Growth, Adipose, Brain, and Skin Alterations Resulting from Targeted Disruption of the Mouse Peroxisome Proliferator-Activated Receptor β(δ)

Abstract

To determine the physiological roles of peroxisome proliferator-activated receptor ␤ (PPAR␤), null mice were constructed by targeted disruption of the ligand binding domain of the murine PPAR␤ gene. Homozygous PPAR␤-null term fetuses were smaller than controls, and this phenotype persisted postnatally. Gonadal adipose stores were smaller, and constitutive mRNA levels of CD36 were higher, in PPAR␤-null mice than in controls. In the brain, myelination of the corpus callosum was altered in PPAR␤-null mice. PPAR␤ was not required for induction of mRNAs involved in epidermal differentiation induced by O-tetradecanoylphorbol-13-acetate (TPA). The hyperplastic response observed in the epidermis after TPA application was significantly greater in the PPAR␤-null mice than in controls. Inflammation induced by TPA in the skin was lower in wild-type mice fed sulindac than in similarly treated PPAR␤-null mice. These results are the first to provide in vivo evidence of significant roles for PPAR␤ in development, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation.

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

“…Examination of the PPARβ/δ null mice has shown a role for this receptor in several biological niches [36]. There is mounting evidence that PPARβ/δ plays a role in ameliorating the hepatotoxic effects of a wide range of xenobiotics including arsenic and acetaminophen (APAP).…”

Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) ligands inhibit growth of UACC903 and MCF7 human cancer cell lines

“…Anti-inflammatory activity of PPARβ/δ and/or PPARβ/δ ligands has been shown in a number of different models including immune cells, colon epithelium, macrophages, cardiomyocytes, keratinocytes, myoblasts, endothelial cells, nerve tissue and hepatocytes Graham et al 2005;Hollingshead et al 2007b;Jakobsen et al 2006;Kim et al 2006;Nagasawa et al 2006;Peters et al 2000;Polak et al 2005;Rival et al 2002;Schmuth et al 2004;Welch et al 2003;Woo et al 2006). There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001).…”

“…There is also strong evidence that ligand activation of PPARβ/δ promotes terminal differentiation in intestinal epithelium, breast and colon cancer cell lines, trophoblasts and primary keratinocytes (Aung et al 2006;Burdick et al 2007;Kim et al 2006;Marin et al 2006;Nadra et al 2006;Schmuth et al 2004;Tan et al 2001;Varnat et al 2006;Westergaard et al 2001). Evidence from a large number of independent laboratories also shows that cell growth is inhibited by PPARβ/δ and its ligands in colonocytes, keratincytes, cardiomyocytes, fibroblasts, endothelial cells and a variety of cancer cell lines (Ali et al 2005;Aung et al 2006;Burdick et al 2007;Fukumoto et al 2005;Hollingshead et al 2007a;Kim et al 2004;Kim et al 2006;Kim et al 2005;Man et al 2007;Marin et al 2006;Martinasso et al 2006;Matthiessen et al 2005;Michalik et al 2001;Müller-Brüsselbach et al 2007;Nadra et al 2006;Ou et al 2007;Peters et al 2000;Planavila et al 2005;Schmuth et al 2004;Tan et al 2001;Teunissen et al 2007;Varnat et al 2006;Westergaard et al 2001). Given the potential of PPARβ/δ ligands as therapeutic agents, it is of great importance to determine the effect of ligand activation of PPARβ/δ on cell growth in vitro and in vivo.…”

PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production

“…6-8 week-old male PPARβ/δ-deficient 35 , obese ob/ob and wild-type mice (Charles River laboratories), fed a chow diet (A03; UAR, France) and maintained in a temperature-controlled room (22°C) on a 12h light-dark cycle, were treated by gavage with vehicle or the PPARβ/δ synthetic agonists (GW0742 or GW501516) at the indicated doses and times. Plasma and several tissues including different intestinal sections (duodenum, jejunum, ileum, and colon) and pancreas were collected after 6h fasting.…”