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Fed- Fast Cycle

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Fed State

Catabolic Pathways

  • release energy by breaking down complex molecules to simpler compounds

  • convergent: wide variety of molecules are transformed into a few common end products (often CO2, ATP, H2O, NH3)

  • ex- glucose to CO2, H2O and ATP

Involves 3 steps: ​

  1. hydrolysis of complex molecules into building blocks (proteins to AA) (polysaccharides to monosaccharides) 

  2. conversion of building blocks to simpler intermediates (glucose to acetyl CoA)

  3. oxidation of acetyl CoA via TCA producing CO2, H2O, and lots of ATP

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Glycolysis              TCA Cycle                  ETS

               

               Pentose Phosphate Pathway 

           

Beta-Oxidation of FA                 Glycogenolysis 

                                     Lipolysis 

Anabolic Pathways

  • consume energy to build complicated molecules from simpler ones, requiring an input of energy

  • divergent: a few biosynthetic precursors form a wide variety of products

  • ex- amino acids to proteins

  • often need reducing power in the form of NADPH from PPP

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Protein Biosynthesis                  Ketogenesis 

               

                    FA de novo synthesis

 

Gluconeogenesis                   Glycogenesis

How does the cell know to store energy nutrients in between meals?

Hormones and substrate levels increase 

(signals & supply) 

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Insulin: Major Anabolic Hormone

  • Hormone seen in the FED state

  • Beta-cells of the pancreas release insulin as a response to carbohydrate ingestion 

  • promotes ATP production and storage pathways 

1. stimulates glucose uptake in muscle & adipose via GLUT4, helping regulate blood glucose levels

2. stimulates lipoprotein lipase

3. promotes storage of glucose as glycogen and triacylglycerol

4. promotes protein synthesis and cell growth 

Inhibits.......

-gluconeogenesis

-glycogenolysis 

-protein degradation

-lipolysis 

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Role of GLUT 2 in insulin release

1. glucose enters pancreas beta-cells via GLUT 2

2. Glucose + ATP --------} Glucose-6-P  + ADP (trapped in cells) 

3. more glucose to go through oxidation-------} more ATP produced

4. ATP/ADP ratio increases--------} insulin being released 

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Energy Stores

- glycogen: short term (24 hrs)  in liver & muscle   

- triglycerides: long term (2 mo) 

- protein: no storage form, purely functional through enzymes, antibodies, muscle, etc. 

After a meal: 

90 g carb

  • glucokinase traps glucose inside liver cells

  • 15-20g to brain

  • 2g to adipose tissue

  • 20g to liver to store as glycogen

  • 45g to muscle- 25g glycogen & 20g ATP

30 g protein

  • 10 g for protein synthesis

  • 20 g catabolized (no storage form) 

  • 4g (dietary glu, asp, gln) metabolized in intestine

  • 4g BCAA to muscle & kidneys for ATP

  • 12g to liver for CO2, urea & glucose

20 g fat

  • digestion via lipases, co-lipase and bile

  • absorption of short chain FA & chylomicrons

  • immediate fate is deposit in adipose tissue with some going to liver & skeletal muscle

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The Liver's role in Metabolism

-receives most absorbed nutrients via portal vein

-processes nutrients & sends them to other organs/tissues

- "cross organ talk" 

Liver & CHO

  • regulation of blood glucose via uptake and trapping

  • gluconeogenesis

  • glycogenesis

  • pentose phosphate pathway

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Liver & lipids

  • FA de novo synthesis to make TAGs

  • Lipoproteins like VLDL, HDL, chylomicron remnants

  • acetyl CoA in liver can be used to make .....

    • bile from cholesterol​

    • ketone bodies

    • TAGs from FA

​

Liver & amino acids

  • site for protein synthesis

  • transamination

  • deamination and urea synthesis

Metabolism of other sugars

Metabolism of GALACTOSE

Galactose is derived from lactose and an isomer of glucose

readily taken up by the liver (doesn't have glucose structure & hexokinase cant recognize it) 

no direct way to metabolize it

GALACTOSE  glucokinase                     GALACTOSE-1-PHOSPHATE 

Leloir Pathway: need all 4 enzymes to convert galactose to G6P to get to glycolysis

​

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Metabolism of SORBITOL

-polyol/ sugar alcohol

-bulk sweetener found in many food products- naturally occurring in berries

-very stable long shelf life and 60% as sweet as sucrose with 1/3 fewer kcal 

-may be resistant to bacteria- doesn't promote tooth decay

-gives a more blunted rise in glucose/insulin

-not as well absorbed as glucose - causes diarrhea & cramping

-converted to FRUCTOSE by succinate dehydrogenase & sorbitol dehydrogenase
-all monosaccharides metabolized to pyruvate, which increases serum lactate- potential lactic acidosis problem

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Metabolism of FRUCTOSE

-found in fruits, honey, sucrose & high fructose corn syrup, high in manufactured foods

- after absorbed, goes to liver via portal vein via GLUT5 & GLUT2

-fructose metabolism differs from glucose metabolism by...

  • ​fructose doesn't stimulate insulin release like glucose does

  • fructose transported by GLUT5 but most cells have few to no GLUT5

  • glucose transported by abundant GLUT4

  • fructose enters pathways that provide glycerol (backbone of TAG) in liver, thus favoring lipogenesis

  • goes through glycolysis faster than glucose

  • bypasses rate-limiting phosphofructokinase step- don't get the cue to stop eating​​

Fructokinase: found in liver/kidney/intestine​

not under hormonal (insulin control) like glucokinase 

FRUCTOSE    fructokinase          FRUCTOSE-1-PHOSPHATE

​

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sucrose= 1:1 ratio of glucose: fructose

ratio in fruit is even so glucose metabolism is favored

manufactured foods have skewed ratio that favors fructose and fat synthesis

the muscle only has hexokinase, so it phosphorylates fructose to F6P directly for glycolysis 

​

More on the fed state: What if you overeat sucrose? 

  • get glucose- insulin increases, body senses fed state making ATP for energy requirements, glycogen & fat synthesis proceed normally

  • get fructose- no insulin needed, easily taken up & phosphorylated by liver getting a lot of substrate for FA synthesis, more substrate for fat synthesis which has already been stimulated by glucose

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Fasting State

Fed state   

Early fasting state

Fasting state

Starvation state

~ 3hr after a meal

>3 hr after a meal to 12~18 hr

18 hr to 2 days after a meal

~ several weeks

After fed state, insulin level decreases ( but never disappears) 

Counter-regulatory effects by other hormones...

  • glucagon

  • epinephrine

  • norepinephrine                       all synergistic

  • glucocorticoids                      & work together  

Breakdown of stores and proteins as fuel pathways (catabolic state) ​

  • glycogen from liver & muscle limited to 72 hrs

  • fat 

  • protein for functions

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Hormones

  • travel to all tissues but only act on receptive tissues

  • diff hormones can have the same/similar effect

  • steroid: glucocorticoids

  • peptide: insulin, glucagon, growth hormone, GI 

  • AA derivatives: catecholamines like norepi & epinephrine 

General role of hormones​

  1. induce changes in the membrane very fast (seconds)

  2. regulate catalytic activity of enzymes fast (minutes)

  3. change the rate of new enzyme synthesis by altering gene expression slowly (hours)

  4. change the rate of cell growth very slowly (days) 

​

​

peptide & AA derivative hormones -don't enter cell

-act at the cell membrane

-change catalytic activity of existing enzymes

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Hormone                   Source                          Target

glucagon                pancreas                             liver

epinephrine           adrenal medulla               liver & muscle

nor-epi                symp. nerve endings           muscle & adipose

Mobile Receptor Model

-Hormone tends to be lipid in nature so can cross through cell membrane (e.g., steroid)

-Receptor is in either the cytoplasm or the nucleus

-The hormone and the receptor bind and travel to the nucleus (or in the nucleus) and bind to the DNA

-Increase or decrease transcription of a specific gene

-Affect enzyme activities by ­inc/dec protein level

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Fixed Receptor Model

-Hormone doesn’t get into cell (non-lipid—can’t cross membrane)

-Attaches to the membrane on the outside via a receptor and changes activities inside cell

-Acts through a series of phosphorylation reactions catalyzed by a class of enzymes called protein kinases (Signal transduction)

 

Hormone = 1st messenger

-Hormone binding its receptor activates adenylate cyclase

-Adenylate cyclase catalyzes formation of cyclic AMP (cAMP)

cAMP = 2nd messenger

-Stimulates a sequence of reactions that activates enzymes by activating Protein kinase

-There can be a whole sequence of protein kinases activated sequentially by each other (Can be many steps)

-Sequence continues until key enzymes are phosphorylated

-Sequence is a cascade of reactions

Fixed receptor model example- glycogenolysis

  • several phosphorylations ending with activation of glycogen phosphorylase

  • at the same time, glycogen synthase is phosphorylated but inactivated

  • insulin in the fed state turns on/activates glycogen synthase

  • glucagon & epinephrine activate cAMP which activates protein kinase that activates glycogen phosphorylase-P and inactivates glycogen synthase-P

Early Fasting State

  • glycogenolysis

    • liver: the major provider of glucose to blood​

    • muscle: only serves its own need

  • gluconeogenesis​

    • also contributes to blood glucose via the cori cycle (lactate to glucose) and glu-ala cycle (ala to glu) ​

  • synthesis of de novo FA & glycogen diminished​

    • low insulin level​

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Glucose- Alanine Cycle

-alanine undergoes transamination to produce glutamate

-deamination: alpha-KG + ammonia

-transamination with OAA yields alpha-KG + Asp

-Glutamate & Asp both contribute to urea cycle

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NH3

alpha-KG

UREA CYCLE

Fasting State

  • glycogen depleted

  • gluconeogenesis becomes more important

    • glucagon & glucocorticoids​

    • AA from muscle protein (major source)

    • glycerol from lipolysis

    • lactate from anaerobic glycolysis

  • ketogenesis (only in liver)​

    • brain, heart & skeletal muscle slowly start to adapt​

Starvation State

  • protein sparing shift from gluconeogenesis to lipolysis

    • tap into deep storage (TAG) 

    • TAG-> FA-> Beta-Ox-> Acetyl CoA-> ketones

    • glycerol-> gluconeogenesis​

  • more ketone bodies synthesized ​

    • more acetyl CoA than TCA can process​

    • brain, heart & skeletal muscle demand less glucose

  • spares proteins​

    • when brain & muscle adapt to ketone bodies they need less glucose, therefore less proteins are broken down to provide precursors for gluconeogenesis​

    • theoretically we can last a long time, but ketoacdosis may kill us before we run out of energy

Lipolysis

  • stress requires energy

  • decreased blood glucose is stress

  • target tissue is the adipose cell  

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©2023 by Syracuse University Dr.Margaret Voss

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