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| Kofi... |
 Posted: Fri Oct 30, 2009 2:41 am |
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Guest
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Crossreference this with the information I posted earlier on TNF-alpha
and VDR resistance.
Diabetes. 2009 May;58(5):1133-43. Epub 2009 Feb 10
Loss-of-function mutation in myostatin reduces tumor necrosis factor
alpha production and protects liver against obesity-induced insulin
resistance.
Wilkes JJ, Lloyd DJ, Gekakis N.
Department of Cell Biology, Scripps Research Institute, La Jolla,
California, USA.
OBJECTIVE: Insulin resistance develops in tandem with obesity. Ablating
myostatin (Mstn) prevents obesity, so we investigated if Mstn deficiency
could improve insulin sensitivity. A loss-of-function mutation
(Mstn(Ln)) in either one or both alleles of the Mstn gene shows how Mstn
deficiency protects whole-body insulin sensitivity. RESEARCH DESIGN AND
METHODS: Mstn(Ln/Ln) mice were weaned onto a high-fat diet (HFD) or
standard diet. HFD-fed Mstn(Ln/Ln) mice exhibited high lean, low-fat
body compositions compared with wild types. Wild-type and heterozygous
and homozygous mutant mice were bled to determine basal levels of
insulin, glucose, and homeostasis model assessment of insulin
resistance. To evaluate postprandial insulin sensitivity between animals
of a similar size, glucose and insulin tolerance tests and
hyperinsulinemic-euglycemic clamp studies were performed with
heterozygous and homozygous mutant mice. Quantitative RT-PCR quantified
TNF proportional, variant, IL-6, IL-1beta, F4/80, GPR43, and CD36
expression in muscle, fat, and liver. Histological analysis measured
hepatosteatosis. RESULTS: Homozygous mutants were glucose tolerant and
protected against overall insulin resistance compared with heterozygous
mice. Hyperinsulinemic-euglycemic clamp studies revealed a dramatically
improved glucose infusion rate, glucose disposal rate, and hepatic
glucose production in 11-month-old Mstn(Ln/Ln) mice on an HFD.
Improvements to muscle and liver insulin sensitivity (approximately
200-400%) correlated with 50-75% decreased tumor necrosis factor
(TNF)alpha production and coincided with severe Mstn deficiency.
Hepatosteatosis appeared to be ameliorated. Short-term treatment of
Mstn(Ln/Ln) mice with recombinant Mstn led to increased plasma TNFalpha
and insulin resistance. CONCLUSIONS: We find that severe Mstn deficiency
caused by Ln (lean) mutations in HFD-fed mice protects muscle and liver
against obesity-induced insulin resistance.
PMID: 19208906 |
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