissue, Liver

Inter-Organ Transport Cycles

Muscle lactate <> Liver glucose (Cori cycle) Muscle alanine <> Liver glucose

Hormonal regulation Signal transduction

Adenylate cyclase, Tyrosine kinase, phospho-inositide

Metabolic Adaptation
Starvation, Diabetes, Obesity

Pathways and Strategies

Glycolysis and Gluconeogenesis Glycogen Synthesis and degradation Fatty Acid Synthesis and degradation Citric Acid Cycle Oxidative phosphorylation Pentose Phosphate pathway Amino Acid Synthesis and degradation

Glycolysis and Gluconeogenesis

Glucose > 2 pyruvate + 2NADH + 2ATP Pyruvate > Lactate under anaerobic conditions PFK - the central regulator of glycolytic flux
Activated by AMP, F-2,6-P2 Inhibited by citrate and ATP

Gluconeogenesis
OAA > PEP FBPase, G6Pase bypass irreversible glycolysis steps

Glycogen Synthesis and degradation

Glycogen is stored in liver and muscle Converted to G6P for glycolysis Glycogen phosphorylase activated by kinases Glycogen synthase activated by phosphatases

Fatty Acid Degradation and Synthesis

Oxidized to acetyl-CoA (C2) units in mitochondria Synthesized in cytoplasm from malonyl-CoA Acetyl CoA carboxylase 1st committed step in synthesis
Activated by citrate, inhibited by palmitoyl CoA

Long term regulation of enzyme levels

Citric Acid Cycle

Oxidation of Acetyl CoA to CO2 and H2O Production of NADH and FADH2 Control points
Citrate synthase, isocitrate dehydrogenase & KG dehydrogenase Flux controlled by product and substrate levels

Oxidative phosphorylation
NADH and FADH2 oxidized to NAD+ and FAD Proton gradient established by Electron transport is used to power ATP synthesis Flux controlled by redox levels, ATP/ADP ratios

Pentose Phosphate pathway

Produces cytoplasmic NADPH
For biosynthesis (eg. fatty acids)

and ribose-5 -phosphate

For nucleotide biosynthesis

Controlled at Glucose-6-P dehydrogenase

NADP+ activates

Amino Acid Degradation and Synthesis

Transamination to ketoAcid Excess nitrogen released through Urea cycle Carbon skeletons recycled into glucose precursors
Pyruvate, OAA, aKG, fumarate, succinyl CoA

Or fatty acid precursors

Ketones - acetyl-CoA, AcetoAcetate

Biosynthesis
Essential AAs must be obtained from diet Nonessential AAs synthesized by simple pathways

Organ specialization
Brain - Glucose consumer Muscle - Consumer - stores glycogen
Anaerobic metabolism can be powered by creatine phosphate (4 s), lactate (20s) recycled by Cori cycle

Adipose Tissue - Storage and resupply of fatty acids as triacyl glycerols Liver - Conversion and Nutrient distribution

Brain - Glucose consumer

Consumes 20% of resting O2 High cost of maintaining membrane potential Normally fueled by glucose exclusively - no glycogen storage Can use ketone bodies in starvation conditions

Muscle
Can burn glucose, fatty acids or ketone bodies
Glycogen used internally Creatine phosphate buffers ATP/ADP ratio

Oxygen resupply limits power output

Fermentation allows short bursts of anaerobic metabolism Lactate dehydrogenase recycles NADH to NAD for glycolysis Lactate exported to liver for gluconeogenesis

Cardiac muscle metabolism is mostly aerobic Muscle can be a source of fuel (AAs) during starvation

Adipose Tissue
~ 20% of body weight - 3 months energy supply Fatty acids stored as triacyl glycerols
Glycerol-3-phosphate levels control triacyl glycerol synthesis rates

Fat cells increase in number not in size Obesity is a major problem

Liver
Intermediary for most dietary nutrients
Nutrients from intestines flow directly via portal vein

Control of blood glucose - glucokinase vs hexokinase

Glucokinase unique to liver, higher Km (~5mM) than hexokinase (< 0.1 mM)

Glucose 6 Phosphate
Converted to glucose for export Converted to glycogen for storage Converted to acetyl-CoA => lipids, cholesterol > Ribose5P, CO2 and NADPH via pentose phosphates

Liver (continued)
Fatty acid metabolism
Synthesis and degradation compartmentalized Ketone bodies produced in times of low blood glucose for export only

Amino acid metabolism

Gluconeogenesis or ketogenesis from amino acids

Detoxification and processing of minor nutrients

Metabolic Adaptation
Starvation - metabolites mobilized from storage, converted from muscle
Limited amounts of glucose synthesized from tri-acyl Glycerol and amino acids Fatty acids =>acetyl CoA => Ketone bodies Glucose needs diminish once brain adapts to ketone bodies

Transport between Organs The Cori Cycle

Lactate dehydrogenase converts pyruvate + NADH to Lactate + NAD + to allow glycolysis to continue during anaerobic metabolism Lactate (reducing equivalents) transported to liver where it is converted back to pyruvate and to glucose via gluconeogenesis

Transport between Organs The Glucose-Alanine cycle

Muscle Aminotransferases convert pyruvate + AA to Alanine + -ketoA Alanine (amino group) transported to liver where it is converted back to pyruvate and to glucose via gluconeogenesis. Amino group can be disposed as urea or recycled to synthesize amino acids

Glucose transporters (GLUT) control flux across membranes

Intestine - GLUT5 and Na+ symport Neural Cells - GLUT1 & GLUT3 Liver- GLUT2 (ER) & GLUT7
High Km - responsive to plasma [glucose]

Muscle and Fat cells - GLUT4

Insulin sensitive transport from vesicles to plasma membrane

Hormonal regulation
Hormones - Small molecules that circulate between cells
E.g. Peptides, steroids, catecholamines

Receptors -Proteins (Usually Membrane Proteins) that bind hormones and initiate a signal transduction cascade. Endocrine glands produce hormones
Pancreatic and cells produce glucagon and insulin Adrenal gland produces epinephrine and norepinephrine

Signal transduction
G-protein coupled receptors
Rhodopsin, -adrenergic receptor are two of many Have 7 transmembrane segments

Heterotrimeric G-proteins
, and subunits Subunit is a GTPase
GTP form active, GDP form inactive Receptor binding stimulates GDP release GTP binds quickly but is hydrolyzed slowly (2 to 3 minutes) Continued activity requires repeated receptor binding and GTP hydrolysis

subunits released from G-GTP

Adenylate cyclase
Converts ATP to cAMP + PPi Activated by Gs (stimulatory) alpha subunit Inhibited by Gi (inhibitory) alpha subunit cAMP activates cAMP dependent kinase (cAPK) cAMP is degraded by phosphodiesterase

Receptor Tyrosine Kinases

Intracellular receptor domain is itself a protein kinase Usually a single transmembrane segment Ligand induced dimerization in the membrane may allow cross phosphorylation and activation Phospho tyrosines interact with SH-2 domains Protein-protein interactions set up a kinase cascade that is opposed by phosphatases.

The Insulin Receptor

Is a transmembrane dimer with Tyrosine kinase activity Ligand binding induces autophosphorylation and activation of kinase activity towards other protein substrates.

Phospho-inositides - messengers for G-protein coupled signaling

Phosphatidylinositol-4,5-bisphosphate (PIP2)
Is a minor membrane lipid Gq:GTP activates phospholipase C phospholipase C cleaves PIP2
Releases Inositol 1,4,5 trisphosphspate ( IP3) and 1,2 diacyl glycerol (DAG) DAG activates protein kinase C IP3 signals calcium release

Metabolic Fuel Reserves

Carbohydrates and lipids can be stored as glycogen and triacyl glycerols respectively Amino acids are either used immediately for energy or protein synthesis Daily required energy ~1800 kcal
(nutritional Calories)

Circulating fuels ~ 120 kcal Glycogen (liver and muscle) ~ 900 kcal
Really only serves to level glucose levels between meals Muscle Protein (to spare) ~ 24,000 kcal

Fat (150 lb x 20% body fat) ~140,000 kcal

Starvation
After the 1st day or two, fat and muscle provide all energy OAA is siphoned off for gluconeogenesis in liver shutting down the citric acid cycle Acetyl CoA from Fatty Acid oxidation is then converted to ketone bodies Eventually Ketone bodies supplant glucose for most tissues Urea Amino Acids Glucose Pyruvate Acetyl CoA OAA X
Citric Acid Cycle

Fatty acids

Ketone bodies

Diabetes Mellitus
Lack of proper regulation of blood glucose
High levels of blood glucose Low levels of glucose import
Glucose shortage in cells leads to ketone body production

Third leading cause of death in US Type 1 - Insulin dependent (secretion problem)

Juvenile onset Pancreatic cells missing or destroyed Autoimmunity?

Type 2 - Insulin independent (receptor/signaling problem)

Associated with aging, obesity

Obesity
Fat deposits are regulated hormonally but there is a significant behavioral component Evolutionarily, having a store of fat is a good thing Mouse obese mutants have a defect in the Leptin gene Leptin is 16kd polypeptide hormone produced by fat cells Leptin receptors are found in the brain
activation leads to appetite suppression and increased energy expenditure

Leptin Research
Amgen payed $25 million for patent rights to leptin in 1994
Leptin has not turned out to be a magic bullet for weight control

Very few obese humans have defects in leptin - rather resistance to high levels Signalling in brain is complex,
transport across the blood/brain barrier may involve a truncated form of the receptor.

Leptin receptors / synthesis in muscle, activate fatty acid metabolism to preserve muscle mass when energy is low and fat reserves remain. Leptin receptors in fat negatively autoregulate leptin production