13. Obesity (3) - adipokines Flashcards Preview

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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

- 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



How is leptin resistance reversed

- 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

- restores insulin sensitivity
- does NOT restore glucose

- skel muscle recovery of adiponectin resistance may not be as important as previously thought


what can be added to diet to increase adiponectin

- through PPAR-gamma activation (transcription factor)
- regulates fatty acid storage and glucose metabolism

- 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

1. induces insulin resistance
- insulin signalling cascade
- promotes lypolysis

2. inhibits adiponectin
- by inducing IL-6

3. in adipose
- supress genes uptake and storage of FFAs and glucose

4. 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

- 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

- insulin resistance
- 2x amount from visceral fat
- impaired in muscle and liver

- 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

- 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)

- 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

- 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

- 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