PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice

<p>Abstract</p> <p>Background</p> <p>Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice.</p> <p>Methods</p> <p>In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD) for 10-weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle.</p> <p>Results</p> <p>Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT-inflammation, ligand-activated PPARgamma improved diet-induced IR and GI.</p> <p>Conclusion</p> <p>Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma´s action.</p

Metabolic Actions of Estrogen Receptor Beta (ERβ) are Mediated by a Negative Cross-Talk with PPARγ

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARγ, in vitro and in high-fat diet (HFD)-fed ERβ -/- mice (βERKO) mice. Our in vitro experiments showed that ERβ inhibits ligand-mediated PPARγ-transcriptional activity. That resulted in a blockade of PPARγ-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERβ-mediated inhibition of PPARγ activity. Consistent with the in vitro data, we observed increased PPARγ activity in gonadal fat from HFD-fed βERKO mice. In consonance with enhanced PPARγ activation, HFD-fed βERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPARγ in HFD-fed βERKO mice, PPARγ signaling was disrupted by PPARγ antisense oligonucleotide (ASO). Blockade of adipose PPARγ by ASO reversed the phenotype of βERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPARγ-regulated adiponectin promoter was enhanced in gonadal fat from βERKO mice indicating that the absence of ERβ in adipose tissue results in exaggerated coactivator binding to a PPARγ target promoter. Collectively, our data provide the first evidence that ERβ-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPARγ signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERβ may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ERβ-selective agonists

The role of Peroxisome Proliferator-Activated Receptor (PPAR)-Activating Angiotensin Type 1-Receptor Blockers in obesity and insulin resistance

HINTERGRUND: Angiotensin Typ 1-Rezeptorblocker (ARB) haben in vielen klinischen Endpunktstudien die Inzidenz von Typ 2 Diabetes mellitus (T2DM) reduziert. Der ARB Telmisartan hat in mehreren klinischen Studien bei Patienten mit arterieller Hypertonie die Plasmatriglyzeride gesenkt. Die molekularen Mechanismen hierfür sind weitgehend unbekannt. Peroxisome proliferator-activated receptors (PPARs) sind nukleäre Hormonrezeptoren und regulieren als Lipidsensoren und Transkriptionsfaktoren den Insulin- und Glukosestoffwechsel und die Energiehomöostase. Sie dienen Medikamenten als molekulare Zielstrukturen zur Therapie metabolischer Störungen wie T2DM, Atherosklerose, Metabolisches Syndrom oder Adipositas. HYPOTHESE: Bestimmte ARB wirken als selektive PPARgamma-Modulatoren (SPPARM) und/oder partielle PPARalpha-Agonisten und sind dadurch an der Verbesserung der Insulinsensitivität und/oder des Lipidstoffwechsels beteiligt. METHODEN: Die Regulation des insulinsensitivierenden Fettgewebshormons Adiponektin durch Angiotensin II und ARB wurde in 3T3-L1-Adipozyten und adipösen Zucker-Ratten untersucht. In vitro in 3T3-L1-Adipozyten, in humanen Adipozyten und in COS-7-Zellen sowie in vivo in diätinduzierten adipösen C57BL/6J-Mäusen wurde die selektive Modulation von PPARgamma getestet. Die Aktivierung von PPARalpha wurde in HepG2-, AML12-, COS-7-Zellen und in vivo in diätinduzierten adipösen C57BL/6J-Mäusen gemessen. ERGEBNISSE: PPARgamma-aktivierende ARB steigern auf posttranskriptioneller Ebene die Expression von Adiponektin unabhängig von ihrer Blockade des Angiotensin Typ 1-Rezeptors (AT1). In vivo verhindert der PPARgamma-aktivierende ARB Irbesartan das Absinken des Adiponektinserumspiegels und verbessert bestimmte Insulinsensitivitätsparameter. Irbesartan und Telmisartan, ebenfalls ein PPARgamma-aktivierender ARB, werden als neue SPPARM charakterisiert. Die selektive PPARgamma-Modulation durch ARB führt zu PPARgamma- Konformationsänderung, zu selektiver Kofaktorrekrutierung, zu einem spezifischen Genexpressionsprofil und zu Insulinsensitivierung in vivo. Telmisartan aktiviert PPARalpha-Zielgene in Leberzellen und ist in vitro im mikromolaren Konzentrationsbereich ein partieller PPARalpha-Ligand. Durch das pharmakokinetische Profil der Substanz mit hohen Wirkstoffmengen in der Leber wird auch in vivo PPARalpha aktiviert, was mit vermehrter Zielgenexpression und reduzierten Triglyzeridspiegeln in der Leber und im Plasma einhergeht. ZUSAMMENFASSUNG: Die vorliegende Arbeit demonstriert, dass einige ARB möglicherweise durch PPARgamma-vermittelte, posttranskriptionelle Mechanismen die Adiponektinkonzentration in Adipozyten erhöhen. Zwei ARB werden als neue SPPARM identifiziert. Selektive PPARgamma-Modulation führt, vergleichbar mit voller PPARgamma-Aktivierung, zu metabolisch vorteilhaften Wirkungen, jedoch ohne die typischen unerwünschten Wirkungen voller PPARgamma-Aktivierung aufzuweisen. Telmisartan wird als partieller PPARalpha-Agonist identifiziert. Auf Grund des pharmakokinetischen Profils scheint diese Wirkung auf die Leber beschränkt zu sein. KLINISCHE PERSPEKTIVE: Durch Kombination von Adiponektininduktion, PPARgamma-Modulation und partieller PPARalpha- Aktivierung zusätzlich zur AT1-Blockade senken ARB auf mehreren Ebenen das kardiovaskuläre Risiko. Die Entwicklung von optimierten SPPARM-ARB könnte Patienten mit Diabetes, Hypertonie oder Metabolischem Syndrom eine neue Therapieoption bieten.BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that act as lipid sensors and transcription factors, and regulate insulin metabolism, glucose metabolism, and energy homeostasis. They are molecular targets for thiazolidinediones and fibrates used for treatment of metabolic diseases like type 2 diabetes mellitus (T2DM), atherosclerosis, metabolic syndrome, and obesity. Adiponectin is an adipose tissue-derived, PPARgamma-responsive protein hormone responsible for insulin sensitization. Angiotensin type 1 receptor blockers (ARBs) reduce the incidence of T2DM in large clinical endpoint studies. The ARB telmisartan reduces plasma triglycerides in patients with arterial hypertension in several clinical studies. A distinct subgroup of ARBs has PPARgamma activating properties. HYPOTHESIS: PPARgamma activating ARBs improve insulin sensitivity and/or lipid metabolism by elevation of adiponectin levels, selective modulation of PPARgamma, and/or partial activation of PPARalpha. METHODS: Regulation of adiponectin by ARBs was examined in 3T3-L1 adipocytes and obese Zucker rats. Selective modulation of PPARgamma by ARBs was tested in vitro in 3T3-L1 and human adipocytes, and in COS-7 cells, and in vivo in diet-induced obese (DIO) C57BL/6J mice. Activation of PPARalpha by ARBs was determined in vitro in HepG2, AML12, and COS-7 cells, and in vivo in C57BL/6J DIO mice. RESULTS: The PPARgamma activating ARBs irbesartan and telmisartan increase posttranscriptional levels of adiponectin in vitro, independent of the angiotensin type 1-receptor (AT1). Irbesartan prevents the decline of serum adiponectin and improves specific parameters of insulin sensitivity in vivo in obese Zucker rats. Treatment with irbesartan and telmisartan leads to a conformational change of PPARgamma, selective cofactor recruitment, and a specific gene expression profile in vitro. Telmisartan induces insulin sensitization in the absence of weight gain in vivo in DIO mice. Telmisartan activates PPARalpha target genes and acts as partial PPARalpha ligand in vitro. In vivo in DIO mice, telmisartan upregulates PPARalpha target genes in liver but not in muscle tissue, and reduces hepatic and plasma triglyceride levels. SUMMARY: The present work demonstrates that irbesartan and telmisartan increase adiponectin levels, possibly by a PPARgamma-mediated, post transcriptional mechanism. Irbesartan and telmisartan are identified as new selective PPARgamma modulators (SPPARMs). Selective PPARgamma modulation by ARBs leads to beneficial metabolic actions in the absence of typical negative side effects observed with full PPARgamma activation. Telmisartan is identified as partial PPARalpha agonist. Due to its pharmacokinetic profile with high hepatic concentrations, this action seems to be specific for the liver. CLINICAL PERSPECTIVE: By combining adiponectin level elevation, selective PPARgamma modulation, and partial PPARalpha activation, in addition to AT1 blockade, ARBs reduce the cardiovascular risk at multiple levels. Improved SPPARM-ARBs could offer new therapeutic options to patients suffering from diabetes, hypertension, or the metabolic syndrome