Lecture 26: Metabolic Integration: Physiology Flashcards
metabolic homeostasis
metabolite levles maintained by reg system
LIVER
Addipose tissue
endocrine organ: controlls fatty acid homeostasis
nrg storage
metabolic adaptations to starvation:
inc in gluconeogensis
switch to dependency of fatty acids as major nrg source
what’s so special about the liver?
it can preform all synth and degredation reactions
metabolic control of carbohydrate, lipid, amino acid metabolism, control of oxidative phosphorylation
other cells (not in liver)
mostly limited to catabolizing glucose and FA to make ATP throuh oxidative phosphorylation
What does the liver do?
processes fats, carbs, proteins (dietary)
synth and distribute lipids, ketone bodies, glucose
converts nitrogen to urea
glucose-6-phosphate
central metabolite!!! used in glycolytic pathway makes lipids, OAA, ketones makes glycogen used in PPP
can ALL HAPPEN IN THE LIVER
what biochemical mechanisms determine glucose-6P flux through these pathways?
enzyme activity
what can glucose-6P be converted to?
glucose 1P (glyc synth)
glucose (go to blood)
fructose 6P: (glycolysis)
6-phosphogluconate (PPP)
Metabolic functions of skeletal muscles: resting
uses fatty acid release from adipose tissue as nrg
b/c ATP needs to be used during contraction
Metabolic functions of skeletal muscles: contracting
use intracellular ATP pool
ATP hydrolysis for myosin/actin interactions
replinishing ATP pool for skeletal muscle
replinished by phosphoryl transfer: use creatine kinase to make
PHOSPHOCREATINE
PHOSPHOCREATINE
can replinish ATP pools for a few seconds of intense activity
directly converts ADP to ATP
pool of PHOSPHOCREATINE gets rebuilt during rest
Adipose tissue
endocrine organ secretes adipokines (peptide hormone) regulate fatty acid secretion and circulation
visceral fat
belly region
surrounds and cushions organs
very metabolically active: Releases lots of adipokines
high CVD risk
subcutaneous fat
less metabolically active
more distance from organs
stored beneath skin
BMI
weight/height^2
waist/hip ration (WHR)
may be better predictor of CVD than BMI
may not be
maybe we just can’t really tell well whose at risk for CVD
Metabolic functions of adipose tissue
regulates triacylglycerol cycle (circulates FAs between adipose and liver)
this is done by adipokines im pretty sure
triacylglycerol cycle
circulates fatty acids and glycerols between adipose tissue and liver
so that they can circulate through the blood (liver so they can be remade into triacylglycerols)
What is the metabolic logic of maintaining circulating fatty acids even though 75% of it is returned to adipose tissue and stored?
when you need it, its available!
what’s the primary nrg source for brain?
glucose
half of it is used by sodium potassium ion transporter
FATTY ACIDS ARE NOT USED IN THE BRAIN
what can/can’t cross blood brain barrier
glucose and ketone bodies can
fatty acids can’t
what are the two metabolic fuels exported by the liver
glucose
triacylglycerol
metabolic homeostasis
maintain balance in the body
requires:
neuronal signaling from brain
release of small molecules into blood (ligands for cell signaling)
why are glucagon and insulin call the ying and yang of homeostasis?
they balance each other
complementary and opposing actions
what causes type 1 diabetes
may lack beta cells
where are glucagon and insulin made
pancreas, islets of Langerhans
alpha cells: glucagon
beta cells: insulin
delta cells: somatostatin
effects of Insulin and Glugacgon signaling on Liver
G: stim glucose export
I: Stim glucose uptake (glycolysis, glyc synth, FA sytn)
effects of Insulin and Glugacgon signaling on skeletal muscle
G: No effect
I: stim glucose uptake by inc glucose transporters, glycolysis, glyc synth
effects of Insulin and Glugacgon signaling on adipose
G: stim fatty acid export
I: stim glucose uptake (transporter levels), inc FA synth, activate FA uptake
effects of Insulin and Glugacgon signaling on brain
G: No effect
I: stim nueronal signaling to DECREASE eating, INCREASE nrg expendature
Glucagon circulates through the body, why does it have no effect in muscle and brain tissue?
skeletal and brain tissues need to use glucose themselves! no need for export!
liver and adipose export glucose and fatty acid for use by rest of body
glucagon still signals in these tissues, they just don’t respond
PPAR proteins
transcriptional regulators in cell nucleuses respond to fatty acids and ecosinods maintain homeostasis Lipid activated
PPAR alpha
Fatty acid ox proteins stimulated
in muscle and liver
fasting response in liver
PPAR delta
fatty acid ox in fat and muscle
produces UPC
PPAR Gamma
activity in adipose, liver, and muscle
whole body insulin sensitivity
lipogenesis and storage
adipogenesis
PPAR activations
Lipid activated!
if fatty acid derived molecs around and bind, they can go to nucleus
PPARs regulate gene expression
get enzymes in to respond to the lipid appropriately
Why is PPAR imporant to us?
drug target for diabetes
try to control adipocyte differntiation and lipid synth in adipose tissue (PPAR gamma)
TZDs
improve insulin sensitivity in type 2 diabetics
activate PPAR gamma target genes involved in lipid synth
side effects of TZDs
water retention
liver damage
why do diabetics who are treated with TZDs see a drop in blood glucose levels but also weight gain
stimulate lipogenesis and adipogenesis
the glucose is being used, but its being used to make fat for storage
Metabolic adaptation to starvation
alter flux of metabolites between various tissues
provide glucose to brain (most important)
RBCs also need glucose–they have no mitochodria and can’t generate ATP
why can’t RBCs utilize fatty acids as an energy source?
no mitochondria to break down fats!
Short term starvation (24 hrs) vs. long term
24 hrs: glycogen and glucose levels drop like crazy, FA and ketone bodies inc
DAYs: glucose levels stabilize, FA and ketone bodies inc
2 major adaptations to short term starvation
- inc gluconeogenesis so we have enough glucose
2. switch to fatty acids as fuel
Why is ketogenesis stimulated?
we have lots of acetyl-CoA and not much OAA
acetyl CoA: b/c its released during fatty acid oxidation
Why store nrg as fat rather than just glycogen?
fat has a lot more nrg, longer survival time, weighs less
What is the stored nrg potential in kJ/g of glycogen and tiracylglycerols based on dry weight data (1cal=2.18 kJ)
TAGs=141,000 Cal/15,000g= 9.4 Cal/g=39.3 kJ/g
Glycogen=900Cal/220 g= 4.1 Cal/g= 17.1 kJ/g
Which is more reduced: 1 mole of Palmitate (C18) or 3 moles of C6 glucose (C18)
palmitate
because of beta ox reactions
If the nrg equivalent of 15 kg of fat in a 70 kg man were stored as glycogen: what is is total mass?
nrg ratio: 39.9/17.1= 2.3X more/g
15 kg fat * 2.3= 34.5 kg glycogen
REMEMBER GLYCOGEN HAS 2g water/1 g glycogen!!!!!!
so 34.5 kg + (2*34.5 kg)= 103.5 kg stored glycogen and water (almost 7X more mass required to store nrg as glycogen in this case)
so 70kg + 103.5 kg= 158.8 kg
study slide 25!!!!!!!!!!!!!!!
study slide 25!!!!!!!!!!!!!!!
Long term starvation (4 things happen)
only need major functions. 4 things happen
1. triacylglycerol hydrolysis from adipose tissue goes up (Release FA to fuel tissues)
2. Liver gluconeogenesis (and kidney) INC to supply body with glucose (to fuel brain)
3. ketone bodies–produced by liver: INC ketogensis in liver
ketone bodies go to heart and brain
4. protein degredation in muscle tissues: we need the carbon for the metabolites to make nrg (lose muscle mass)
