13. Obesity (3) - adipokines Flashcards
Leptin definition
protein secreted by adipose tissue (adipokine)
- signals brain to maintain energy balance
increase leptin
- > decrease food intake (CNS)
- > increase energy expenditure (peripheral tissue)
Leptin treatment in lipodystrophy (little to no fat stores)
leptin low because not enough adipose to make it
- insulin resistant because no signal to stop eating
leptin infusion (3 months)
- recovered insulin sensitivity
- mechanism -> caloric intake decreased by 50%
- CNS -> tells them to stop eating
how leptin improves insulin sensitivity through “peripheral mechanism”
leptin affects insulin signalling pathway
increase
- IRS 1 protein content
- insulin stimulated PI 3-kinase pathway activity
- akt phosphorylation
- membrane and total GLUT4
leptin and FA oxidation
increases FA oxidation in skeletal muscle
- AMPK activation
problem with leptin in obese state
increase amounts in blood due to mroe adipose tissue but…
Leptin Resistance
- stimulatory effect of leptin lost in muscle (peripheral)
- and regulation of energy balance (CNS)
- analogous to insulin resistance
*paradox
How is leptin resistance reversed
exercise
- recovers leptin stimulated fat oxidation in skeletal muscle
- even while maintaining high fat diet that lead to the obesity
side note
- also recovers insulin-stimulated glucose uptake
adiponectin relationship to body fat
inverse relationship
- hormone like protein derived from adipose tissue
- as adipose tissue accumulates, inhibits the release of adiponectin
what does adiponectin do?
decrease inflammation
increase insulin sensitivity
increase fatty acid oxidation
2 circulating forms of adiponectin
- concentration
- whats the receptor
- where does it act
globular head (1%)
- binds AdipoR1
- primarily found in muscle
full-length (99%)
- binds AdipoR2
- primarily found in liver
Adiponectin in obesity
adiponectin resistance and reduced levels
- blunted activation of AMPKalpha2 (subunit of AMPK) from adiponectin
- therefore decreased FA oxidation
adiponectin relation to insulin sensitivity with high fat diet
Adiponectin resistance develops prior to insulin secretion in high fat diet
- BUT does not cause insulin resistance
Exercise
- restores insulin sensitivity
- does NOT restore glucose
Significance
- skel muscle recovery of adiponectin resistance may not be as important as previously thought
what can be added to diet to increase adiponectin
Omega-3
- through PPAR-gamma activation (transcription factor)
- regulates fatty acid storage and glucose metabolism
Study
- omega-3 “prevented” but did not treat impairment in adiponectin stimulated FA oxidation
*note - does recover insulin sensitivity (just like exercise)
tumor necrosis factor (TNF)-alpha in obese
mRNA and protein over expressed in adipose tissue
- induces insulin resistance
- insulin signalling cascade
- promotes lypolysis - inhibits adiponectin
- by inducing IL-6 - in adipose
- supress genes uptake and storage of FFAs and glucose - in liver
- suppress genes involved in glucose uptake and FA oxidation
how TNF-a induces insulin resistance
activates NFkB
- inhibits signalling cascade in multiple tissues
- phosphorylates serine of IRS-1
- suppression of AS160 phosphorylation (near end of signalling cascade)
*point -> directly impairs glucose uptake and metabolism by altering insulin signal transduction
exercise on TNF-a during high fat diet
decreases TNF-a gene expression
- even with no body or adipose mass loss
- also suppressed MCP-1 gene expression
- both inflammatory mediators
how
- higher mRNA expression of TLR4 (induces inflammatory cytokine production during high fat diet)
- attenuated (reduced) during exercise
2 main points with exercise and inflammation in high fat diet
exercise induces switch M1 macrophages to M2 macrophages in obese adipose tissue
inhibit TLR4 expression, which induces inflammatory cytokine production -> reduce inflammation
IL-6 production
traditional inflammatory cytokine
- from many tissues
- 30% from adipose (adipokine)
- muscle releases during exercise (myokine)
IL-6 in muscle
muscle releases IL-6 during exercise
- elevated IL-6 levels in muscle and plasma during exercise
IL-6 on insulin sensitivity
Rest
- insulin resistance
- 2x amount from visceral fat
- impaired in muscle and liver
Exercise
- improves sensitivity
- stimulates AMPK in muscle
- released from contracting muscle, feedback to increase hepatic glucose production and lipolysis
** acute vs chronic
Chronic vs Acute IL-6
IL-6 activates JAK-STAT pathway
Chronic = Good
- Akt phosphorylation via mTOR
- Akt serine phosphorylation of IRS-1 (active)
Acute = impaired
- JAK-STAT activate SOCS
- suppressor of cytokine signalling
- inhibits IRS1 tyrosine phosphorylation
Good adipokines
leptin
- increases AMPK activation (FA oxidation
- increases insulin signalling pathways (irs-1 content, PI 3-kinase activity, akt phosphorylation, plama membrane and total glut 4)
- *can develop resistance (reversed with exercise)
Adiponectin
- decrease inflammation
- increase IS
- increase FA oxidation
Bad adipokines
Tumor Necrosis Factor (TNF-alpha)
- mRNA and protein overexpression in adipose tissue
- impairs insulin signalling and insulin stimulated gluc uptake
- inhibits adiponectin
- induces IL-6
- activates NFkB (inhibit insulin signalling cascade)
- serine phosphorylation IRS1 (off)
- suppressed phosphorylation of AS160 (near bottom of insulin signalling pathway)
- decreased with exercise independent w/o weight reduction
IL-6
- when chronically activated **
- activates JAK-STAT pathway
- chronic IL-6 cause serine phosphorylation of IRS-1 via mTOR (impaired insulin signalling and IR)
When IL-6 is good
exercise
- IL-6 stims AMPK in muscle
- IL-6 released from contracting muscle
- increase hepatic glucose production and lipolysis
JAK-STAT pathway
- activates SOCS (suppressor of cytokine signalling)
- inhibits tyrosine phosphorylation of IRS-1
