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.
