Integration of Control Flashcards by Celia W

Coordination and control of flux in mammals?

Hormones

Tissue-specific metabolism (dividing labour - screenshot part I)

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Glucose in the liver?

Related to transport of G6P
Entry of glucose through GLUT2 (as no conc gradient)
Phosphorylated by glucokinase
G6P formed

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G6P in the liver?

Dephos -- glucose to other tissues
Liver glycogen
Glycolysis for acCoA/ATP
Glycolysis for acCoA/FAs/TAGs for export
Pentose phosphate pathway for NADPH and ribose-5-phosphate for nucleotides

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AAs in liver?

Proteins for liver /other tissues
Precursors of hormones/nucleotides
Transamination to CAC intermediates or pyruvate for gluconeogenesis
Converted to acCoA for energy in liver or lipid conversion

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AAs from muscle degradation?

Starvation states

Enter glucose alanine cycle – alanine to liver for urea synthesis

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FAs in liver?

Liver lipid synthesis
Oxidised to acCoA and NADH for CAC and oxphos = ATP for liver cells
Excess acCoA = ketone bodies or cholesterol

Converted to phospholipids/TAGs/exported

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Cori cycle; activity effect on muscle

Between liver and muscle to support exercise/movement

Moderate activity = ATP from aerobic FA and glucose oxidation
Intense = anaerobic = muscle glycogen broken down, building up pyruvate (+NADPH = lactate)

To recover from intense activity, lactic acid is exported to the liver — pyruvate – gluconeogenesis — glucose — muscle export to replenish glycogen
This requires oxygen - O2 debt

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Glucose-alanine cycle

Acts with the Cori cycle
Reduces lactate, converting pyruvate to alanine in muscle — liver

AAs transferred onto alanine (a-keto – glutamate reaction) forms pyruvate for gluconeogenesis

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Overall, what does insulin do?

Indicates high glucose
Synthesis of fat, glycogen and protein, inhibits breakdown of such
Glucose uptake into cells

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Overall, what does glucagon do?

Low glucose

Breakdown of fat, glycogen and protein, inhibits synthesis of such

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Overall, what does adrenaline do?

Signals urgent need for energy (immediate impact)

Breakdown of fat, glycogen and protein, inhibits synthesis of such

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Role of pancreas?

B cells = insulin
A cells = glucagon
Secreted into hepatic portal vein = directly to the liver for greatest effect

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Mechanisms of insulin action

Binds tyrosine kinase cell-surface receptor, autophosphorylates itself and IRS-1
IRS-1 activates MAPK = TFs and PKB/Akt = fine enzyme control, regulatory proteins like phosphatases, vesicles,

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Glucagon signalling

GPCRs – activate adenylyl cyclase for ATP — cAMP, acting in turn on PKA

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Adrenaline signalling

Stimulated by stress signals, released from adrenal medulla

Acts with PKA cascade

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Long-term regulation

Due to lifestyle e.g. diet and exercise
Changes at transcriptional level through TFs
Insulin = FOXO1 TF, where high insulin activating PKB moves FOXO1 to cytosol for degradation, suppressing gluconeogenic genes

ChREBP (respond to carbs, in liver and adipose tissue)
PPARs (respond to FAs from dietary lipids) - isoforms of this act in liver, muscle, adipose tissue

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Therapeutic uses of PPAR isoforms?

Peroxisome proliferator-activated receptors
PPARy ligands - type 2 diabetes
PPARa - in liver/muscle, allow FA uptake and b oxidation
PPARd - muscle/adipose, obesity

Feeding/starvation in different species

Rat/mouse models have different feeding habits to us (e.g. during darkness)
e.g. mouse models = alternate day starvation improves synapse connections, but defo not in humans

Potential advantages of food restriction?

Regenerating diabetic pancreases

Promoting cell regeneration

Glucose metabolism in starvation?

Can occur in most cells e.g. from muscle/lipid breakdown
Sometimes cells cannot do this e.g. in anaerobic conditions, no mitochondria like RBCs, those that cannot metabolise AAs or FAs

Protein breakdown in tissues without glucose?

Brain neurones - produce lactate and CO2
RBCs and renal medulla - lactate and pyruvate
Muscle - alanine

Sources of glucose through starvation

Fed = from bloodstream
About 24 hours in = liver glycogen, gluconeogensis activated by glucagon
From 36 hours on = amino acids, first derived from gluconeogenesis and then from muscles
About day 30 = ketone bodies used

Early starvation?

Glycogen breakdown in liver switched on, TAG breakdown in adipocytes
Providing glucose to tissues with absolute requirement like the brain

2-4 days into starvation?

No glycogen = AA generation increased form proteins
TAG breakdown increased
FAs in liver – ketone bodies
GLUT4 changes = reduced glucose uptake, ketone bodies used instead along with FAs; carnitine biosynthetic pathways activate

Prolonged starvation?

Ketone bodies become primary source, proteins degraded

Brain/neural mechanisms in starvation?

Satiety centre stimulated by peptides releases from GI tract Satiety centre invokes neuronal control e.g. affects liver metabolism Higher regions control satiety centre e.g. hypothalamus

Diabetes

Unbalanced insulin; detected through GTT Many types with varying causes even within each one: Type I Type II Gestational MODY

Effect of untreated diabetes?

Acute effects - nerve cells impaired in response to hypoglycaemia Chronic effects - usually on blood cells causing heart disease, as well as neuropathies, retinopathies (blindness), nephropathy

Type 1 diabetes

Can be virally/chemically induced, causing an autoimmune condition Genetic cause - beta cells cannot secrete insulin

Therapies for type 1 diabetes

Insulin injection e.g. E. coli derived Beta cell replacement Prevention of disease development (stopping viral. /chemical causes); some antibodies block the autoimmune response

Type II

Insulin may be present, but cells are unresponsive | Linked to age and obesity, plus includes gestational forms

Treatments for type 2?

Improving function of beta cells like secretagogues Improving insulin action thorough mimetics or sensitisers Lifestyle changes

Insulin secretagogues - bind SUR

e.g. Glibenclamide Inhibits ATP dependent K+ channels to cause a potassium build up, inducing calcium channel opening and thus insulin secretion

Insulin mimetics (usually first line choice)

Activate AMPK to increase glucose uptake

Insulin sensitisers - bind PPARy

Improves signalling of insulin i.e. acts on various components of signalling pathway (not well understood) through transcriptional activation of insulin target genes

"Coca colonisation"

Unhealthy food choices/industry underly many current health risks

Mechanisms of obesity in white and brown adipose tissue?

Progenitor cells determine the number of adipocytes in white tissue, which is not changeable Brown tissue uncouples the proton gradient for FA metabolism = heat, and can be favoured by certain food types

Genetic components of obesity?

High heritability - 50,90% Obesity genes linked to physiological regulation of adiposity and body weight, triggered by environment e.g. thrifty phenotype

Specific genes - linkage and mutation in obesity

Leptin and leptin receptor, involved in cascade impacting transcription Naturally produced in adipocytes to promote fullness, and prevent laying down of TAGs Leptin receptors in hypothalamus regulate satiety centre Believed to set body weight Proteolytic cleavage of neuropeptide precursors in appetite brain areas also involved - proteases not encoded = impairment FTO - hypothalamus, unclear mechanism

Treatments for obesity

``` Lifestyle/genetics Food intake decreasing Blocking nutrient absorption in gut Increasing thermogenesis Modulate fat storage/metabolism Modulate central control of body weight e.g. brain areas, hormones, leptin ```