Unit 7: Metabolism and Energy Balance

what are the 3 possible fates for ingested macromolecules

fuel - metabolizes to provide energy

build - synthesis reactions for growth and maintenance of tissues

store - as glycogen (liver, skeletal muscles, or fat)

what are the 2 states metabolism is divided into? are they catabolic or anabolic

fed / absorptive state - anabolic products of digestion being absorbed and used for synthesis or stored

fasted / post absorptive state - catabolic, body taps into stores

what are 3 nutrient pools available for immediate use (mostly circulating in plasma)

• glucose

• free fatty acids

• AAs

explain the enzymes that control direction of metabolism

Fed state:

• metabolism is under the influence of insulin → enzyme activity for forward reaction inc

• enzymes for glycogen breakdown are inhibited

  • net glycogen synthesis

Fasted-state:

• metabolic under influence of glucagon, etc.

• enzymes that break down glycogen are more active

  • enzymes for glycogen synthesis are inhibited

what is gluconeogenisis

producing glucose from lactate, glycerol, or AAs

• usually done in the liver during the fasting state

  • triggered by glucagon or cortisol

what is glycogenisis

converting glucose to glycogen to be stored

• usually done in liver and skeletal muscle during the fed state

  • triggered by insulin

what is the diff between glycogen and glucagon

Glycogen is a stored form of glucose found in the liver and muscles, used for quick energy.

Glucagon is a hormone released by the pancreas when blood sugar is low; it signals the liver to break down glycogen or make new glucose to raise blood sugar levels.

explain the nutrient storage depots of carbohydrates, fats, and proteins (and what happens in the TCA cycle) in the fed state

Fed State (high insulin, low glucagon)

• The body stores nutrients:

• Carbohydrates get stored as Glycogen:

  • Excess glucose is stored as glycogen in liver & muscle (glycogenesis)

• Carbohydrates → Fat:

  • Glycogen stores are full → extra glucose is converted to fatty acids (FAs) → combined with glycerol → stored as triglycerides (TGs) in adipose tissue (lipogenesis).

• Proteins → Body Proteins:

  • Proteogenisis

  • Excess AAs (not used for proteins) can be converted to pyruvate or acetyl-CoA where it’ll be turned to → FAs (fatty acids) → TGs (tri glycerides).

  
  TCA Cycle: ATP production

Main hormone: Insulin promotes uptake & storage of glucose, AAs, and FAs

explain the nutrient storage depots of carbohydrates, fats, and proteins (and what happens in the TCA cycle) in the fasted state

Fasted State (low insulin, high glucagon)

• The body mobilizes stores for energy:

• Glycogen → Glucose: (Glycogenolysis)

  • glycogen in liver→ releases glucose into blood to maintain normal blood sugar.

  • glycogen in muscle → can NOT be exported as free glucose

    • can only be used by that muscle OR exported as pyruvate or lactate to the liver where it would undergo gluconeogenisis

• Proteins → AAs → Glucose:

  • during extreme starvation

  • Muscle protein breakdown (proteolysis) to make AAs

    • liver converts them (via gluconeogenesis) into glucose.

    • OR they can be used within the muscle

• Fats:

  • TGs in adipose tissue are broken down to make FAs + Glycerol:

    • Glycerol → exported to liver to undergo glueoneogenisis (prod glucose)

    • FAs → undergo beta oxidation (E prod)

      • make Acetyl-CoA

      • if fatty acids are exported to liver, liver uses it to prod keytone bodies from FAs (through ketogenisis)

• FAs → Acetyl-CoA → Ketone Bodies: In prolonged fasting, liver uses FAs to make ketone bodies → alternative fuel for brain & tissues.

Main hormone: Glucagon promotes breakdown of glycogen, fat, and protein to maintain blood glucose & provide energy

what is beta oxidation

a metabolic process that breaks down fatty acids to produce energy (acetyl-CoA)

what are triglycerides broken down into during the fasted state?

into free fatty acids and glycerol (lipolysis)

• then fatty acids to acetyl Co-A (beta-oxidation)

can muscle help with E prod? if so how

Muscle can indirectly help w E by breaking down glycogen into pyruvate or lactate and exporting it to the liver where it can undergo glycogenesis

what does the brain use for energy

glucose and ketones

when does ketogenesis occur

if lipolysis proceeds faster than acetyl CoA is being used in the TCA cycle (have excess CoA that is broken down into ketone bodies)

what does ketogenesis do

forms keytone bodies

• can enter blood and serve as energy substrates for brain during times of starvation

  • know your starving bc fats are being broken down for energy faster than ATP is being produced for energy

what type of diet typically results in ketones synthesis

typically generated by low carb, high fat/protein diets (dont have carbs needed to undergo TCA cycle fast enough → body breaks down CoA to substitute)

why can ketones become dangerous in the body

certain ketone bodies are strong metabolic acids that can disrupt acid-base balance (called keto acidosis)

what is homeostatic eating

• eating when energy fuels are depleted

• not eating when energy fuels are sufficient

  • metabolically-driven eating

what is non-homeostatic eating and what does it involve

• eating in the complete absence of hunger

• eating despite large fat reserves

  • involves cognitive, reward, emotional factors

  • has neural parallels w addiction mechanisms

    • hedonic eating

what is hedonic eating

when food is consumed primarily for pleasure and enjoyment, rather than to satisfy hunger or nutritional needs

where are the “hunger”/”feeding” centre and “satiety” centres located

they are the 2 centers in the hypothalamus

what is the glucostatic theory

• theory that food intake is regulated by glucose levels, monitored by centres in the hypothalamus

  • plasma glucose low → satiety centre (in hypo) is suppressed → feeding centre is dominant

what is the lipostatic theory? what resulted in the development of this theory

• theory that signals from fat stores to brain modulates eating behaviour

  • discovery of protein hormone synthesized in white adipose tissue (meant to maintain a certain amount of fat)

    • protein hormone was called leptin (leptos = thin)

what does leptin do

tells the body to stop eating / when it has enough fat reserves

explain the story behind leptin and the ob/ob mouse

a spontaneous mut in rat colony in lab

• mice were obese, voracious eaters

• mut identified as ob/ob

  • protein product was leptin

  • mice homo for a mut in that gene were obese

• another mut w similar phenotype was discovered to be mutation in leptin receptor

  • db/db

t/f: the body has more mechanisms to tell you to stop eating then to eat

true

what are signals from the gut that inc appetite

from stomach:

• inc ghrelin

  • secreted by cells of empty stomach

what are signals from the gut that dec appetite in the stomach, upper small intestine, and lower small intestine/colon respectively

stomach:

• inc stretch

• inc acid (detected by acid-sensing ion channels)

upper small intestine:

• inc CCK (in response to fat/protein in lumen)

• inc glucose in lumen

lower small intestine/ colon

• inc peptide YY (PYY) → inhibits relase of neuropeptide Y

• GLP-1 (incretins)

  • both triggered by macronutrients in lumen and also neural reflex from upper small intestine

what is neuropeptide Y

a key neurotransmitter in stimulation of appetite

• many hormones, neuropeptides, and products of adipocytes interact to influence appetite

Fat cells produce leptin, communicates above hypo feeding center (inhibits) to neuropeptide Y -> says to hypo to slow down food intake and also dec other neuro and hormones

what is hungry brain

• larger animals (eg humans) have significant E stores - can go w out food for relatively long periods

  • BUT food restriction and fat depletion eventually lead to “hungry brain”

    • brain's inability to regulate appetite effectively

Good at defending the LOWER limits of fat supply (not depleting ALL of it and eating en mass when get close) → do not want to even get close to our lower limits so we get really hungry fast → trying not to eat even w prolonged hunger can result in hungry brain

with all our homeostatic mechanisms, why are humans obese

• hungry brain

• modern environment acts on higher brain regions to over-stimulate food intake

• procuring food is no longer demanding or dangerous (easily accessible)

• exceeding upper limits of body weight is no longer disadvantage in terms of preditor-prey

• many obese humans become leptin-resistant

  • happens in many seasonal animals → elevated leptin doesn’t stop apetite in summer when food is abundant, but leptin sensitivity is restored in winter (making them want to eat less)

    • food is always readily availible so always in “summer” state

what were the first 2 reported cases of leptin deficiency in humans

• 2 severely obese first cousins from highly consanguineous (inbred) Pakistani family in UK

  • both born w homozygous frame-shift mut in lep (leptin) gene

• 5 other cases have been identified (from 4 other unrelated pakistani families)

how is metabolism regulated through the endocrine and NS respectively

endocrine - primary role

• prod of endocrine pancreas

  • insulin/glucagon ratio

neural - regulation of food intake

• endocrine pancreas is also innervated (autonomic responses)

what is the diff between glycogenolysis and glyconeogenesis

• Glycogenolysis = break down glycogen for glucose (quick energy).

• Gluconeogenesis = build new glucose from scratch (sustains blood sugar when glycogen is gone).

when do insulin levels increase? what are some processes that increase when insulin is increased

fed (absorptive state) triggers insulin release

• energy production → glucolysis (breaking down glucose for E)

• energy storage → glycogenesis (short-term) + lipogenesis (long-term)

• protein synthesis (build things in body - eg muscle)

when do glucagon levels increase? what are some processes that increase when glucagon is increased

during the fasted (postabsorptive) state:

• inc glyconeogenolysis (prod glucose for energy)

• inc glyconeogenisis

• inc ketogenesis

what happens to plasma insulin and glucagon levels immediately after a meal

• plasma insulin inc immediately after meal

  • slowly dec after

• plasma glucagon dec right after a meal

  • slowly inc after

what are the islets of langerhan → where are they located, what do they secrete, and how

lo

• mix of…

  • beta cells making insulin

  • alpha cells making glucagon

  • D cells making somatostatin

• majority are insulin producing

• ductless granular cells (hormones)

t/f: the islets of langerhan are composed of exocrine tissue

F → endocrine

when are B-cells triggered and what does that do

releases insulin

• inc plasma glucose & AAs

• inc incretins

• inc parasympathetic system

explain how and when B-cells are triggered

in fed state

eating → triggers, distension of GI tract, carbs in gut lumen, and nutrient digestion and absorption

1. Distension of GI tract

   • triggers stretch receptors

   • inc sensory neuron input to CNS (integrates)

   • inc parasymp response (rest and digest)

   • triggers B-cells

2. Carbs in gut lumen (eg glucose)

   • endocrine cells of small intestine sense and integrate info and trigger release of incretins (GLP-1 & GLP)

   • incretins trigger B-cells

3. nutrient digestion and absorption

   • inc plasma AAs & plasma glucose

   • triggers B-cells

     • (and plasma glucose inhibits alpha-cells)

explain how B-cells do at rest

blood glucose is low (hence why at rest)

• metabolism slows

• glucose cannot enter B cells via GLUT2 transporters

• dec ATP production

• KATP channels (ATP-gated K channels on B cells) open, K leaves

• cell is at resting mem pot

• no insulin is released via exocytosis bc v-gated Ca channels remain closed

explain how pancreatic B-cells release insulin

• high blood glucose

• glucose enters B cells via GLUT2 transporters

• metabolism inc

• inc ATP prod

• KATP channels close (K+ stuck in cell)

• cell depolarizes → Ca channels open

• triggers exocytosis of insulin

which cells does insulin usually act on? what does that do? (4 things)

• primarily works on cells that express GLUT4 transporter → striated muscle, adipose tissue

• and the liver.

 

• stimulates inc of glucose transport into the aforementioned target cells (via GLUT4)

• Inc glucose uptake from those various targets results in…

  • inc glycolysis (inc glucose metabolism to prod ATP)

  • inc glycogenesis (inc glycogen production for short-term energy storage)

  • inc lipogenesis (fat synthesis → for long-term energy storage)

  • inc protein synthesis (for building things within the body like within straited muscle)

 

BASICALLY insulin promotes enzyme activity that uses glucose.

what is insulin’s general mechanism of action (how does it GENERALLY work on target cells)

1. binds to tyrosine kinase receptor

2. receptor phosphorylates insulin-receptor substrates (IRS) on inside of mem

3. 2nd messenger pathways alter protein synthesis & existing proteins

   1. mem transport is modified

   2. cell metabolism is changed

      • change enzyme activity OR

      • change transcription factors which change enzyme activity

how does insulin effect muscle and adipose tissue in the fasted vs fed states

Fasted:

• no insulin

• insulin can’t bind to receptor

• no GLUT4 transporters get put on mem

Fed:

• insulin binds to receptor

• triggers signal transduction cascade

• GLUT4 inserted into mem via exocytosis

• glucose moves into cell

explain how insulin effects hepatocytes

hepatocytes contain glucose transporters called GLUT2 transporters

fasted state:

• blood glucose is low, insulin is low

• hepatocytes make glucose and export it via GLUT2 transporters

fed state:

• blood glucose is high, insulin is high

• gradient favours glucose import via GLUT2

• insulin signalling activates hexokinase

  • converts glucose to other things, keeps it low in cells

what is another term for glycolysis

glucose oxidation

is insulin catabolic or anabolic? explain why

anabolic

• activates enzymes that enhance…

  • glycolysis (glucose oxidation)

  • glycogenesis

  • lipogenesis (conversion of excess glucose or AA to triglycerides)

  • AA utilization / protein synthesis

• inhibits enzymes that enhance…

  • gluconeogenesis

  • glycogenolysis

  • lipolysis

  • beta oxidation of fatty acids

  • proteolysis

what is diabetes mellitus

group of diseases characterized by elevated blood glucose

what is hyperglycemia

high blood glucose

explain type 1 vs type 2 diabetes

type 1 → inadequate insulin secretion

type 2 → abnormal target cell responsiveness

what are the diffs in blood glucose levels in those w and w out diabetes after taking oral glucose. consider type 1 vs type 2

without → should see a spike in blood glucose levels that comes down and returns to normal after couple hours

with type 1 AND/OR 2 → diabetes (it doesn't matter in this case if it's type 1 or 2), their body would not be able to properly partake in its absorptive state actions, including breaking down glucose. So their blood glucose levels would spike and stay higher for significantly longer

does insulin stay longer higher in type 1 or 2 diabetes

Both T1DM & T2DM show a delayed/abnormal glucose clearance, leading to prolonged hyperglycemia on an oral glucose challenge.

• T1DM: Almost no insulin → glucose stays high.

• T2DM: Delayed, insufficient insulin + insulin resistance → glucose stays high longer.

t/f: does diabetes have mostly harmless effects overall

false → it is metabolically catastrophic.

which type of diabetes is more common

type 2 (insulin resistance) → accounts for around 90% of diabetes

• was once celled “mature onset” diabetes vs juvenile

t/f: type 2 diabetes can be coupled with low, normal, or high insulin secretion and have approx the same effects across

true

what are some defining physical characteristics of type 2 diabetes

acute symptoms are not as severe as type 1 BUT metabolism is not norma'l

• atherosclerosis (buildup of fats, cholesterol and other substances in and on the artery walls) and hypertension often occur tg

  • typically in conjunction w obesity

    • metabolic syndrome

what is it called if you have at least 3 of these

metabolic syndrome

what is another member of the secretin family of peptides other than secretin, GIP, and GLP-1)

glucagon

what does glucagon antagonize

the effects of insulin

what is glucagon’s main target

the liver

what is glucagon’s main function? how much glucose is broken down at what times by what

to prevent hypoglycemia (low blood sugar)

• during overnight fast, ~75% of glucose from liver comes from glycogenolysis (first step)

• 25% from glycogenolysis ~25% from gluconeogenesis (second step)

where is the adrenal gland located

on the kidneys

what does the adrenal gland produce

catecholamines - mostly epinephrine (adrenaline) → medulla is main source

explain the hypothalamic-pituitary-adrenal axis (with target organs and effects)

what are glucocorticoids

a type of steroid hormone produced by the adrenal glands, or synthetically created, that play a crucial role in regulating various bodily functions, including metabolism and the immune response

which cells have receptors for glucocorticoids

all nucleated cells

what kinds of effects do glucocorticoids have

mostly longer-term (genomic) effects → bc steroid

• inc expression of enzymes

• inc expression of receptors for other regulatory hormones

what are the 2 general effects of glucocorticoids

1. prevention of hypoglycemia

   • adipose → lipolysis → FAs for energy, glycerol

   • muscle → proteolysis → AAs

   • liver → gluconeogenesis

   permissive for full effects of glucagon and epinephrine

2. suppress immune response

what did Hans Selye find out ab stress

• developed concept that wide variety of “stressors” caused generic responses…

  • adrenal hypertrophy (bc trophic hormone was high)

  • atrophy of thymus / lymph nodes

  • GI ulcers

• failure to cope w / adapt to stresses caused diseases of adaptation (ulcers, hypertension, etc)

• led to many hypothalamic-pituitary axis breakthroughs

explain epinephrine in the fight or flight response

• quick response

  • norepinephrine from sympathetic post-ganglionic neurons

  • epinephrine from adrenal medulla

    • rapid effects but short half-life (~2 mins)

• metabolic effects: mobilize energy sources

  • dec insulin release, inc glucagon release

  • adipose → lipolysis → FAs for E, glycerol

  • muscle → glycogenolysis

  • liver → glycogenolysis, gluconogenisis

effects similar to glucagon but receptors expressed on broader range of target cells

• tips balance to cranking up metabolism, breaking down fats, muscle, etc

what are 2 cortisol pathologies? explain them

hypercortisolism (Cushing’s syndrome, high cort)

• primary → cortisol-secreting adrenal tumors (not regulated by ACTH)

• secondary → pituitary tumor that over-secretes ACTH

• iatrogenic → secondary to cortisol therapy for other conditions

hypocortisolism

• primary → adrenal insufficiency (addison’s diseae)

  • adrenal gland develops abnormally

  • can b bc muts in key steroidogenic enzymes

    • congenital (born w) adrenal hyperplasia → enlarged adrenal gland

    • adrenal gland damaged / distroyed (autoimmute)

• secondary → lack of ACTH

how do glucagon, epinephrine, and cortisol work on blood glucose

synergistically

which hormones act the fed state

only insulin

which hormones act in fasted state

epinephrine, glucagon, cortisol

where can gluconeogenesis occur

ONLY EVER OCCURS in liver

what do epinephrine, glycagon, and cortisol do in the fasted state (check this slide later)

epinephrine:

• all liver functions in fasted state

  • glycogenolysis (in liver)

  • gluconeogenesis (only ever happens in liver)

• glycogenolysis (in muscle)

• lipolysis

  • can be used by muscle or go to liver

glucagon:

• can only act on liver so has 3 options

  • glycogenolysis (in liver)

• ketogenisis

• proteolysis

  • lipolysis

    • gluconeogenesis (only ever in liver)

what is thyroid homrone classified as

an amino acid derivative (from tyrosine, contains iodine)

• only known use of iodine in the body

what is thyroid hormone’s mechanism of action similar to

steroids → lipophilic, travels in circulation bound to thyroid-binding glubulin

• binds to nuclear receptor

what is thyroid hormone’s main circulating form and its most active form? how does it switch btwn the 2

T4 - main circulating form

T5 - most active form, converted w in target cell by deiodinases (removing iodine)

what are some actions of thyroid hormone (what does it do)

• essential for normal growth / development, especially NS

  • thyroid hormone levels checked in all newborns in canada

• not essential in adults but affects quality of life

• main fx → provide substrates for oxidative metabolism

  • inc O2 consumption and generation of heat (thermogenesis) in most tissues (maintains basal metabolic rate)

    • inc activity of Na/K pump

  • interacts w other hormones to modulate carb, protein, and lipid metabolism

what is hypothyroidism? what are some of its symptoms and its main cause

low O2 consumption, dec metabolic rate (cold intolerant)

• neurological effects, fatigue

• effects on skin, nails, hair

most common cause of hypothyroidism

• iodine deficiency → enlarged thyroid gland → called “goitre”

what is hyperthyroidism? what are some of its symptoms and its main cause

inc o2 consumption, inc heat production (heat intolerant)

• muscle weakness (protein catabolism/breakdown)

• neurological, cardiac effects

• exophthalmos (protruding eyes)

most common cause:

• Graves disease → autoantibodies that resemble TSH overstimulate thyroid gland (not subject to - feedback regulation)

t/f: growth hormone can only effect target cells directly. explain

false → effects both direct and indirect

direct:

• target cells that express GH receptor

indirect:

• mediated by insulin-like growth factors (IGFs = somadomedins) prod by liver or target cell themselves

what are some metabolic actions of growth hormone

• carbohydrate - indirect effects lead to inc plasma glucose

• fats - inc lipolysis, inc oxidation

  • catabolic w respect to CHOs and fat “anti-insulin” effects

• protein - inc AA uptake, inc protein synthesis, dec oxidation for E

  • anabolic w respect to proteins (pro insulin)

what are some growth actions of growth hormone

inc cartilage, bone, and muscle growth

explain why a deficiency in growth hormone could occur and what a common thing associated w it

• due to GH hyposecretion and GH-receptor muts

  • dwarfism (though GH issues are not common cause)

what are some common things associated w excess growth hormone

depends on whether excess GH happens before or after closure of growth plates

before → gigantism

after → acromegaly

what does most Ca in the body do

composes the extracellular matrix of bones and teeth (99% of it in the body does this)

• bone resevoir is main source of Ca but very little of it is free for exchange

what do osteoblasts do

lay down Ca-PO4 (build extracellular matrix of bones)

what do osteoclasts do

secrete enzymes / H+ that dissolve mineral matrix → resorption (incorporate Ca in matrix into bone)

what drives bone resorption (note: not reabsorption) and what does that do

parathyroid hormone and vitamin D

• inc osteoclast activity relative to osteoblasts

how much ingested Ca is absorbed and how

about 1.3 absorbed → through transcellular and paracellular routes

how is Ca expelled out of body

primarily via kidneys → freely filtered, most reabsorbed

• hormonally controlled reabsorption at distal nephron only

what is vitamin D

a family of fat-soluble vitamins → derivatives of cholesterol

• get from plant/animal sources

• UV rays from sun activates the precursor stored in our skin

• liver adds hydroxy

• kidney adds hydroxy

• now works

what is 1-25-dyhydroxy cholecalciferol

Vitamin D

what is calcitriol

vitamin D

explain hwo Ca homeostasis is regulated

1. parathyroid hormone

   • released in response to hypocalcemia

   • drived release of V D3

2. Vitamin D3

   • released in response to PTH after being activated

tg they:

• inc Ca absorption form intestine

• inc Ca reabsorption in distal nephron (kidney)

• inc resprotion from bone (inc osteoclast)