Integration of Metabolism Flashcards
1
Q
learning objectives integration of metabolism
A
- To compare and contrast the regulation of overall human metabolism with respect to carbohydrate, lipid, and protein metabolism and identify key molecules that act as junction points.
- To summarize how different tissues/organs (e.g., liver, adipose tissue, brain, heart, and skeletal muscle) are adapted to their unique metabolic needs.
- To compare and contrast the three systems of ATP generation and describe the temporal utilization of each: phosphagen, glycolysis and aerobic respiration.
- To evaluate the role of hormones in inducing satiety signals.
- To compare and contrast the role of various metabolic systems in fed, fasting, and starvation models, including the effects of hormones (insulin, glucagon, and epinephrine) in these pathways.
- Analyze the concept of energy homeostasis with special focus on AMP kinase (energy sensor)
2
Q
What are the major pathways of metabolism?
A
- Glycolysis
- Citric Acid Cycle
- Oxidative Phosphorylation
- Gluconeogenesis
- Pentose Phosphate Pathway
- Glycogen Metabolism
- Fatty Acid Metabolism
- Amino Acid Metabolism
- Nucleotide Metabolism
3
Q
What are the THREE key molecules that act as metabolic junction points?
A
- Glucose-6-phosphate (can turn into Glucose, Glycogen, Pyruvate, Ribose-5-P)
- Pyruvate (can turn into Acetyl-CoA, Lactate, Alanine, OAA)
- Acetyl-CoA (can turn into CO2, Fatty Acids, Ketone bodies)
4
Q
Tissues/Organs Are Specialized graphic
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5
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Metabolic Interrelations graphic
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6
Q
Whis is the Liver the ‘MVP of Metabolism’?
A
- Liver receives blood from enteric circulation (via portal vein) and from periphery (via hepatic artery).
- Processes most incoming nutrients
- Responds quickly to dietary conditions
- Maintains constant concentrations of nutrients in blood regardless of food intake
- Synthesizes and secretes proteins (plasma proteins, antibodies, acute phase proteins)
- Processes and detoxifies toxins and waste products
- Primarily depends on β-oxidation of fatty acids for its own energy needs.
7
Q
Why is Adipose ‘The Main Assist’?
A
- Synthesizes and stores triacylglycerols (TAGs) as signaled by insulin (fed state)
- Uses fatty acids (from chylomicrons and VLDL) to make TAGs
- Uses glucose from blood to make TAGs
- Degrades TAGs and releases fatty acids and glycerol for other tissues to use as signaled by glucagon/epinephrine (hunger, exercise)
8
Q
What are the two types of adipose tissues?
A
- White adipose and brown adipose tissue
- White fat is accumulated fat from surplus calories
-Subcutaneous, large effect on hormone regulation
•Brown fat has high levels of thermogenin
-Burn calories and generates heat (the “good” fat)
Brown fat: smaller, oily droplets. Contain mitochondria
white fat: Large oily droplets
9
Q
Why is the brain ‘an Energy Consumer?’
A
- High dependence on blood glucose
- Uses 20% of total O2 consumed by resting human (although only 2% of body mass)
- Some glycogen in astrocytes. Breaks down to release glucose which can be used by neurons.
- Lactate released from astrocytes used as well
- During starvation switches to metabolism of ketone bodies for energy needs
- Metabolized by TCA cycle
- Prevents protein breakdown for energy purposes
- Uses amino acids for synthetic purposes – make neurotransmitters and peptide hormones
- Glucose transported into brain by GLUT3 (has a very low Km for glucose, meaning that the glucose is almost always saturated).
- Fatty acids do not serve as a fuel source since they are bound to albumin in the plasma and cannot cross the blood brain barrier
10
Q
Astrocyte - Neuron Lactate Shuttle graphic
A
11
Q
What does metabolism in the heart look like?
A
- Cardiac muscle is exclusively aerobic as evidenced by the density of mitochondria in heart muscle.
- Complete oxidation of glucose via TCA cycle and OxPhos and beta oxidation of fatty acids serve as major fuel.
- Also uses ketone bodies. Heart muscle consumes acetoacetate in preference to glucose.
- Also uses amino acids (particularly branched chain amino acids)
- The heart has virtually no glycogen reserves.
- Lack of O2 leads to tissue death (myocardial infarction)
- Heart muscle functions almost exclusively aerobically
- Heart muscle consumes other TCA derivatives (acetoacetate) in preference to glucose.
12
Q
Why is skeletal muscle ‘The Consumer”?
A
- Rich in glycogen (contains 75% of the body’s glycogen stores).
- Glycogen readily broken down to G-6-P. Used by the muscle for glycolysis.
- Lacks glucose 6-phosphatase, so muscle retains glucose, its preferred fuel for bursts of activity.
- Also uses fatty acids and ketone bodies for energy
13
Q
energy systems graphic
A
14
Q
What are the types of fuel sources by INCREASING speed and DECREASING total energy production?
A
•Phosphagen: regeneration of ATP by phosphocreatine
-Phosphocreatine kinase
- Generation of ATP by glycolysis and glycogenolysis
- Generation of ATP by oxidative phosphorylation, fatty acid metabolism
15
Q
What is the phospagen system?
A
- Short bursts of heavy activity; i.e. sprinting
- Quick exhaustion of ATP stores (within 1-2 sec.)
- Replenished by metabolism of phosphocreatine (within 5-6 sec.)
‒Stored in muscle to quickly regenerate ATP from ADP
16
Q
What is anaerobic glycolysis?
A
- Further intense activity (past the ATP-PC phase), ~30 seconds
- Oxidation of free blood glucose or glycogen (glycogenolysis)
- Next, formation of lactate
- Glycogen —> G-6P —> pyruvate à lactate
- Causes decrease in power and muscle fatigue
- Must shift to a longer, more sustainable energy production system
- In the Cori cycle, the lactate formed flows to the liver, where it is converted into glucose; shifts part of the metabolic burden of muscle to the liver.
17
Q
What is the fate of lactate in the cori cycle?
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- Cori cycle: cooperation between muscle and liver
- Regenerate glucose from lactate
18
Q
What is oxidative phosphorylation?
A
- Metabolic processes result in the reduction of co-enzymes (i.e. formation of NADH and FADH2)
- OXPHOS: Production of energy from the oxidation of NADH and FADH2 (2.5 and 1.5 ATP, respectively)
- Pumping protons out of the mitochondrial matrix
–Builds proton concentration in the intermembrane space
- Produces ATP via ATP synthase
- Previously discussed metabolic processes result in the reduction of co-enzymes
- Oxidative phosphorylation uses these reduced co-enzymes and reduces them to generate large amounts of energy
- Shuffling electrons, hence the phrase electron transport chain
- Production of free protons that are pumped out of the mitochondrial matrix and used to for ATP
19
Q
The fed state graphic
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20
Q
What happens in the liver during the fed state?
A
- Glycolysis
- Glycogen synthesis
- TG synthesis
21
Q
The Fasting State graphic
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22
Q
What happens in the liver during the fasting state?
A
- Glycogenolysis
- Gluconeogenesis
- Fatty Acid Oxidation
- Ketone Body Formation
23
Q
Starvation prolong fasting state graphic
A
24
Q
What happens with insulin during high blood glucose?
A
- Fed state —> high blood glucose —> insulin
- Insulin deficiency or resistance can lead to hyperglycemia, metabolic syndrome, and diabetes
Insulin —> fed —> excess glucose
25
What happens with glucagon during low blood glucose?
Glucagon ---\> hungry ---\> make glucose (i.e. gluconeogenesis)
26
What are the physiological and metabolic effects of epinephrine?
FIGHT OR FLIGHT
## Footnote
Epinephrine ---\> get ready ---\> make glucose
27
What are the TWO satiation signal molecules?
Glucagon like peptide -1 (GLP-1)
Cholecystokinin
28
Describe the appetite suppressors/signals from the GI tract.
* Short-term signals: relay feelings of satiety from gut to various regions of the brain (reduce urge to eat).
* Cholecystokinin (CCK): a family of peptide hormones secreted into the blood by cells in the duodenum and jejunum regions of the small intestine as a postprandial satiation signal.
* CCK binds to its receptor, a GPCR, located in various peripheral neurons, that relay signals to the brain.
* Binding initiates a signal-transduction pathway in the brain that generates a feeling of satiety.
* CCK also helps in digestion, stimulating secretion of pancreatic enzymes and bile salts from gallbladder.
* Another gut signal is the hormone glucagon like peptide 1 (GLP-1).
* Secreted by intestinal L cells, hormone secreting cells present throughout the lining of the GI tract.
* GLP-1 has a variety of effects, mediated via binding to its receptor (a GPCR).
* GLP-1 induces feelings of satiety that inhibit further eating,
* It also potentiates glucose-induced insulin secretion by β cells of pancreas while inhibiting glucagon secretion.
29
What are the effects of GLP-1 Receptor Agonists?
•The effects of GLP-1 only last for a few minutes, but GLP-1 receptor agonists can last for hours or days.
–Increase insulin synthesis and release
–Decrease glucagon release
–Slow emptying of the stomach’s contents into the intestines
–Helps feel full after a meal, eat less
•Examples: Dulaglutide (Trulicity), Semaglutide (Ozempic), and Liraglutide (Victoza)
30
What are the effects of Sodium Glucose Cotransporter 2 (SGLT-2) Inhibitors?
* SGLT 2 inhibitors
* Being used as another class of medications for regulating blood sugar in Type 2 Diabetes
* Associated with weight loss and improved blood sugar control
* Examples: Canagliflozin (Invokana), dapagliflozin (Farxiga) and empagliflozin (Jardiance).
31
Describe the appetite enhancers/signals from the GI tract.
* Ghrelin, a peptide secreted by stomach, acts on regions of the hypothalamus to stimulate appetite through its receptor, a GPCR.
* Ghrelin secretion increases before a meal and decreases afterward.
32
What is the Role of Leptin and Insulin in Regulation of Caloric Homeostasis?
* Two key signal molecules regulate energy homeostasis over the time scale of hours or days.
* Leptin – a hormone secreted by adipocytes (reports on the status of triacylglycerol stores).
* Insulin – secreted by β cells of pancreas (reports on the status of blood glucose, i.e., carbohydrate availability.)
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What is Leptin?
* Adipose tissue, a very active endocrine tissue
* Secretes adipokines (e.g., leptin, adiponectin), which regulate host of physiological processes.
* Leptin secreted by adipose tissue in direct proportion to fat mass
* More fat more leptin
* Leptin receptors present all over body, their signaling:
–Increase sensitivity of muscle and liver to insulin
–Stimulate β oxidation of FAs
–Decrease TAG synthesis
34
What are the effects of Leptin on the brain?
1. Leptin acts through its receptor
- Receptor expressed in several brain regions
- Most importantly in the hypothalamus
2. Regulates body weight
- Inhibiting food intake
- Stimulating energy expenditure
3. Mice lacking leptin are obese but lose weight if given leptin
Leptin Knockout Mice
* Display hyperphagia
* Hyperlipidemia
* Insensitivity to insulin
35
Describe Leptin and Insulin resistance.
- Contribute to obesity
- Very complex, many unknown factors
- Role of a group of proteins called the Suppressors of Cytokine Signaling (SOCS)
- Inhibit receptor action by:
---\>Binding to receptor
---\>Binding to other components of the signaling pathway
---\>Enhancing proteolytic degradation of the receptor
-SOCS knockout mouse – display enhanced sensitivity to leptin, and are resistant to weight gain, even on a high fat diet.
36
Describe Overall Energy Sensor in Cells.
* Cells constantly adapt their metabolism to meet their energy needs and respond to nutrient availability.
* Eukaryotes have evolved a very sophisticated system to sense low cellular ATP levels.
* This is accomplished via the serine/threonine kinase AMP-activated protein kinase (AMPK) complex.
* Under conditions of low energy, AMPK phosphorylates specific enzymes and growth control nodes to increase ATP generation and decrease ATP consumption.
AMP-activated protein kinase (AMPK) is the cellular energy sensor
Metabolic inputs to AMPK determine whether its output (kinase activity) takes place or not
Inactivated by ATP
Activated by AMP
When activated it phosphorylates many key targets controlling cellular energy production and consumption
Activation leads to decrease in anabolic pathways and increase in catabolic pathways.
Activated AMPK reprograms metabolism towards breakdown
The competition between ATP and AMP for binding to AMPK allosteric sites determines its activity
•AMPK exists universally as complexes of three different protein subunits (heterotrimers) comprising a catalytic α subunit that carries the protein kinase activity, and regulatory β and γ subunits.
AMPK activation causes a metabolic switch from anabolism to catabolism
37
Regulation of Energy Homeostasis by AMPK graphic
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What are the Factors that Affect AMPK?
