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- Mechanisms by which Thiazolidinediones Enhance Insulin Actio...Mechanisms by which Thiazolidinediones Enhance Insulin Action
Trends in Endocrinology & Metabolism, Volume 10, Issue 1, 1 January 1999, Pages 9-13
Mauricio J Reginato and Mitchell A Lazar
AbstractThiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor, peroxisome proliferator-activated receptor γ (PPARγ). PPARγ is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.
Abstract | Full Text | PDF (243 kb) - PPARγ and the Treatment of Insulin ResistancePPARγ and the Treatment of Insulin Resistance
Trends in Endocrinology & Metabolism, Volume 11, Issue 9, 1 November 2000, Pages 362-368
Jerrold M Olefsky and Alan R Saltiel
AbstractNumerous studies across several population groups have indicated that insulin resistance plays a central role in the development of type 2 diabetes mellitus (T2DM). Moreover, this disorder is also strongly associated with other metabolic syndromes, including hypertension, dyslipidemias and polycystic ovarian syndrome (PCOS). Recent advances have demonstrated that pharmacological agents of the thiazolidinedione class can reverse insulin resistance and profoundly improve many of these associated symptoms. These effects have been documented in a variety of genetic and acquired animal models of insulin resistance, as well as in numerous clinical trials in patients with insulin resistance. These compounds appear to enhance insulin action by modulating the activity of the nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ. This activation results in changes in the expression of a number of genes that are critically involved in glucose and lipid metabolism, as well as in insulin signal transduction. While precise events that occur downstream from PPARγ modulation remain uncertain, new insights are emerging from knockout studies in mice and the identification of genetic variants in humans. These findings indicate that there is still much to learn about the molecular biology and physiology of these interesting receptors, and that research in this area can lead to more effective and safer drugs to treat insulin resistance and associated syndromes.
Abstract | Full Text | PDF (131 kb) - PPARγ in Monocytes: Less Pain, Any Gain?PPARγ in Monocytes: Less Pain, Any Gain?
Cell, Volume 93, Issue 2, 17 April 1998, Pages 153-155
Bruce M Spiegelman
Full Text | PDF (54 kb) - …more
Copyright © 1998 Cell Press. All rights reserved.
Molecular Cell, Volume 1, Issue 3, 465-470, 1 February 1998
doi:10.1016/S1097-2765(00)80047-7
Article
Terminal Differentiation of Human Breast Cancer through PPARγ
Elisabetta Mueller1, 2, Pasha Sarraf1, 2, Peter Tontonoz2, 3, Ronald M. Evans3, 4, Katherine J. Martin1, Ming Zhang1, Christopher Fletcher5, 6, Samuel Singer5, 7 and Bruce M. Spiegelman1, 1, *, 
1 Department of Cancer Biology, Dana-Farber Cancer Institute and, Harvard Medical School, Boston, Massachusetts 02115, USA
2 Department of Pathology, UCSD Medical Center, San Diego, California 92103, USA
3 Gene Expression Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA
4 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
5 Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
6 Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA
7 Department of Surgery, Harvard Medical School, Boston, Massachusetts 02115, USA
Corresponding author: Bruce M. Spiegelman, 617 632 3567 (phone), 617 632 4655 (fax)Summary
We have previously demonstrated that PPARγ stimulates the terminal differentiation of adipocyte precursors when activated by synthetic ligands, such as the antidiabetic thiazolidinedione (TZD) drugs. We show here that PPARγ is expressed at significant levels in human primary and metastatic breast adenocarcinomas. Ligand activation of this receptor in cultured breast cancer cells causes extensive lipid accumulation, changes in breast epithelial gene expression associated with a more differentiated, less malignant state, and a reduction in growth rate and clonogenic capacity of the cells. Inhibition of MAP kinase, shown previously to be a powerful negative regulator of PPARγ, improves the TZD ligand sensitivity of nonresponsive cells. These data suggest that the PPARγ transcriptional pathway can induce terminal differentiation of malignant breast epithelial cells and thus may provide a novel, nontoxic therapy for human breast cancer.
