Subtle regulation of metabolic homeostasis

phosphorylation (kinases) and dephosphorylation (phosphatases) specific for substrate

important which AA phosphorylated, can be activatory or inhibitory

PKA doesn’t recognize substrate but specific sequence

Akt kinase needs two phosphorylations to be fully activated

active if allosteric binding site (of glucose) is empty

binding of glucose induces different conformation

removal of phosphorylation by phosphatase in this conformation (inactive enzyme)

product far away from 1. reaction inhibits enzyme from beginning

or product inhibition: inhibits enzyme it is produced from

inactive: regulatory subunits not bound by cAMP and associated with catalytic subunit

binding of cAMP buries autoinhibitory domains, catalytic subunits dissociates and active

exocrine (digestive enzymes)

endocrine (insulin & glucagon)

regulated via hormones

A & B chain linked by 2 S-S chains, 1 S-S link in A

α-helix

Pre-pro-insulin with signal peptide, chain B, peptide C & chain A

to pro-insulin cleavage of signal peptide in trans-Golgi

stored like that in vesicles and upon delivery cleavage into insulin & C peptide

long process: 1-24h —>need storage

test secretion in ELISA with Ab against C peptide (more accurate as in some diseases unfunctional pro-insulin secreted that is still recognized by insulin Ab)

Glucose

Neural influences

Vagal activity (Ach)

ßadrenergic stimulation

Amino acids

Glucagon (to regulate itself, when too much glucose is produced)

Gastrointestinal hormones—>incretins (GLP-1 & GIP)

—>energy availability - storage hormone

—>cholinergic nervous system; vagus nerve (parasympathetic)

Fasting

Exercise

Somatostatin

Neural influences

Sympathetic activity: α-adrenergic stimulation (norepinephrine, epinephrine)

—>energy needs (fasting, exercise, stress,…)

—>sympathetic activation

due to Ca2+ (increased by incretins)

biphasic (time-dependent mobilization of secretory granules from the reserve pool)

IR-A: in fetal tissues, cancer cells, brain & ovary signals cell growth

IR-B: on most important insulin-sensitive tissues (liver, adipose tissue, skeletal muscle

1. Insulin binding —>dimerization

2. conformational changes

3. autophosphorylation of tyrosine residues = activation of Tyr kinase activity of IR

4. Phosphorylation IRS (IR substrates 1-4)

5. intracellular cascade

   —>PI3K pathway: increases glucose & protein metabolism & lipid synthesis

   —>MAP kinases pathway: cell growth, differentiation

secreted when glycemia & AA in blood

↑metabolism and storage

• skeletal muscles, adipose tissue

  ↑uptake glucose (GLUT4), glycolysis, glycogenogenesis, lipogenesis

  ↓lipolysis

• liver

  ↓Neoglucogenesis, glycogenolysis

↓[Glc] circulating = hormone of storage = secreted after meal

primary sequence of 29 AA

α-helix

in α-cells

1. low glucose sensed via GLUT2

2. low KATP channel activity

3. moderate depolarization

4. Na+ channel activation

5. high P/Q-type Ca2+ channel activity

6. stimulated secretion glucagon

KATP channel closure stimulates insulin secretion but inhibits glucagon release

α-cell depolarization reduces voltage-gated Ca2+ entry & glucagon release

GPCR

interacts with guanylate nucleotide

activation of adenylate cyclase and production of cAMP (second messenger) —>aktivation PKA

stimulates degradation (glycogen & lipids) and the production of hepatic glucose

reduce use of glucose

• adrenal cortex: mineralcorticoids, glucocorticoids (cortisol), gonadocorticoids

• medulla: catecholamines (epinephrine (adrenaline) and norepinephrine)

  
  

activate sympathetic system

↑heart rate, metabolism, bronchial dilatation, vasconstriction & pressure

= adrenaline

α-receptor: inhibit adenylate-cyclase—>decrease cAMP

ß-receptor: activate adenylate-cyclase—>increase cAMP

acute stress hormone—>energy supply

activates glycogenolysis, lipolysis, gluconeogenesis

inhibits: lipogenesis, glycogenogenesis

sympathomimetic: accelerates heart rate, increases oxygen flux through mitochondria respiratory chain

steroid hormones —>lipophil

enter cytoplasm & bind receptor

translocation of activated TF into nucleus

slower response but adaptation to chronical stress

stress adaptation

increased energy metabolism: carbohydrates (increased neoglucogenesis & decreased insulin sensitivity), proteins ( increased neoglucogenesis from AA), lipids (increased lipolysis

Insulin: promotes fuel storage after meal, promotes growth

Glucagon: mobilizes fuel, maintains blood glucose levels during fasting

epinephrine: mobilizes fuels during acute stress

cortisol: provides for changing requirement over long-term

nutrient concentration in the blood more or less stable

—>permanent cellular use

—>post-prandial storage of nutrients in excess & mobilization when fasting

ATP

produced in catabolic reaction from energy-containing nutrients —>energy depleted end products

unit for measurement of heat = calorie

quantity of heat needed to increase temperature of 1g water by 1 °C

1 kilocalorie = 1000 calorie = 4.2 kJoules

measurement of energy

indirect: concentration of oxygen

direct: measurement of heat

lipids (9.3kcal/g)

carbohydrates (4.1kcal/g)

BUT also higher consumption of O2

—>depends on condition which source of energy used

adipose tissue: triglycerides (10-15 kg)

liver: glycogen (100g)

muscle: glycogen (300g) but not available for periphery

Brain: 60% (can’t use lipids)

red blood cells

under substrate specific conditions (insulin)

adipose tissue, liver & muscle

need certain concentration

if lower: decline in attention & motor abilities, sweat, hunger, nausea

under critical threshold: lethargy, coma, irreversible damages and death

only in liver

(adipose tissue can produce fatty acids —>alternative source of energy)

degradation of proteins

degradation of Amino acids

oxidation of amino acids (acetyl CoA)

glucose

ketone bodies (during long fasting, can also be used by brain)

cellular organelle

10-thousands per cell depending on energy demand

powerhouses of the cells (oxidative phosphorylation & ATP production)

from glucose 2 3C bodies (pyruvate)

first part in cytosol

pyruvate activated to acetyl-CoA

1 pyruvate yields: 15 ATP

1 glucose 38 ATP

in mitochondria matrix

FA normally bound to albumin

can cross endothelial barrier (lipophil) or use transporters (with C>12 via flip-flop, FABPm, FAT/CD36, FATP)

if C>20 oxidation in the peroxisome

otherwise to acyl-CoA in the mitochondria and ß-oxidation

activation in cytosol, ß-oxidation in mitochondria matrix

per cycle: 1 FADH2, 1 NADH, 1 acetyl-CoA, 1acyl-CoA (n-2)

translocation of acyl-CoA via carnitine palmitoyltransferase system (important for regulation of ß-oxidation)

in intermembrane space

uses NADH2 from glycolysis, Krebs & ß-oxidation

FADH2 from krebs & ß-oxidation

final electron acceptor oxygen —>water

translocation of protons

gradient used by F0F1 ATP synthase—>ATP-production

glucose: 36 ATP

fatty acid (C16): 129 ATP

ATP/ADP antiport

H+/H2PO4- symport

high ATP/ADP in cytoplasm —>cellular work

low ATP/ADP in mitochondria—>ATP synthesis

modulation of heat production

modulation of ROS production

UCP1: most known, brown adipose tissue

UCP2: ß-cells

UCP3: muscle

UCP4: brain

AMP-activated protein kinase

senses energy level (ratio AMP/ATP)

if depletion ATP activated to increase energy supply