Glucagon secretion and signalling Flashcards
How are alpha cells activated? What do they secrete and stimulate?
Describe glucose distribution in the body in the fasting state.
During fasting, low blood glucose levels activate alpha cells, causing them to secrete glucagon granules (fusion with plasma membrane).
Glucagon stimulates glucose mobilization through gluconeogenesis and fatty acid oxidation.
In the fasting state, dropping blood glucose levels will stimulate glucagon secretion by alpha cells.
Glucagon will affect metabolism in WAT, the liver and muscle tissue to increase glucose blood levels (through gluconeogenesis and glycogenolysis) and supply glucose to exercising muscle, RBCs, and the brain.
What are the systemic effects of glucagon?
Glucagon will act on multiple tissues:
1. Glucagon will act on white adipose tissue, increasing lipolysis to yield FA (beta oxidation in the liver for ATP) and glycerol (gluconeogenesis) and decreasing lipid/TG biosynthesis to avoid FA storage.
- Glucagon acts on muscle, increasing glycogenolysis, glycolysis (of glucose coming from glycogen) and protein degradation (glucogenic AA used for gluconeogenesis).
-Increased lactate production feeds into gluconeogenesis. - Glucagon acts on the liver
-Increases glycogenolysis, gluconeogenesis, ketogenesis (fuel brain) and beta oxidation (ATP).
-Decreases glycogenesis, glycolysis and lipogenesis.
How does signaling to glucagon-sensitive tissues occur?
Describe GPCR protein signaling (goal, overall function and deactivation of the pathway)
How would interference from caffeine affect glucagon signaling and overall muscular performance?
Glucagon signalling occurs through GPCR: family of signaling proteins. Contain extracellular ligand-binding domain and intracellular G protein.
Goal: Transmission of info from one side of the membrane to the other rapidly (by massively amplifying the signal).
Function:
1. Ligand (glucagon) binds to GPCR, causing conformational change of the G protein and activating adenylate cyclase and amplifying the signal.
- Adenylate cyclase activate cAMP (second messenger), further amplifying the signal.
- cAMP acts through kinase (PKA) to modulate different proteins necessary for response to fasting or fight-or-flight response (4 cAMP needed for 1 PKA, to activate catalytic subunits, all-or-nothing enzymatic response).
Deactivation: Phosphodiesterase inactivates cAMP by converting it to AMP
Interference possible from caffeine (meaning cAMP is elevated for slightly longer, meaning longer signalling of glucagon, longer glycolysis, etc)..
Longer glycolysis, means for more ATP production, and more muscular performance
Describe G protein subunits, activiation and deactivation
intracellular G protein has 3 subunits.
-Gamma subunit:
-Beta subunit:
-Alpha subunit:
Activation of G protein:
Alpha subunit is in GDP-bound state (off state)
Upon ligand binding,
GEF (Guanine nucleotide exchange factor) exchanges bound GDP for GTP.
Alpha subunit is in GTP-bound state (on state)
Inducing separation of gamma and beta subunits, rendering the G protein active
Inactivation of G protein:
GAP (GTPase Activating protein) dephoshorylates GTP bound to alpha subunit, returning the alpha subunit to GDP-bound state, rendering the G protein inactive.
What is the glucagon-mediated pathway for glycogenolysis from glucagon to glucose? In liver V.S. muscle?
What does the debranching enzyme do?
During the ___ state, glycogen phosphorylase is phosphorylated by ___ rendering it ____ for ____and during the ____ state, its dephosphorylated by _____ rendering it _____.
Glucagon -> GPCR signaling -> PKA phosphorylates Glycogen phosphorylase (active) -> yields G1P from glycogen non-reducing ends
-GP removes glucose units from the non-reducing end og glycogen.
In liver:
G1P -> G6P -> Glucose (by glucose-6-phosphatase NO glycolysis because fasting state)
In msc:
G1P -> G6P -> Pyruvate (through glycolysis, no glucose-6-phosphatase),
Debranching enzyme: when glycogen phosphorylase arrives at branching point of glycogen, debranching enzyme moves branch point to non reducing end of glycogen main chain, so that glycogen phosphorylase can continue.
-moves polymers with a-1,6-glycosidic bonds to the main chain.
During the fasting state, glycogen phosphorylase is phosphorylated by PKA (glucagon-mediated) rendering it active for glycogenolysis and during the fed state, its dephosphorylated by PP1 (insulin-mediated) rendering it inactive.
Draw reciprocal regulation of glycogen metabolism (insulin V.S. glucagon effects)
slide 67
What effect does glucagon have on gluconeogenesis and glycolysis in the liver?
Why does glucagon inhibit glycolysis in the liver?
Is glycolysis activated in other key tissues?
Identify where glycerol and glucogenic AA from lipid and protein degradation come into gluconeogenesis for support?
Glucagon will
Stimulate gluconeogenesis:
-activates PEP carboxykinase* (PEPCK)
-activates pyruvate carboxylase* (PC) through acetylCoA (from high FA oxidation rates)
-activates FBPase 1 through citrate (from high FA oxidation rates)
*PEP carboxykinase and Pyruvate Carboxylase Overcomes irreversible reaction of pyruvate kinase in glycolysis.
Inhibit glycolysis: irreversible steps are inhibited.
-inhibits hexokinase/glucokinase directly
-inhibits PFK1 through high citrate concentrations (related to high FA oxidation rates)
-inhibits pyruvate kinase directly
Glucagon inhibits glycolysis in the liver, to ensure that it insteads distributes glucose in the bloodstream for other bodly tissues instead of consuming it.
Yes, depending on the tissue.
In muscle tissue, glycolysis is increased by glucagon to generate ATP quickly.
In the brain too
Glycerol enter into gluconeogenesis as glyceraldehyde-3-phosphate (G3P)
Glucogenic AA enter into gluconeogenesis through pyruvate, oxaloacetate, a-ketoglutarate, succinylCoA and fumarate.
Describe how gluconeogenesis is an inter-organ pathway during vigourous exercises and fasting.
During vigourous exercise: CORI CYCLE
glucagon signalizes simultaneously to all these tissues.
-In muscle: glucose -> lactate through glycolysis
-In bloodstream: lactate goes to the liver
-In liver: lactate -> glucose through gluconeogenesis
-In bloodstream: glucose goes to the muscle.
During fasting:
-In muscle: protein degradation yields glucogenic AA
-In bloodstream: AA (ex: alanine) go to the liver
-In liver: AA -> glucose through gluconeognesis
-in adipose tissue: lipolysis yields glycerol + FA from TG
-in bloodstream: glycerol goes to liver
-in liver: glycerol -> glucose through gluconeogenesis
What is the effect of reciprocal regulation by glucagon on the bifunction enzyme PFK2/FBPase-2?
Glucagon is an allosteric activator of FBPase-2, which catalyzes F26BP -> F6P
Absence of F26BP, means that FBPase-1 stops being actively allosterically inhibited by F26BP.
FBPase-1 catalyzes F16BP -> F6P, going in the direction of gluconeogenesis.
Alternatively, absence of FBPase-2 hinders PFK1’s catalytic activity, because it isn’t present to allosterically activate it anymore.
PFK1 catalyzes F6P -> F16BP, going in the direction of glycolysis.
Describe the metabolic pathway for fat mobilization during starvation.
What is the effect of glucagon on ACC?
In adipocytes:
Glucagon, through GPCR and PKA, signals for increase hormone sensitive lipase, which de-esterifies glycerol backbone of TG ito yield FA and glycerol.
Fatty acids travel in the bloodstream, bound to albumin (carrier for hydrophobic lipid), to the liver.
In the liver, FA go through beta-oxidation to yield AcetylCoA, which can be metabolized for ATP.
Glycerol can enter gluconeogenesis.
Glucagon is an allosteric inhibitor of AcetylCoA carboxylase, which catalyzes AcetylCoA -> MalonylCoA (lipogenesis).
-PKA phosphorylates ACC, turning it off fully.
What is hepatic zonation?
Describe liver physiology.
How nutrient availability between the portal vessels and central vein alter the differing hepatocytes’ metabolic ability?
Hepatic zonation: describes the fact that not all hepatocytes are the same, they are very heterogeneous cells and differ greatly
In the liver, there are liver lobules, that contain portal vessels (coming from the portal vein) on the outside of the lobule as well as a central vein, to which the portal vessels feed into.
From the exterior to the interior of the liver lobule, there are different classes of hepatocytes with different metabolic specializations, ranging from periportal cells, to mid-lobular cells to pericentral cells.
Blood coming from portal vessels is rich in oxygen and nutrients, meaning periportal cells will specialize in metabolic pathways that reflect that, such as:
-gluconeogenesis: high nutrients = high glycolysis in msc producing lactate*
-beta-oxidation*
Blood nearing the central vein is lower in nutrients and oxygen, meaning pericentral cells will specialize in metabolic pathways that reflect that, such as: **link with insulin
-glycolysis: hypoxia will cause accumulation of HIF-1a, leading to gene transcription for glycolysis. Additionally low glucose = insulin secretion = activation of glycolysis.
-lipogenesis: metabolites of glycolysis will reinforce glycolysis and also initate ChREBP to activate gene transcription alongside SREBP to increase lipogenesis. Insulin also activates SREBP.
How does nutrient availability and hepatocyte specialization alter risk of metabolic injury?
Hepatocytes that are very oxidative (periportal cells)
Hepatocytes engaged in glycolysis and lipogenesis are more vulnerable to oxidative stress.
When the body is in a hypoxic state, pericentral cells are the first to experience oxygen deficiency due to the oxygen gradient in liver lobules. They are already in operating in an oxygen deficient environment, so less oxygen exposes them to oxidative stress.
**Mitochondria is inhibited by HIF-1a in response to hypoxia.
Less oxidative phosphorylation, means for less utilization oxygen, which becomes ROS superoxide (O2-)
In the context of a high fat diet, fat can accumulate in the liver, and oxidative stress in combination with fat accumulation can lead to development of NAFLD in pericentral cells first due to their positioning in relation to the nutrient/oxygen gradient.
