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Metabolic Interdep. of Maj Org – Flashcards

Patricia Smith

7 July 2022

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question

Radioimmunoassay (RIA)

answer

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

question

cellular consequences of hormone-receptor interaction

answer

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

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Nitric Oxide

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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

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paracrine hormones

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released into extracellular space and diffuse to neighboring target cells

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autocrine hormones

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

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exocrine hormone

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

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water-soluble hormones
(amines, peptides, eicosanoids)

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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)

question

water-INsoluble hormones

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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

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catecholamine hormones

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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

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eicosanoids

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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

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proteolysis

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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.

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vitamin D hormone

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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

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retinoid hormones

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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

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thyroid hormones

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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

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hypothalamus

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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

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posterior pituitary

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

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anterior pituitary

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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

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big things poppin' in the LIVER

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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

question

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

answer

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

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metabolism of amino acids in the liver

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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

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lipid metabolism in the liver

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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

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adipocytes and fatty acids

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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

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energy source for resting muscle

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

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

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energy source of moderately active muscle

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

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energy source of maximally active muscle

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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

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what is the creatine kinase reaction?

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phosphocreatine + ADP ↔ creatine + ATP

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

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what is the Cori cycle?

answer

LACTATE         ←          GLYCOGEN         (MUSCLE)
                ATP release
↓                                      ↑

BLOOD LACTATE       BLOOD GLUCOSE

↓                          ↑

LACTATE         →          GLUCOSE              (LIVER)
   ATP inclusion

question

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

answer

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.

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what are the major qualities of fast twitch muscle?

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"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

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what are the major qualities of slow twitch muscle?

answer

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

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how does cardiac muscle differ from skeletal muscle?

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heart is CONTINUOUSLY active in regular contraction/relaxation

heart is PURELY AEROBIC at all times

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what fuels cardiac myocytes?

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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**

question

what ketone body is used by brain?

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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

question

what are neurons' main fuel?

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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

question

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

answer

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.

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

answer

alpha cells: glucagon

beta cells: insulin

delta cells: somatostatin

question

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

answer

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

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how does insulin counter high glucose?

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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

question

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

answer

GLYCOGEN: liver, muscle
triacylglycerides: adipose

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what are the main actions of glucagon?

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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

question

how does liver fuel itself during fasting state?

answer

Fatty acids = principal fuel

excess acetyl coA converted to ketone bodies, transported to brain and other tissues when blood glucose is low

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how does glucagon regulate glycolysis and gluconeogenesis?

answer

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

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glucagon's effect on adipose tissue?

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

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

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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)

question

Fructose 2,6-Bisphosphate

answer

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**

question

what are the fuel reserves of a healthy human?

answer

glycogen: in liver (majority) and muscle

adipose: triacylglyceride storage

tissue proteins: can be degraded when necessary

question

acetyl-coA regulates fate of pyruvate. how?

answer

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

question

liver fuel metabolism during fasting

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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

question

starvation & fuel concentrations: what's the pattern?

answer

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**

question

epinephrine increases energy sources for impending activity

answer

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

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epinephrine and glucagon

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work together to encourage the release of stored fuel and to prevent fuel storage

epinephrine activates glucagon secretion, inhibits insulin secretion

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what does cortisol do?

answer

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

question

what are the tissue specific effects of cortisol?

answer

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

question

leptin?

answer

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)

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leptin stimulates sympathetic nervous system

answer

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

question

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

answer

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

question

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

answer

OREXIGENIC (APPETITE STIMULATING)
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**

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NEUROPEPTIDE Y (NPY)

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

question

GHRELIN

answer

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.

question

PYY3-36

answer

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

question

leptin signalling cascade highlights

answer

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

question

why is leptin not a culprit for obesity?

answer

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.

question

what effect does leptin have on insulin?

answer

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

question

adiponectin

answer

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

question

adiponectin & DM II

answer

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

question

PPAR
(peroxisome proliferator activated receptors)

answer

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**

Metabolic Interdep. of Maj Org – Flashcards

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