Term
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Definition
- bodies evolved to opportunistically stores excess calories
- loss of predation |
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Term
| part of brain that integrates satiety signals |
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Definition
| - arcuate nucleas of the hypothalamus |
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Term
| origins of satiety signals |
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Definition
pancreas
- α-cells: glucagon
- β-cells: Ins
GI tract
adipocytes |
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Term
|
Definition
- short term satiety
- choelcystokinin/CCK
- glucagon-like peptide 1/GLP-1
- Ghrelin |
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Term
|
Definition
- short term signal of postprandial satiety
- peptide hormone
- secreted by duodenum and jejunum
- targets peripheral neurons
(also stimulates bile salt secretion) |
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Term
|
Definition
- short term signal of postprandial satiety
- peptide hormone
- secreted by GI L-cells
- targets pancreas
- promotes the effect of glucose on β-cell secretion of Ins
- inhibits glucagon secretion |
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Term
|
Definition
- short term signal of hunger
- peptide hormone
- secreted by stomach
- targets hypothalamus
- STIMULATE appetite - increased before meal |
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Term
|
Definition
- long term homeostatic control
- leptin
- adiponectin (similar effects as leptin)
- RBP4 and resisten |
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Term
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Definition
- type of adipokines (endocrine signal of the adipose)
- leptin secretion directly proportional to amount of TAG stored)
targets muscle and liver:
- promotes the affects of Ins on target tissue
- stimualtes β-oxidation of FA and decrases TAG synthesis (saves tissues from "lipotoxicity" -> impairment due to xs lipid stores)
targets brain:
- inhibits orexigenic peptide secretion (NPY/AgRP)
- fasting (no leptin) stimulates NPY/AgRP secretion
- promotes POMC-MSH pathway: activates anorexigenic neurons
- fasting and AgRP inhibits MSH |
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Term
|
Definition
lack leptin
- hyperphagia
- hyperlipidemia (xs liver in muscle and liver)
- Ins insensitivity |
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Term
|
Definition
- signals well-fed sate through AMP-dependent protein kinases
- AMPKs promote catabolic activity (FA oxidation) |
|
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Term
|
Definition
- promote ins resistance
- purpose is possibly to modulate the effects of leptin
- enlarged adipocytes may secrete so much RBP4 and resistin that they contribute to pathological ins resistance |
|
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Term
| why isn't leptin doing its job in obesity? |
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Definition
- leptin resistance
- high blood leptin fails to trigger anorexigenic response
- may be caused by Suppressors of Cytokine Signaling/SOCS |
|
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Term
|
Definition
- suppressors of cytokine signaling
- inhibit receptor response to cytokine (leptin) signal
- bind to phosphotyrosines on Ins Receptor or other downstream members of pathway = disrupted signal flow
- SOCS binding may enhance degradation by proteosomes |
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Term
|
Definition
- appetite stimulating
- NPR/Neropeptide Y
- AgRP/Agouti-Related Peptide |
|
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Term
| anorexigenic neuropepetides |
|
Definition
- appetite suppressing
- POMC
- MSH |
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Term
|
Definition
- low carb/high protein
- proteins induce satiety better
- proteins require more energy to digest |
|
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Term
|
Definition
- xs energy stored as TAG
- all xs carbs and amino acid stored as fat
- fat accumulates in liver and muscle -> triggers ins resistance and pancreatic failure |
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Term
|
Definition
- liver overproduction of glucose
- underutilization of glucose in other oragns |
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Term
|
Definition
- insulin-dependent diabetes mellitus
- autoimmune
- β-cell destruction = no Ins release
- required Ins injections |
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Term
|
Definition
insulin-resistant diabetes mellitus
- normal/high blood levels of ins |
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Term
| major predisposing factor of TIIDM |
|
Definition
|
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Term
|
Definition
Ins ->
Receptor Tyrosine Kinase phosphorylation ->
IRS-1 (SH2 domains) bind phosphotyrosine ->
IRS-1 tyrosines phosphorylated ->
PI3K (SH2 domains) bind IRS-1 phosphotyrosines ->
PI3K converts PIP2 to PIP3 ->
PIP3 (second messenger) activates PDK ->
PDK activates Akt (aka PKB) ->
Akt:
1)facilitates insertion of GLUT 4 into cell membrane of muscle and adipose
2)promotes glycogen synthesis by inhibiting GSK |
|
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Term
| Down-regulating Ins pathway |
|
Definition
1) phosphatase deactivation of PIP3 and receptor
2) PKC phosphoryates Ser/Thr on receptor
3) SOCS - facilitate proteosome degradation of receptor and IRS-1 |
|
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Term
| phosphatases that down-regulate ins signal |
|
Definition
- Tyrosine Phosphatase IB -> targets receptor
- PTEN -> targets PIP3 |
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Term
| TIIDM and Metabolic Syndrome |
|
Definition
Met Syndrome is precursor to TIIDM
Met Syndrome includes:
- obesity
- ins resistance
- hyperglycemia
- dislipidemia |
|
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Term
| what do muscle cells do with xs TAG |
|
Definition
- muscle uses fatty acids for fuel
- if too much FA, β-oxidation can't keep up
- FA accumulates in mito ->
spills to cyto ->
reincorporate into TAG ->
cytoplasmic DAG and ceramide increase ->
DAG activates PKC ->
PKC phosphohrylates Ser/Thr residues of IRS and Ins Receptor
and
Ceramide inhibits PDK and Akt so can't place GLUT 4
= Ins insensitivity |
|
|
Term
| how does pancreas secrete insulin |
|
Definition
- pancreas displays GSIS/Glucose-Stimulated Insulin Secretion
- β-cells: ER processes proinuslin to insulin
- Ins stored in secretory vesicles
- GLUT2 (high Km) in β-cells takes up glucose
- glucose used for ox-phos -> increased ATP
- high energy charge -> Ca++ uptake
- Ca++ uptake -> insulin release |
|
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Term
| how does muscle ins resistance lead to pancreatic failure |
|
Definition
- muscles fail to take up glucose
- sustained high glucose levels in blood
- GLUT2 keeps taking up glucose
- Energy charge stays high
- β cells try to keep up with false demand for higher insulin
- ER STRESS: misfolded proteins accumulate
- UPR: Unfolded Protein Response pathway activated (stop protein synthesis except for chaperones)
- proteosomes degrade misfolded proteins
- Apoptosis is stress continues
- loss of β-cell population |
|
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Term
|
Definition
- diet and exercise
- if pancreatic failure: ins injections
- metformin/glucophage: activate AMPK and
AMPK promotes catabolic processes (like leptin) |
|
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Term
|
Definition
- high glucagon:ins ratio = fasting mode
- liver remains in gluconeogenic and ketogenic states |
|
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Term
| TIDM and the gluconeogenic liver |
|
Definition
high glucagon:ins = xs glucose release
1) decrease in Fructose 2,6-bispohsphate (low F2,6BP promotes Fructose 1,6-bisphosphatase) ->
glycolysis inhibited and gluconeogenesis stimulated
2) promotes glycogen breakdown |
|
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Term
| TIDM and the ketogenic liver |
|
Definition
- bodies response to lack of glucose for fuel = uncontrolled FA and protein breakdown
- β-oxidation converts it to acetyl CoA
- loss of OAA (from glucose) stalls acetyl CoA entry into the CAC
- xs acetyl CoA accumulates as ketone bodies
- lowered pH, dehydration, coma |
|
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Term
|
Definition
- too much sugar in blood for renal tubules to reabsorb it all
- water follows sugar into the tubules
- xs thirst and hunger |
|
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Term
| what triggers mitochondrial biogenesis |
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Definition
|
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Term
| biochemical effect of exercise |
|
Definition
- muscle signaled to contract
- ca++ released
- Ca++ = second messenger -> activates CaM kinases and AMPK
- CaM Kinases and AMPk -> transcription factors activated:
1) more enzymes for β-oxdation of FA's
2) more mitochondria generated
= better able to metabolize FA's ->
stop accumulation of FA's from leading to PKC activation and Ins Recetpr/IRS dysfunction |
|
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Term
|
Definition
sprinting:
- mostly ATP and then Creatine Phosphate
- followed by muscle glycogen for anaerobic glycolysis
- elevated lactic acid -> acidosis |
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Term
|
Definition
distance running
- run through ATP/Crt Phosphate fast
- muscle glycogen used for ox phos (slower than anaerobic glycolysis hence slower pace than sprinting)
- liver glycogen breakdown and adipocyte TAG breakdown work together |
|
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Term
| For marathon runners, why are equal amounts of glycogen and FA consumed instead of all glycogen, then the FA's? |
|
Definition
glycogen breakdown is controlled to keep blood glucose low:
maintains a high glucagon:ins ratio ->
promotes TAG mobilization and FA release ->
muscles use β-oxidation to breakdown FA to acetyl CoA ->
high acetyl CoA inhibits PDH Complex and spares glucose |
|
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Term
|
Definition
| - supercompensation: after glycogen depletion, body will respond to a carb-heavy meal by over-storing glycogen |
|
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Term
|
Definition
nightly cycle with 3 stages:
1) well-fed/post-dinner state
2) early fast during night
3) refed state after brreakfast
- blood glucose maintained all-the-while |
|
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Term
|
Definition
- first state of starved-fed cycle
- high ins:glucagon = fed state
- stimulates anabolic activity: fuel storage, protein synthesis
liver: increased glycogen synthesis, inhibit gluconeogenesis/accelerate glycolysis
muscle: increased glycogen synthesis, protein synthesis (V,I,L uptake)
adipose: increased TAG synthesis (via glycerol 3-phosphate synthesis) |
|
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Term
| why does insulin accelerate glycolysis and inhibit gluconeogenesis |
|
Definition
- glycolysis leads to acetyl CoA production
- Acetyal CoA allows for anabolic FA synthesis = stored fuel |
|
|
Term
| how does liver trap excess glucose |
|
Definition
- GLUT 2 (high Km) responds to xs glucose by taking up glucose
- only liver has GLUCOKINASE ->
glucose 6-phosphate build up ->
glycogen buildup |
|
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Term
|
Definition
- high Km isozyme of hexokinase
- NOT inhibited by Glucose 6-phosphate like other hexokinases |
|
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Term
| affect of glucose on liver |
|
Definition
| - glycogen buildup via GLUT2/glucokinase, and acts on phosphorylase a (glucose sensor) by promoting its sensitivity to protein phosphatase 1/PP1 |
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Term
| Postabsorptive State/Early Fasting |
|
Definition
- drop in blood-glucose
- rising glucagon:ins ratio
Liver: main target
- inhibit glycogen synthesis and promote breakdown via phosphorylase kinase (stimulate phosphorylase, inhibit synthase)
- promote gluconeogenesis via lower Fructose 2,6-BP
- when glycogen exhausted, use lactate,alanine,and glycerol to replenish glucose
- use FA as fuel
Muslce:
- uses FA as fuel
Adipocytes:
- inhibit FA synthesis (less pyruvate and inhibit acetyl CoA carboxylase)
- lipolysis of TAG |
|
|
Term
| mechanism for glucagon's effect on glycogen metabolism |
|
Definition
cAMP pathway ->
acivate protein kinases ->
increased phosphorylase a activity/decreased glycogen synthase a activity
*lowered blood glucose enhances the affects of glucose by destabilizing phosphorylase a |
|
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Term
|
Definition
tissues take up TAG
LIVER:
- leaves glucose for other tissues
- CONTINUES with gluconeogenesis with glucose going to replenish liver glycogen
- when glycogen is replenishes, uses xs glucose for FA synthesis |
|
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Term
|
Definition
| supply glucose to brain and RBC's |
|
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Term
|
Definition
| due to lack of protein storage, must preserve remaining protein to protect muscle mass |
|
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Term
| Fasting: adaptation to lack of glucose as fuel |
|
Definition
| - fuel shifts to fatty acids and ketone bodies |
|
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Term
|
Definition
- mostly liver gluconeogenesis and adipose mobilization of TAG
- liver and muscle use FA for fuel
- accumulated pyruvate, lactate, alanine, and glycerol go to liver to replenish glucose |
|
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Term
|
Definition
- OAA supply runs down so ketone bodies accumulate
- brain and heart increasingly switch ketones for fuel |
|
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Term
| Several weeks of starvation |
|
Definition
- use ketone for fuel and very low reliance on glucose at this point
- muscle degradation has been limited
- survival proportional to remaining TAG supply |
|
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Term
| No more TAG stores during starvation |
|
Definition
| - protein degradation leads to death |
|
|
Term
| major problem with xs ethanol |
|
Definition
NADH accumulates:
- can't run gluconeogenesis (can't convert lactate back to pyruvate) and can't run CAC without NAD+
- lactic acid -> lactic acidosis |
|
|
Term
| how is ehthanol as a waste product managed |
|
Definition
- cannot be excreted
- converted to acetate |
|
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Term
| conversion of ethanol to acetate |
|
Definition
Alcohol Dehydrogenase:
EtOH + NAD+ -> Acetaldehyde + NADH + H+
Acetaldehyde Dehydrogenase:
Adetaldehyde + NAD+ -> Acetate + NADH + H+ |
|
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Term
| consequences of high NADH on liver |
|
Definition
- high NADH promotes fatty acid synthesis
- TAG accumulate in liver
- fatty liver |
|
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Term
|
Definition
- pathway for ethanol metabolism involving cytochrome P450
- Microsomal Ethanol-Oxidizing System
- reduces NADPH while oxidizing ethanol to acetate
- generates free radicals |
|
|
Term
| what happens to excess acetate in high ethanol diet |
|
Definition
- can't run CAC due to limited NAD+
- ketone bodies for -> ketoacidosis
- acetaldehyde builds up -> reactive species causes liver damage/cell death |
|
|
Term
| First stage of liver damage |
|
Definition
|
|
Term
| second stage of liver damage |
|
Definition
| - alcoholic hepatitis: groups of cells inflame and die |
|
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Term
| third stage of liver damage |
|
Definition
| - cirrhosis: scarring inhibits function -> can't convert ammonia to urea -> ammonia buildup is toxic |
|
|
Term
| ethanol consumption and vitamin metabolism |
|
Definition
Vit A:
- can't be activated to retinoic acid
- improper growth development
- fetal alcohol syndrome
Vit C:
- needed for stable collagen: hydroxy-proline cannot be syntehsized
- causes scurvy: skin lesions/vessel fragility |
|
|
Term
| Wernicke-Korsakoff syndrom |
|
Definition
- consequences of malnutrition related to xs ethanol consumption
- lack of thiamine
- like beriberi (neurological)
- can't run pyruvate dehydrogenase without thiamine pyrophosphate |
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