Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS One. 2014 May 8;9(5):e96323. doi: 10.1371/journal.pone.0096323. eCollection 2014.

Partial agonist, telmisartan, maintains PPARγ serine 112 phosphorylation, and does not affect osteoblast differentiation and bone mass.

Author information

1
Department of Orthopaedic Surgery, University of Toledo College of Medicine, Toledo, Ohio, United States of America; Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
2
Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America; Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
3
Department of Orthopaedic Surgery, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
4
Department of Orthopaedic Surgery, University of Toledo College of Medicine, Toledo, Ohio, United States of America; Department of Physiology and Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America; Center for Diabetes and Endocrine Research, University of Toledo College of Medicine, Toledo, Ohio, United States of America.

Abstract

Peroxisome proliferator activated receptor gamma (PPARγ) controls both glucose metabolism and an allocation of marrow mesenchymal stem cells (MSCs) toward osteoblast and adipocyte lineages. Its activity is determined by interaction with a ligand which directs posttranscriptional modifications of PPARγ protein including dephosphorylation of Ser112 and Ser273, which results in acquiring of pro-adipocytic and insulin-sensitizing activities, respectively. PPARγ full agonist TZD rosiglitazone (ROSI) decreases phosphorylation of both Ser112 and Ser273 and its prolonged use causes bone loss in part due to diversion of MSCs differentiation from osteoblastic toward adipocytic lineage. Telmisartan (TEL), an anti-hypertensive drug from the class of angiotensin receptor blockers, also acts as a partial PPARγ agonist with insulin-sensitizing and a weak pro-adipocytic activity. TEL decreased S273pPPARγ and did not affect S112pPPARγ levels in a model of marrow MSC differentiation, U-33/γ2 cells. In contrast to ROSI, TEL did not affect osteoblast phenotype and actively blocked ROSI-induced anti-osteoblastic activity and dephosphorylation of S112pPPARγ. The effect of TEL on bone was tested side-by-side with ROSI. In contrast to ROSI, TEL administration did not affect bone mass and bone biomechanical properties measured by micro-indentation method and did not induce fat accumulation in bone, and it partially protected from ROSI-induced bone loss. In addition, TEL induced "browning" of epididymal white adipose tissue marked by increased expression of UCP1, FoxC2, Wnt10b and IGFBP2 and increased overall energy expenditure. These studies point to the complexity of mechanisms by which PPARγ acquires anti-osteoblastic and pro-adipocytic activities and suggest an importance of Ser112 phosphorylation status as being a part of the mechanism regulating this process. These studies showed that TEL acts as a full PPARγ agonist for insulin-sensitizing activity and as a partial agonist/partial antagonist for pro-adipocytic and anti-osteoblastic activities. They also suggest a relationship between PPARγ fat "browning" activity and a lack of anti-osteoblastic activity.

PMID:
24810249
PMCID:
PMC4014504
DOI:
10.1371/journal.pone.0096323
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center