6Obesity - Obesity and Diabetes (Part 4) Flashcards
How do we sense signals from adipose tissues?
We sense signals from adipose tissue:
Adipose tissues release small amounts of FFAs and inflammatory cytokines = this is normal and required for tissue homeostasis
However, in obesity the adipose tissue mass expands but the lean body mass (the mass of the other organs) does not = concomitant increase in the levels of the FFAs and inflammatory cytokines = amount release is far greater than is needed in the liver, pancreas and muscle tissues.
What happens as adipose tissue mass increases?
When adipose tissue mass increases, you get hypoxia and cell death of adipocytes = leading to an increase in pro-inflammatory cytokines
Macrophages are also recruited which also release pro-inflammatory cytokines
In obesity, not only does the release of pro-inflammatory cytokines increase but the release of anti-inflammatory insulin-sensitised markers decreases.
What is tumour necrosis factor alpha?
Pro-inflammatory cytokine made in adipocytes
Expressed as 26kDa precursor (sits in extracellular matrix) and cleaved to 17kDa
Two main membrane receptors: TNFR 1 and TNFR 2
Most biological effects appear to be mediated by TNFR 1
Increased expression and circulating levels in obesity
Causes insulin resistance
What adipokines are involved in obesity induced diabetes and what is their overall effect?
TNF-alpha and Interleukin-6 are bad
Adiponectin is good
TNF-alpha and Interleukin-6 levels increase in obesity and adiponectin levels decrease
What evidence is there for TNF-alpha promoting insulin resistance?
TNF-alpha concentrations increase in obesity and impaired oral glucose tolerance test (OGTT)
Causes increased FFA concentrations and triglycerides when administered acutely
Infusion of TNF-alpha neutralising antibody into Fa/Fa rats caused a 2-fold increase in insulin mediated glucose disposal
BUT TNF-alpha knockout mice when crossed with diabetic or obese strains do not always show improved insulin signalling = no single gene, no single process that you can target to as pathways are integrated
What are the effects of TNF-alpha?
Increase in fatty acid concentrations
Increase hepatic triglyceride production
Downregulate GLUT4 = decreases insulin mediated glucose metabolism
Inhibit insulin receptor autophosphorylation and IRS-1 tyrosyl phosphorylation
Increase IRS-1 serine/threonine phosphorylation
Inhibit PPAR-gamma synthesis and/or function and impair adipocyte function via NFκB activation = ectopic accumulation of fatty acids
How does TNF-alpha signalling work?
TNF-alpha binds to TNFR1 receptor. TNFR1 via MADD activates p44/p42 MAP kinase/ERK
TNFR1 via TRADD and TRAF-2 activates JNK/SAPK
Both MAPK/ERK and JNK/SAPK can lead to insulin resistance
TNFR1 can alse activate P38 MAPK via TRADD, TRAF-2 and NIK. p38 MAPK can phosphorylate IKK which can lead to insulin resistance
TNFR1 can also activate pathways which lead to the production of ceramide:
Neutral SMase = TNFR1 activates Neutral SMase via FAN. Neutral SMase can lead to ceramide formation
Acidic SMase = TNFR1 activates Acidic SMase via FADD. Acidic SMase can lead to ceramide formation
What effect does TNF-alpha have on IRS-1?
TNF-ALPHA CAUSES ALTERNATE PHOSPHORYLATION OF IRS
TNF-alpha can activate JNK leading to phosphorylation of Ser307
TNF-alpha can cause mTOR to phosphorylate Ser612 and Ser 632 = this inhibits PI3 kinase binding and inhibits the ability to phosphorylate tyrosine 608 and 628 = leading to an overall reduction in the interaction of IRS1 with PI3 kinase
How does TNF-alpha effect insulin-mediated glucose uptake?
FFA and TNF-alpha cause serine and threonine phosphorylation which reduces insulin-mediated Tyr phosphorylation
What is interleukin-6?
IL-6 is found in high concentrations in people with obesity
IL-6 leads to JAK/STAT signalling
Leading to SOCS3 (Silencer of Cytokine Signalling) activation
How does SOCS3 inhibit insulin signalling?
SOCS3 displays binding affinity for phosphorylated tyrosine residues on the insulin receptor (IR) = this prevents IRS-1 from associating with the insulin receptor = decrease in insulin signalling cascase SOCS3 can also associate with the phosphorylated tyrosines on IRS-1 = it then recruits Elongin, Cul-5 (a class of ubiquitin ligase) E1 and E2 ligases associate with Cul-5 (acting as an E3 ligase) and causes the polyubiquitination of IRS-1 = leading to it being degraded by the proteasome
What is adiponectin?
Anti-inflammatory action = blocks TNF-alpha activation of NFκB by blocking IκB phosphorylation
Reduces hepatic glucose and triglyceride output
Increases muscle and liver fatty acid oxidation reducing insulin resistance
What can adiponectin activate in the liver and skeletal muscle?
ADIPONECTIN CAN ACTIVATE AMPK AND PPARα IN THE LIVER AND SKELETAL MUSCLE
When adiponectin binds to AdipoR1 it activates AMPK
When adiponectin binds to AdipoR2 it activates PPARα
AMPK stimulates beta-oxidation of fatty acids
PPARα is anti-inflammatory and causes an upregulation of enzymes involved in beta-oxidation
Both of these things lead to decreased triglyceride content and increased insulin sensitivity.
Metformin upregulates AMPK
What did the diabetes prevention program show?
Diet and exercise target was more than 7% weight loss and more than 150 min exercise per week (moderate intensity e.g. brisk walking)
