Endocrine Signalling From Adipose Tissue (5/6) Flashcards
What is the Randle Hypothesis?
Mechanism of inhibition of glucose utilization by fatty acid oxidation
How does endocrine signalling from adipose tissue change in obesity?
The release of FFA and pro-inflammatory cytokines is increased due to the increased size in adipose tissue
This causes an influx to other organs and fat accumulation there
Increased glucose output from the liver
Decreased glucose uptake by muscles
How does fatty acid oxidation inhibit glucose utilisation?
Acetyl-CoA is produced from fatty acid oxidation and glycolysis
It is converted into citrate which moves into the cytoplasm
Citrate can be converted back into acetyl-CoA and then malonyl-CoA
However, it can also inhibit GLUT4 (glucose uptake) and PFK-1 (glycolysis enzyme)
What does an overload of glucose and/or fatty acids cause?
Excess energy production
Overproduction of acetyl-CoA
This inhibits glucose uptake and causes an increased uptake of fat in muscles
How is the action of malonyl-CoA implicated in obesity?
In healthy tissue malonyl-CoA inhibits CPT1
In obesity, too much fat is entering the cells - overwhelms malonyl-CoA
What causes muscle insulin resitance?
Genes
Aging
Obesity
What does muscle insulin resistance lead to?
β-cell compensation (hyperinsulinemia), then decompensation (some die)
Increased lipolysis in visceral fat (FA increase)
Increased gluconeogenesis in the liver (glucose output increase)
Together, these lead to impaired glucose tolerance -> decreased insulin secretion -> diabetes
What does insulin binding to its receptor cause?
Insulin interacts with the α-subunits of its receptor
This increases the autophosphorylation and the tyrosine kinase activity of the β-subunits
It phosphorylates docking proteins:
-SHC
-IRS1
-APS (PH and SH2 domains)
What does the phosphorylation of docking protein SHC activate in insulin signalling?
Recruitment of the Grb2–SOS
MAPK pathway activated
Ras -> Raf -> MEK -> MAPK -> cell growth/ gene expression regulation
What does the phosphorylation of docking protein IRS1 activate in insulin signalling?
Association between PI3-kinase (PI3K) and IRS-1 increases the amount of PI3P
This activates PDK1 and its effectors: the Ser/Thr kinases PKB and atypical PKCζ
These kinases are involved in the stimulation of glucose uptake
PKB is also involved in insulin-induced glycogen synthesis- phosphorylatesm(inactivates) glycogen synthase kinase-3
What does the phosphorylation of docking protein APS activate in insulin signalling?
APS and the CAP–Cbl complex interact, allowing the tyrosine phosphorylation of Cbl by the insulin receptor
This mediates glucose transport by a pathway dependent on the activation of the small GTPase TC10
How does fatty acid accumulation affect insulin receptor substrate 1 (IRS1)?
Increased FFAs activate JNK and PKCθ
JNK phosphorylates Ser 307 (also activated by insulin but increased with FFA presence)
PKCθ alternatively phosphorylates at Ser612 and Ser632 (insulin phosphorylates Tyr608 and Tyr628) - less affinity for PI3K if alternatively phosphorylated- more insulin needed for same signal
What is ceramide produced in response to?
Stress stimuli including in obesity (e.g., chemotherapy, inflammatory agonists, saturated fatty acids)
How is ceramide synthesised?
By a de novo biosynthesis from precursor palmitate
Through the activation of inflammatory pathways triggered by TLR4 recognition of saturated fatty acids, which induce the upregulation of genes driving ceramide biosynthesis
Through the breakdown of more-complex sphingolipids as part of a “salvage pathway”
Through the disruption of endoplasmic reticulum homeostasis (ER stress)
How is ceramide synthesis regulation implicated in diabetes?
The action of adiponectin at AdipoR1/AdipoR2 receptors activate their ceramidase activity which decreases ceramide production by converting it into sphingosine.
In diabetes, adiponectin levels are decreased.
What does ceramide accumulation lead to?
Impaired cellular function, including insulin action
Ceramide directly activates PKCζ isoform which phosphorylates and inhibits the translocation of Akt/PKB
Stimulates the activity of a cytosolic protein phosphatase 2A (PP2A)- phosphatase that dephosphorylating Akt/PKB
Induce further ER stress and mitochondrial dysfunction
What cells are common in lean adipose tissue?
M2 macrophages
Th2 cells
Tregs
iNKT cells
Eosinophils
What cells are common in obese adipose tissue?
Increased influx of monocytes
Proinflammatory M1 macrophages
Th1 cells
Th17 cells
Neutrophils
B cells
What happens to adipocytes in obesity?
They become overloaded with fat burst -> cell death
What are the 2 types of macrophages?
M1: pro-inflammatory
M2: anti-inflammatory
What changes occur in adipose tissue in obesity?
Lean adipose: type 2 environment - type 2 cytokines: IL-4, IL-5, and IL-13, cell surface molecule interactions
Obesity: type 1 inflammation due to activation of M1 macrophages etc.
Increase of saturated fatty acids, AT hypoxia, danger-associated molecular patterns (DAMPs), and metabolic endotoxemia with increased plasma levels of lipopolysaccharide (LPS)
What is the difference between white and beige adipocytes?
White adipocytes: store fat
Beige adipocytes: generate heat in cold conditions
What happens to the number of white and beige adipocytes in obesity?
Decrease in beige adipocytes due to change in cytokines released
What is dysfunctional adipose remodelling?
When beige adipogenesis is suppressed and insulin resistance is induced
Which receptors detect TNFα?
TNFR1 (mainly) and TNFR2
Which adipokine levels change in obesity?
Decrease in adiponectin
Increase in TNF-α and IL-6
What is TNFα?
Pro-inflammatory cytokine synthesised in adipocytes
26kDa precursor - cleaved to 17kDa
What does TNFα do in obesity?
Promotes insulin resistance
What are the effects of elevated TNFα levels?
Increase FFA levels
Increase hepatic triglyceride production
Downregulate GLUT-4
Inhibit insulin receptor autophosphorylation and IRS-1 tyrosyl phosphorylation
Increase IRS-1 serine/threonine phosphorylation- causes alternate phosphorylation of IRS through activation of mTOR: decreases signal transduction
Inhibit PPARγ synthesis and/or function and impair adipocyte function via NFkB activation
What happens in TNFα signalling?
Sphingomyelinase activation
Increase fats (e.g., ceramide)
What happens in insulin-mediated glucose uptake?
Insulin -> activates insulin receptor (autophosphorylates) -> PI3K -> PDK -> AKT -> GLUT4 translocates to membrane -> glucose uptake
What is the role of IL-6?
Activates pro-inflammatory cytokines
Also activates SOCS: silencer of cytokine signalling
What is the role of SOCS3?
Inhibits insulin signalling:
Binds to phosphorylated JAK and insulin receptor IR
Can also bind to elongin which ubiquitinated IRS1 and 2: degradation
Less insulin signal transduction
What is adiponectin?
Anti-inflammatory action – blocks TNFα activation of NFκB by blocking IκB phosphorylation
Reduces hepatic glucose and triglyceride output
Increases muscle and liver fatty acid oxidation reducing insulin resistance
What is the role of adiponectin in skeletal muscle?
AdipoR1/AdipoR2 -> APPL1/APPL2 -> enhance fatty acid oxidation through MAPK-PPARα-mediated expression and activation of ACOX1 and AMPK-NAD+/NADH-mediated response of ACC
Activated AdipoR1/AdipoR2 also increase mitochondrial biogenesis through APPL1-SERCA-Ca2+-CaMKKβ or LKB1-AMPK-NAD+/NADH-SIRT1-mediated activation of PGC1α
Activation of adiponectin receptors enhances glucose uptake via APPL1-Rab5 or APPL1-AMP-AMPK-mediated translocation of GLUT4 as well as attenuation of Rheb-mTOR-S6K1-induced inhibition of insulin signalling
What is the role of adiponectin and AdipoR1 in the liver?
AdipoR1 activates AMPK via APPL1/LKB1 or APPL1/PLC/Ca2+/CaMKK mediated signalling pathways
Activated AMPK:
Inhibits the activities of PEPCK and G6Pase through the activation of EGR1 and DUSP4, which leads to decreased gluconeogenesis
Also decreases lipid biosynthesis through inhibiting sterol regulatory element-binding transcription factor 1c (SREBP1c)-mediated transcription of acetyl-CoA carboxylase (ACC), FAS and stearoyl-CoA desaturase (SCD)1
Increases abnormality in mitochondrial morphologies and fatty acid oxidation via sequestering the inhibitory effect of ACC-1 on carnitine palmitoyltransferase (CPT)-1 activation
What is the role of adiponectin and AdipoR2 in the liver?
AdipoR2 activates:
Fatty acid oxidation through PPARα-induced activation of acyl-CoA oxidase (ACO) and uncoupling protein (UCP)2
Adiponectin also protects hepatocytes through the inhibition of ROS-mediated activation of proinflammatory molecules including TNF-α and MCP1
How does adiponectin relate to insulin?
Adiponectin increases insulin sensitivity through the activation of AdipoR1/R2 following CDase-mediated degradation of ceramides
