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in 3T3-L1 Adipocytes and is a Target for Transactivation by PPAR
1 Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio, United States
* To whom correspondence should be addressed. E-mail: csmas{at}meduohio.edu.
The minimal adipose phenotype of hormone sensitive lipase null mice suggested other hormonally responsive lipase(s) were present in adipocytes. Recent studies have characterized a new adipose triglyceride lipase, ATGL/PNPLA2/destnutrin/iPLA2
/TTS2.2. We had previously cloned a novel adipose-enriched transcript by differential screening and recently determined its identity with murine ATGL. We report here on the regulation of ATGL by TNF
and insulin in 3T3-L1 adipocytes and identify ATGL as a target for transcriptional activation by the key adipogenic transcription factor PPAR
. 100 nM insulin resulted in a marked decrease in ATGL transcript that was effectively blocked by inhibitors for PI3 kinase and p70 ribosomal protein-S6 kinase. TNF treatment decreased ATGL transcript in a time dependent manner that paralleled TNF downregulation of PPAR, with a maximal decrease noted by 6 hr. TNF effects on ATGL were attenuated by pretreatment with PD98059, LY294002, or rapamycin, suggesting involvement of the p44/42 MAP kinase, PI3K and p70 ribosomal protein-S6 kinase signals. To study transcriptional regulation of ATGL, we cloned 2979 bp of the murine ATGL 5' flanking region. Compared to promoterless pGL2-Basic, the -2979/+21 ATGL luciferase construct demonstrated a 120-fold and 40-fold increase in activity in white and brown adipocytes, respectively. Luciferase reporter activities for a series of 8 ATGL promoter deletions revealed that the -928/+21, -1738/+21, -1979/+21, and -2979/+21 constructs were transactivated by PPAR. Our findings identify the novel lipase ATGL to be a target for gene for TNF and insulin action in adipocytes and reveal it is subject to transcriptional control by PPAR-mediated signals.
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