Silencing Jnk1 and Jnk2 accelerates basal lipolysis and promotes fatty acid re-esterification in mouse adipocytes.

Abstract:

AIMS/HYPOTHESIS:Elevated plasma levels of NEFA impair insulin action. Given the positive linear correlation between NEFA released by adipocytes and plasma NEFA levels, identification of mechanisms controlling adipocyte lipolysis and NEFA release could provide a guide to new therapies for insulin resistance and type 2 diabetes. METHODS:Short hairpin RNA-mediated gene ablation was used to determine the functions of c-Jun N-terminal kinase (JNK)1 and JNK2 in adipocytes. RESULTS:Combined JNK1/JNK2 deficiency drastically increased basal glycerol release, whereas individual JNK1- or JNK2-deficiency had no effect, indicating that JNK1/JNK2-deficiency enhances basal lipolysis, whereas the alternate subtype compensates for a single JNK subtype deficiency in the regulation of basal lipolysis. The profoundly increased glycerol release associated with JNK1/JNK2-deficiency was not accompanied by a concomitant increase in NEFA release over time. In addition, JNK1-deficiency, but not JNK2-deficiency, drastically decreased NEFA release as compared with that in JNK-intact cells, a result of increased NEFA re-esterification. In microarray, quantitative RT-PCR and western blotting, JNK1-, JNK2- and JNK1/JNK2-deficiencies selectively upregulated many genes involved in NEFA management, without affecting the expression of genes involved in insulin signalling. Assays using reporter genes driven by peroxisome proliferator-activated receptor gamma (PPAR-gamma)-responsive promoters indicate distinct roles for JNK1 and JNK2 in regulating the transcriptional effects of PPAR-gamma. CONCLUSIONS/INTERPRETATION:While JNK1 and JNK2 have shared roles in the regulation of basal lipolysis, JNK1 has a more profound role in supporting baseline NEFA release. Inhibition of JNK1 activity in adipocytes has potential therapeutic uses for management of elevated circulating NEFA levels at the onset of insulin resistance.

journal_name

Diabetologia

journal_title

Diabetologia

authors

Rozo AV,Vijayvargia R,Weiss HR,Ruan H

doi

10.1007/s00125-008-1036-6

subject

Has Abstract

pub_date

2008-08-01 00:00:00

pages

1493-504

issue

8

eissn

0012-186X

issn

1432-0428

journal_volume

51

pub_type

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