Intro To Metabolism Flashcards
Devoted to the capture of useful energy from high-energy compounds, and to the breakdown of compounds to simpler constituents
Catabolic Pathways
The small molecules that are the reactants and products of a reaction are called
Metabolites, enzymes, and energy
Signal transduction pathways regulate
Metabolism
Signaling molecules become activated by modifications such as
Phosphorylation
A major role of the hormones involved in metabolic homeostasis is to maintain blood glucose levels above
60mg/100mL
It is also important that fasting glucose levels remain below
100mg/dL
The stored form of fuels, in particular adipose tissue, directly correlated with
Leptin and Insulin Levels
Sense blood glucose and use this information to regulate food intake
Glucoreceptors in the hypothalamus
Stimulates anabolic metabolism
mTOR signaling pathway
The mechanistic target of rapamycin (mTOR) signaling pathway controls
Metabolism and cell growth
Stimulates multiple anabolic pathways in the response to the presence of nutrients and growth factors such as insulin
mTOR protein complex 1 (mTORC1)
Controls a number of mechanisms involved in protein, lipid, and nucleotide synthesis to produce macromolecules required for cell growth
mTORC1
mTOR also negatively regulates catabolic processes such as
Autophagy and lysosome biogenesis
Which signaling pathway stimulates catabolic metabolism?
AMPK signaling pathway
Activated when metabolic demand exceeds metbolic supply, resulting in a decrease in the ATP/ADP ratio
AMP-activated Protein Kinase
Together, act as nutrient and energy sensors and regulate metabolism in conjunction with hormones
mTORC1 and AMPK
Metabolic pathways generate substrates that are used as post-translational modifications to control
Signal Transduction
Glycosylation, acetylation, mehtylation, and prenylation change activity, localization, and stability of
Target proteins
Also modify DNA and histones, leading to epigenetic alterations that influence gene expression and chromatin structure
Acetylation and methylation
Insulin binding to the insulin receptor triggers the PI3K/mTOR pathway, thus promoting
Anabolic Metabolism
Insulin is secreted into the portal vein, but almost half is degraded before leaving the
Liver
Serum insulin levels normally begin to rise within 10 minutes after ingestion of food and reach a peak in
30-45 minutes
Permit a rate of glucose influx that is proportional to the blood concentration in the physiological range
-In beta cells
GLUT2
The rate limiting step for glucose metabolism in the beta cell and the major mechanism of glucose sensing production of ATP
Glucose phosphorylation by Glucokinase (Hexokinase)
Inhibits the ATP-sensitive K+ channel and leads to depolarization, while also opening Ca2+ channel, leading to insulin exocytosis
Glucose phosphorylation by Glucokinase (Hexokinase)
Insulin gene expression and islet cell biogenesis are dependent on several transcription factors that are specific to the
Pancreas, liver, and kidney
Bind to K channels to block activity and promote insulin release
Sulfonylurea drugs
The most important hormone coordinating the use of fuel
Insulin
The primary hormone that orchestrates fuel use and storage during the fed state
Insulin
Insulin is synthesized in the beta cells as a prepro-hormone consisting of peptides
A, B, and C (a connecting peptide)
About 5-10% of the final secreted product is still in the form of
-no insulin activity
Proinsulin
Genes coding for insulin are transcribed to mRNA in the
Nucleus
mRNA then moves into the cytoplasm and translation occurs with formation of an N-terminal hydrophobic signal sequence that targets the nascent chain into the
ER
Further elongation of the nascent chain into the lumen of the ER results in the formation of
Preproinsulin
The signal sequence is then cleaved, forming
Proinsulin
Proinsulin is transported from the ER to the Golgi where it is cleaved, forming the
Insulin and C-peptide
Insulin and C-peptide are stored in
Secretory granules
Secretory granules are secreted by exocytosis, releasing
Insulin and C-peptide
A good indicator of insulin production due to its longer half life
C-peptide
Used to differentiate the cause of high insulin in patients
-i.e. increased endogenous production vs exogenous overdose
C-peptide levels
Activates protein kinases such as Akt that negatively regulate repressors of the anabolic effects of insulin
Insulin signaling
Repressing these factors (such as FOXO, TSC2, and GSK3) promotes
Glucose metabolism and the other effects of insulin
In the liver, insulin stimulates glucose uptake by
-Leads to subsequent glycolysis
GLUT-2
Once hepatic glycogen stores are replenished (80-100g), excess glucose is used for the synthesis of
Triglycerides
The glucose that is not captured by the liver contributes to the postprandial rise in
Peripheral Glucose levels
Refers to the ability of an individual to minimize the increase in blood glucose concentration after a meal
Glucose tolerance
A primary way by which insulin promotes glucose tolerance is the activation of
GLUT4 in skeletal muscle
Stimulates the translocation of GLUT4 transporters to the cell membrane
Insulin
Insulin also stimulates GLUT4 dependent uptake of glucose and subsequent glycolysis in
Adipose tissue
Utilizes glycolysis for energy needs, but also for generation of glycerol-3-P required for reesterification of FFAs into triglycerides
Adipose TIssue
Stimulates the expression of LPL within adipose, promoting the release of FFAs from chylomicrons
Insulin
Under resting conditions, Rab10 is constitutively inactivated by TBC1D4/AS160 through its
GAP activity
Inactive Rab10 is then unable to target the
GLUT4 containing vesicles
Upon insulin stimulation, the insulin receptor phosphorylates
IRS-1
IRS-1 then activates
PI3K
Produced by PI3K at the plasma membrane where it activates Akt/PKB
PIP3
The activated Akt phosphorylates a variety of target molecules including
TBC1D4
Phosphorylated TBC1D4 then loses its GAP activity, and thus Rab10 is activated, promoting translocation of
GLUT4 to the plasma membrane
Glucagon and Epinephrine bind to
G-protein coupled receptors
Epinephrine and glucagon both function to control
Glycogen metabolism
Glucagon and epinephrine both trigger the production of cAMP and the activation of
PKA
Has epinephrine receptors but no glucagon receptors
Muscle
In the muscle, glycogen metabolism stimulated by Epi produces
Lactate
In the liver, epinephrine and glucagon stimulate the breakdown of glycogen to
Glucose phosphate
Represent the primary hormones that induce the mobilization of energy stores and new synthesis of glucose and ketone bodies during the fasting state
Glucagon and catelcholamines
Glucagon and catecholamines also promote proteolysis and the release of
Amino acids
Activation of the pituitary-adrenal axis is a prominent neuroendocrine response to
Stress
Stimulation of this axis results in hypothalamic secretion of
Corticotrophin-Releasing Factor (CRF)
CRF then stimultes the pituitary to release
ACTH
Which part of the hypothalamus is responsible for the integrated response to stress?
Paraventricular nucleus
Which three things mediate much of the neurogenic stimulation of CRF production
Norepi, Seratonin, and Acetylcholine
Binds to G-protein coupled receptor to manage acute stress
Epinephrine
The same signaling pathways can be used for both
Glucagon and epinephrine
Epinephrine responds to
Stress
Glucagon responds to
Low blood sugar
Caffeine, theophylline, and other members of the methylxanthine group of compounds inhibit
Phosphodiesterase
Inhibiting phosphodiesterase leads to an increase in cellular levels of
cAMP
Cortisol is present in the blood bound to
Corticosteroid-binding globulin (CBG)
When cortisol binds its receptor, the steroid-receptor complex enters the nucleus as a dimer and binds to the
Glucocorticoid Response Element (GRE)
GH stimulates growth primarily through the regulation of the growth-promoting hormone
IGF
Also has metabolic functions such as raising blood glucose by decreasing peripheral tissue utilization
GH
Promotes lypolysis and thus increases the availability of glycerol and FFas as fuel for muscle work
GH
During periods of metabolic demand, GH shunts the metabolic pathways from glycogenolysis to the metabolism of FFAs into
Acteyl CoA
The only proglycemic hormone
GH
GH directly blocks glucose uptake by skeletal muscle, and thus promotes
Insulin resistance
Increase the basal rate of oxygen consumption and heat production
Thyroid hormones
Potentiates stimulatory effects of epi, norepi, glucagon, cortisol, and GH on gluconeogenesis, lipolysis, ketogenesis, and proteolysis
T3
The overall metabolic effect of thyroid hormone is accelerating the response to
Starvation
How many types of intracellular thyroid hormone receptors are there?
Two
The unoccupied thyroid hormone receptor is bound to DNA and it represses
Transcription
Therefore, thyroid hormone receptor acts as a repressor in the absence of
Thyroid hormone
What is the first compound common to the catabolism oarbohydrates, lipids, proteins, and ethanol?
Acetyl CoA
Can humans synthesize fatty acids from glucose?
No
Which 4 amino acids can glucose NOT synthesize?
Leu, Ile, Lys, and Phe
