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
