Metabolic Interdep. of Maj Org

Radioimmunoassay (RIA)

  • allows for precise measurement of hormones present in VERY low concentrations in blood/tissues
  • hormone-specific antibodies are key feature
  • low concentration of radiolabeled hormone is incubated with a fixed amount of antibody specific to that hormone or a fixed amount of antibody and various concentrations of unlabelled hormone
  • ELISA (enzyme linked immunosorbtion assay) is non-radioactive variant of RIA

cellular consequences of hormone-receptor interaction

  • change in membrane potential resulting from opening/closing of hormone-gated ion channel
  • receptor enzyme activated by hormone
  • second messenger (cAMP, IP3, etc) generated inside the cell acts as allosteric regulator of enzymes
  • receptor w/ no intrinsic activity recruits cytosolic protein kinase, which passes on signal
  • adhesion receptor interacts w/ proteins in ECM and conveys message to cytoskeleton
  • steroid molecule interacts with nuclear receptor, altering mRNA transcription

Nitric Oxide

  • like water insoluble hormones (steroid, vit D, retinoid, thyroid), NO can pass through the plasma membrane of target cells
  •  activates the cytosolic receptor guanylyl cyclase to increase the concentration of cGMP
  • synthesized from arginine and oxygen via NO synthase

paracrine hormones

released into extracellular space and diffuse to neighboring target cells

autocrine hormones

released by and affect the same cell; binding to receptors on the cell surface

exocrine hormone

hormones that travel through ducts instead of blood stream to reach their target cells

water-soluble hormones

(amines, peptides, eicosanoids)

  • peptides, amines, eicosanoids
  • act extracellularly by binding to specific cell surface receptors
  • hormone receptor acts as signal transducer & signal amplifier
  • examples:
    • insulin, glucagon
    • epinephrine
    • prostaglandin (made from EFAs)

water-INsoluble hormones

 

  • steroids, vitamin D, retinoid, thyroid
  • pass through plasma membrane to reach receptor in the nucleus
  • hormone-receptor complex interacts with DNA and alters expression of specific genes (transcriptional regulation!)
  • examples:
    • testersterone
    • 1,25 dihydroxycholecalciferol
    • retinoic acid
    • T3

catecholamine hormones

  • water-soluble; plasma membrane receptors
  • catecholamines produced in brain,function as NTs
  • epinephrine and norepinephrine (from tyrosine) are also hormones, produced/secreted in adrenal glands and in the adrenergic neurons of the brain
  • via second messengers, mediate physiological response to acute stress

eicosanoids

  • prostaglandins, thromboxanes, leukotrienes
  • synthesized from 20-carbon polyunsaturated essential fatty acid, arachidonate
  • never stored; produced only when needed from arachidonate released from membrane phospholipids via phospholipase A2
  • paracrine hormones
  • prostaglandins: contraction of smooth muscle (intestine, uterus); pain/inflammation mediation in all tissues

proteolysis

  • generates multiple active hormones from the same prehormone  via specific points of cleavage
  • examples: pre-opiomelanocortin (POMC) gene produces a, b, delta MSH; ACTH, endorphin, etc.

vitamin D hormone

7 DHC –>
Vitamin D3 (cholecalciferol) –>
25-hydroxycholecalciferol –>
1,25 Dihydroxycholecalciferol (calcitriol)
 
  • calcitriol works w/ PTH to regulate calcium level in blood
  • nuclear receptors; activates synthesis of intestinal calcium binding protein essential for uptake of dietary calcium
 
 

retinoid hormones

B-Carotene –> Vitamin A1 (retinol) –> retinoic acid

  • regulate growth, survival, differentiation of cells via nuclear retinoid receptors
  • prohormone retinol is synthesized from vitamin A in the liver, primarily
  • many tissues convert retinol to active hormone retinoic acid (RA)
  • all tissues are retinoid targets
  • in adults, most important targets:
    • cornea
    • skin
    • epithelia of lungs
    • trachea
    • immune system

thyroid hormones

thyroglobulin –>
iodination of tyrosine residues in thyroid –>
thyroxin (T4)
triiodothyronine (T3)
  •  thyroid receptors act through nuclear receptors to mediate energy-yeilding metabolism, especially in liver and muscle.
  • increase expression of genes encoding key catabolic enzymes
 

hypothalamus

  • coordination center of the endocrine system
  • receieves and integrates messages from the CNS
  • in response to the messages, it produces regulatory hormones (releasing factors) that pass directly to nearby pituitary gland via special blood vessels and neurons that connect the hypothalamus and the pituitary gland

posterior pituitary

  • axonal endings of neurons that originate in the hypothalamus
  • these neurons stimulate production of oxytocin and vassopressin 
  • stored in secretory granules, awaiting release signal

anterior pituitary

  • responds to hypothalamic hormones (releasing factors) that are carried in the special blood vessels connecting them
  • produce tropic hormones (tropins) in response
    • tropins activate the next level of endocrine glands, including: adrenal cortex, thyroid gland, ovaries, testes

big things poppin’ in the LIVER

some of the important tasks of the liver:
  • processing fat, carbs, proteins
  • synthesizing ; distributing lipids, ketone bodies, and glucose for other tissues
  • urea cycle (excess nitrogen conversion into urea)
  • remarkable metabolic flexibility: enzyme turnover rate is 5-10x greater than in other tissues

Glucose 6-Phosphate is at crossroads of carb metabolism in the liver

G6P can proceed down a number of paths:
  • conversion into glucose–> bloodstream
  • storage as glycogen
  • pentose phosphate pathway->R 5P ->nucleotides
  • glycolysis & oxidative phosphorylation
  • TAG/phospholipid synthesis via acetyl-coA

metabolism of amino acids in the liver

  • amino acids entering liver are precursors for proteins
  • nucleotide, hormone, porphyrins made
  • conversion to acetyl-CoA (TCA or fatty acid synthesis)
  • liver has high protein turnover rate and also makes most plasma proteins
  • during intervals between meals, some muscle protein is degraded into amino acids; alanine is deaminated in the liver to yield pyruvate; this pyruvate then goes on to be made into glucose or enters TCA

lipid metabolism in the liver

  • liver lipid conversion
  • b-oxidation, then TCA & oxidative phosphoryl.
  • ketone bodies for use in other tissues
  • acetyl-coA into cholesterol, then either bile salts or steroid hormones synthesized
  • plasma lipoproteins
  • free fatty acids transported on serum albumin

adipocytes and fatty acids

  • metabolically active in glycolysis, TCA, and ox. phospor.
  • in high carb conditions, glucose broken down to acetyl-CoA in adipocytes, then liver presides over fatty acid synthesis –> TAGs (stored in adipocytes)
  • low carb conditions, TAGs broken down into fatty acids; stimulated by epinephrine –> cAMP-dependent phospohorylation of perilipin, giving TAGs in the lipid droplet conformation needed for release of FAs via TAG lipase

energy source for resting muscle

  • ketone bodies (from the liver)
  • fatty acids (from adipose tissue)

  • both converted into acetyl-CoA and undergo oxidative phosphorylation to generate ATP

energy source of moderately active muscle

  • ketone bodies
  • fatty acids
  • blood glucose (glycolysis, TCA, ox phos)

energy source of maximally active muscle

demand for ATP is so great that blood flow cannot provide enough O2 to support ox phosp.
 
  • stored muscle glycogen is broken down 
  • EPINEPHRINE increases rate of muscle glycogen breakdown and release of glucose from liver
  • PHOSPHOCREATINE is final energy source
    • regenerates ATP from ADP during periods of active contraction and glycolysis

what is the creatine kinase reaction?

 

phosphocreatine + ADP ↔ creatine + ATP

 

  • during recovery period, creatine kinase resynthesizes phosphocreatine from creatine at expense of ATP

what is the Cori cycle?

LACTATE         ←          GLYCOGEN         (MUSCLE)
                ATP release
↓                                      ↑
 
BLOOD LACTATE       BLOOD GLUCOSE  
 
↓                                      ↑
 
LACTATE         →          GLUCOSE              (LIVER)
               ATP inclusion

what do extemely active muscles use as energy and what are the product and implications of this energy process?

active muscles use their glycogen stores and break it down via glycolysis.  The product is lactate, which builds up in the muscle as ATP is produced.
 
Lactate is transported to liver via the blood, where it is converted to glucose (gluconeogenesis).  This glucose is transported to the muscle to replenish the glycogen stores lost during exertion.

what are the major qualities of fast twitch muscle?

  • "white" muscle
  • fewer mitochondria
  • fewer blood vessels (less ox phosph.)
  • develops  greater tension faster–> FAST
  • quicker to fatigue because uses ATP faster than it can replenish

what are the major qualities of slow twitch muscle?

  • low tension
  • highly resistant to fatigue (constant ATP supply)
  • high concentration of mitochondria
  • highly vascularized (plenty of O2)
  • constantly produces ATP via slow, yet steady oxidative phosphorylation

how does cardiac muscle differ from skeletal muscle?

  • heart is CONTINUOUSLY active in regular contraction/relaxation

  • heart is PURELY AEROBIC at all times

what fuels cardiac myocytes?

MAINLY free fatty acids
 
some glucose
 
some ketone bodies
 
**phosphocreatine is very limited**
 
**important to note, there are NO glycogen.lipid stores to provide back up energy**

what ketone body is used by brain?

β-hydroxybutyrate

 

**oxidizing ability of this particular ketone body is an essential feature of brain during periods of fasting where glycogen stores of liver have been depleted

what are neurons’ main fuel?

MAIN SOURCE= GLUCOSE

very active glycolysis, TCA, and oxidative phosp. to provide the brain with all the ATP it needs

 

  • astrocytes can also oxidize fatty acids 
  • very little glycogen stored in brain; as such, highly dependent on incoming glucose from the blood

why is a steady flow of ATP essential for the brain’s specific functions?

energy is required to create and maintain the electrical potential across the neuronal plasma membrane.
 
the membrane contains ATP-driven antiporter (Na+ K+ ATPase) which pumps 2 K+ in and 3 Na+ out.

Name the 3 types of endocrine cells residing in pancreas’ Islet of Langerhans. What do each cell type secrete?

alpha cells: glucagon
 
beta cells: insulin
 
delta cells: somatostatin

how is insulin secretion regulated by glucose concentration? provide general steps.

  1. glucose enters B-cell via GLUT2 transporter
  2. glycolysis to create ATP
  3. increase in [ATP]closes ATP-dependent K+ channel, depolarizing membrane (halt in K+ eflux)
  4. depolarization leads to opening of voltage-sensitive Ca2+ channels: INFLUX of calcium
  5. spike in [Ca] triggers exocytotic release of insulin

how does insulin counter high glucose?

  • insulin stimulates glucose uptake in adipose and muscle
  • in liver, insulin activates glycogen synthase to form glycogen; glycogen phosphorylase is inactivated
  • in LIVER, insulin promotes storage of excess fuel as fat
    • excess glucose –>TAGs, exported as VLDL
    • excess amino acids–>pyruvate, acetyl CoA–>lipid synthesis
  • insulin stimulates TAG synthesis in adipose

insulin favors conversion of excess blood glucose into what storage forms??

  • GLYCOGEN: liver, muscle
  • triacylglycerides: adipose

what are the main actions of glucagon?

predominates in fasting state to raise blook glucose
 
  • breakdown of liver glycogen
    • activates glycogen phosphorylase
    • inhibits glycogen synthase via cAMP dependent phosphorylation of regulated enzymes
  • inhibits glycolysis
  • stimulates gluceoneogenesis

 

how does liver fuel itself during fasting state?

Fatty acids = principal fuel
 
 
excess acetyl coA converted to ketone bodies, transported to brain and other tissues when blood glucose is low

how does glucagon regulate glycolysis and gluconeogenesis?

  1.  LOWER [Fructose 2,6-Bisphosphate]
  2. INHIBIT PYRUVATE KINASE
    • crucial enzyme in glycolysis
    • blocks conversion of PEP to pyruvate (and thus, no TCA, ox phos)
  3. STIMULATE synthesis of PEP CARBOXYKINASE
    • this gluconeogenic enzyme stimulated by excess in PEP concentration

glucagon’s effect on adipose tissue?

activates TAG breakdown by cAMP dependent phosphorylation of perilipin and TAG lipase

why is releasing fatty acids from adipose tissue crucial in low glucose conditions?

all tissues in body need energy, but most are able to oxidize the fatty acids into acetyl coA and obtain required ATP via TCA
 
The brain is completely glucose dependent (and also ketone bodies); so what circulating glucose there is can go to feed the brain
 
Other tissues can make use of the free fatty acids (liver, muscle, etc)

Fructose 2,6-Bisphosphate

allosteric inhibitor of gluconeogenic enzyme Fructose 1,6-Bisphosphate
 
activator of PFK-1, an essential glycolytic enzyme
 
**GLUCAGON downregulates the concentration of Fructose 2,6-Bisphosphate to encourage gluconeogenesis and to inhibit glycolysis**

what are the fuel reserves of a healthy human?

  • glycogen: in liver (majority) and muscle

  • adipose: triacylglyceride storage

  • tissue proteins: can be degraded when necessary

acetyl-coA regulates fate of pyruvate. how?

acetyl coA allosterically inhibits pyruvate dehydrogenase (blocks pyruvate–> acetyl coA)
 
acetyl coA stimulates pyruvate carboxylase, or the production of oxaloacetate from pyruvate
 
overall: during prolonged fasting, acetyl coA pushes metabolism towards gluconeogenesis, the first step of which is conversion of pyruvate–>oxaloacetate
 
 

liver fuel metabolism during fasting

  • protein degradation yields glucogenic amino acids
  • urea exported to the kidney and excreted in urine
  • TCA intermediates (oxaloacetate) diverted to gluconeogenesis
  • newly made glucose exported to brain
  • fatty acids from adipose oxidized as fuel, producing acetyl-coA
  • lack oxaloacetate prevents acetyl-coA entry into TCA; acetyl-coA accumulates
  • acetyl-coA accumulation favors ketone body synthesis
  • ketone bodies exported via bloodstream to the brain, which uses them as fuel

starvation & fuel concentrations: what’s the pattern?

  • glucose level drops after 2 days
  • ketone body levels rise between 2-4 days to supplement glucose; acetoacetate and b-hydroxybutyrate
  • fatty acid level constant

fatty acids don’t serve as fuel for brain because they can’t cross blood-brain barrier**

epinephrine increases energy sources for impending activity

  • under stressful situations, neuronal signals trigger release of epinephrine and norepinephrine from adrenal medulla
  • epinephrine acts on liver, muscle, adipose
  • stimulates breakdown of glycogen (activate glycogen phosphorylase, inactivate glycogen synthase) in LIVER
  • promotes anaerobic breakdown of muscle glycogen via lactic acid fermentation, raises glycolytic ATP through stimulating F2,6BP, a key allosteric activator of PFK1
  • stimulates increased fat mobilization in adipose tissue via perilipin and TAG lipase

epinephrine and glucagon

work together to encourage the release of stored fuel and to prevent fuel storage
 
epinephrine activates glucagon secretion, inhibits insulin secretion

what does cortisol do?

responds to variety of stressors: anxiety, fear, pain, hemorrhage, starvation, infection
 
acts on muscle, liver, adipose to supply fuel to withstand long-term stress
 
slow acting hormone that changes types/amounts of enzymes synthesized in its target cells versus regulating activity of enzymes already present

what are the tissue specific effects of cortisol?

LIVER: gluconeogenesis for glucose storage in liver or for immediate exportation to hungry tissues
 
MUSCLE: protein degradation for amino acids that may be used in liver as energy source
 
ADIPOSE: increase rate of fatty acid release from TAGs; FAs exported to other tissues; glycerol sent to liver for use in gluconeogenesis
 
net effect: restore blood glucose to normal level and to increase glycogen stores; prepare for fight or flight response associated with prolonged stress
 
counterbalances INSULIN’s metabolic effects

leptin?

  • produced in adipocytes, delivered via blood to brain, acts on receptors in hypothalamus
  • supresses appetite
  • leptin (OB) KO mice show constant physiological state of starvation
  • DB gene encodes leptin receptor (expressed in arcuate nucleus of hypothalamus)

leptin stimulates sympathetic nervous system

  • increase BP
  • increase HR
  • thermogenesis via uncoupling in the ETC in the mitochondria of adipocytes

norepinephrine and B3 Adrenergic receptor. what is the Signalling cascade?

  • norepinephrine binds to b3 adrenergic receptor
  • via g protein,adenylyl cyclase is stimulated and [cAMP] increases
  • cAMP activates PKA, which phosphorylates perilipin and hormone-sensitive lipase to release TAGs for beta oxidation
  • cAMP also upregulates gene encoding UCP, which forms pore in mito membrane allow entrance of protons w/o passing through ATP syntase complex

continual oxidation of fuel (FAs in adipocytes) w/o ATP synthesis; energy dissipated as HEAT, calories/stored fat are consumed in large amounts

what are the 2 types of nuerosecretory cells in arcuate nucleus that receive hormonal input and replay neuronal sigals to muscle, liver, adipose?

  1. OREXIGENIC (APPETITE STIMULATING)
  2. ANOREXIGENIC (APPETITE-SUPPRESSING)
**LEPTIN AND INSULIN ACT ON ANOREXIGENIC CELLS TO RELEASE α-MELANOCYTE-STIMULATING HORMONE (MSH); MSH SAYS: EAT LESS, METABOLIZE MORE!!!
 
**anything that stimulates one cell type, will inhibit the other**

NEUROPEPTIDE Y (NPY)

  • RELEASED BY OREXIGENIC CELLS (APPETITE STIMULATING) –> EAT MORE!
  • Leptin and Insulin  act on orexigenic cells to INHIBIT their release of NPY

GHRELIN

  • gastric hormone
  • stimulates appetite by activating NPY-expressing cells (orexigenic neurosecretory cells)
  • receptors in pituitary and hypothalamus, heart, muscle, and adipocytes
  • injection of ghrelin produces sensation of hunger
  • in prader willi, blood levels of ghrelin are VERY HIGH (leading to extreme obesity)
  • ghrelin levels rise sharply just BEFORE a meal–>feeling hunger –>insulin levels rise immediately AFTER a meal, in reponse to spike in blood glucose.

PYY3-36

  • released from small intestine/colon in response to food intake
  • inhibits orexigenic neurons, thereby curtailing appetite by inhibiting release of NPY (thereby reducing hunger)
  • PYY3-36 levels rise after a meal as an appetite suppressor, travels in blood to act on the orexigenic neurons in arcuate nucleus
  • humans injected with PYY3-36 feel no hunger

leptin signalling cascade highlights

  • signal transduced via JAK-STAT
  • receptor dimerizes upon leptin binding
  • phosphorylated STATs dimerize & move to nucleus
  • target genes stimulated:
    • POMC (precursor of a-MSH)
  • a-MSH –> appetite suppression

why is leptin not a culprit for obesity?

leptin concentrations are compensatory to obesity; obesity is often accompanied by increased leptin level in blood
 
other factors must be involved.
 
leptin system evolved not to restrict weight,but to regulate the starvation response by reversing thermogenic process, allowing fuel conservation

what effect does leptin have on insulin?

  • synergy between insulin and leptin
  • leptin makes liver and muscle cells more sensitive to insulin –> more glucose storage, less energy utlization

adiponectin

peptide hormone produced in ADIPOSE exclusively; acts indirectly via activation of reg enzyme AMPK by cAMP; SHIFTS METABOLISM TOWARDS OXIDATION OF FATTY ACIDS (and away from glucose/lipid synthesis)
 
muscle
  • increased FA uptake
  • increased B oxidation
  • increased glucose uptake
liver
  • increased glycolysis
  • decreased gluconeogenesis
  • decreased FA synthesis

adiponectin & DM II

mice with defective adiponectin were insulin insentive
 
thiazolidinediones (drug to treat Diabetes Mellitus II) increase adiponectin mRNA expression in adipose tissue; also activate AMPK
 
adiponectin via AMPK modulates cells’ sensitivity to insulin
 
 
 
 

PPAR

(peroxisome proliferator activated receptors)

  • ligand-activated transcription factors
  • respond to changes in dietary lipid, altering expression of muscle and liver genes involved in fat metabolism
  • LIGANDS= fatty acids/derivatives, some synthetic agonists like THIAZOLIDINEDIONES
PPAR: KEY REGULATOR OF FAT OXIDATION (stimulates 9 genes for b-oxidation and energy dissipation via UCP in the mitochondria)
 
OUTCOME: FAT DEPLETION AND PREVENTION OF OBESITY
 
**POTENTIAL ANTI-OBESITY DRUG TARGET**

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