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Clin Endocrinol (Oxf) 75:2X7-288. doi: 10.111 l/j. 1365-2265.2011.04168.x Contents 1 Sex-Specific Differences in Obesity and Metabolic Disorders .................................................. 388 2 Treatment of Metabolic Disorders and PPARs .......................................................................... 389 2.1 Mechanism of PPARs Activation .................................................................................. 390 3 PPARgamma and Sex-Specific Differences in Treatment of Metabolic Disorders ................... 392 3.1 Sex-Specific Differences in T2DM and Coronary Artery Disease Patients ..................... 392 3.2 Sex-Specific Differences and TZD-Specific Side Effects ................................................ 393 3.3 Pharmacokinetic of TZDs ........................................................................... 394 3.4 Sex-Specific Differences and Polymorphism of PPARgamma ........................................ 394 3.5 PPARgamma and Estrogens ............................................................................................ 395 4 PPARalpha and Sex-Specific Differences in the Treatment of Metabolic Disorders .... 397 4.1 Sex-Specific Differences in Fibrate Treatment ................................................................ 398 4.2 Clinical Studies ............................................................................................................... 398 4.3 Animal Studies ................................................................................................................ 399 4.4 PPARalpha and Estrogens/ERs ....................................................................................... 400 4.5 PPARalpha and Anti-inflammatory Effects ..................................................................... 401 5 Clinical Implications ................................................................................................................. 402 6 Conclusion and Perspectives .................................................................................................... 402 References ....................................................................................................................................... 403 Abstract The influence of sex on ihe development of obesity, Type 2 Diabetes Mellitus (T2DM), and dyslipidemia is well documented, although the molecular mechanism underlying those differences reminds elusive. Ligands of peroxisome proliferator-activated receptors (PPARs) are used as oral antidiabetics (PPARgamma agonists: thiazolidinediones, TZDs), or for the treatment of dyslipidemia and cardiovascular diseases, due to their lipid-lowering properties (PPARalpha agonists: fibrates), as PPARs control transcription of a set of genes V. Benz • U. Kintscher (P5) • A. Foryst-Ludwig Institute of Pharmacology, Center for Cardiovascular Research (CCR), Charite-Universitatsmedizin Berlin, Hessische Street 3-4, 10115 Berlin, Germany e-mail: [email protected]; [email protected]; [email protected] V. Regitz-Zagrosek (ed.), Sex and Gender Differences in Pharmacology, 387 Handbook of Experimental Pharmacology 214, DOI 10.1007/978-3-642-30726-3J8, © Springer-Verlag Berlin Heidelberg 2012 involved in the regulation of lipid and carbohydrate metabolism. Given a high protein (FABPc), sterol regulatory binding protein-lc (SREBP-lc) (Tarnopolsky prevalence of those metabolic disorders, and thus a broad use of PPAR agonists, the 2008), and Fatty Acid Translocase/CD36 (Kiens et al. 2004). present review will discuss distinct aspects of sex-specific differences in antiobesity Although the prevalence of diabetes seems to be comparable in women and men, a treatment using those groups of PPAR ligands. study performed by Vaccaro and colleagues (2008) on T2DM-patients in Italy showed a significantly higher average body mass index (BMI) in diabetic women, Keywords PPARgamma • PPARalpha • Nuclear receptor cross talk • Type 2 diabetes when compared to men. Also glycated hemoglobin (HbAlc) and plasma mellitus • Hypertriglyceridemia • Hypercholesterolemia • TZDs • Fibrates LDL-cholesterol were increased, reflecting a more adverse cardiovascular risk factors profile with a pronounced negative effect on the development of cardiovascular diseases in diabetic women compared to men. Abbreviations Also other studies indicated an increased cardiovascular risk in women with T2DM, when compared to diabetic men (Rivellese et al. 2010) but the cause of those BMI Body mass index sex-specific differences is not completely understood, and could be CAD Coronary artery disease explained—according to the work from Rivellese and colleagues—by biological ER Estrogen receptor and behavioral differences, such as heavier burden of cardiovascular risk factors, NHR Nuclear hormone receptor functional and structural differences of the cardiovascular system, and discrepancy in medical treatment and treatment response. PPAR Peroxisome proliferator-activated receptor The common problem with the identification of sex-specific differences is RXR Retinoid acid receptor connected with the fact that women are underrepresented in most of the clinical T2DM Type 2 diabetes mellitus studies. For years it has been a common standard (in human and animal studies) to TZD Thiazolidinediones include only males due to unwanted effects of sex hormones. But the role of sex hormones is, as investigated in the last years, tremendous and not negligible. Even if women are increasingly involved in clinical trials nowadays, the study design and 1 Sex-Specific Differences in Obesity and Metabolic Disorders randomization of the groups often unable the analysis of sex-specific information, such as sex-related differences in pharmacokinetics and pharmacodynamics, as well It is well known that glucose and lipid metabolism, and as a consequence whole as sex-specific side effect profiles (Gandhi et al. 2004). Only few studies subdivide body composition, differ between sexes (Dayspring and Pokrywka 2010; Hsieh et groups for specific analysis of sex interactions. In addition, women who are al. 2007). Women exhibit a greater accumulation of adipose tissue, predominantly in included in the studies are mainly postmenopausal. In summary, although the gluteal-femoral region of the body, whereas men show increased accumulation of sex-specific aspects of obesity are well known, sex-specific strategies for the abdominal fat, which has been associated since years with a higher risk for treatment of metabolic disorders and diabetes are not available at the moment. cardiovascular morbidity/mortality, development of T2DM, and other metabolic complications (Kissebah et al. 1982; Ross et al. 2002; Yusuf et al. 2005). This sex-specific pattern changes after menopause when a redistribution of fat from subcutaneous to visceral depots occurs. Differences between the basal and stimulated 2 Treatment of Metabolic Disorders and PPARs lipolysis of different fat depots as well as differences between males and females have been identified in different studies, but results remain controversial (Blaak2001). The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear There are consistent results in regard to lipolysis and fat oxidation during hormone receptors (NHR) superfamily, consisting of several transcription factors endurance training. When compared with men women have better ultra-endurance and transcriptional regulators, such as thyroid receptors, estrogen receptors (ERs), capacity and oxidize more fat (Carter et al. 2001; Maher et al. 2009). Interestingly, retinoid acid receptors (RXRs), and others (Ferre 2004; Lonard and O'Mai ley different studies showed in the muscle of women when compared to male tissue a 2006). PPARs control transcription of a set of genes involved in the regulation of higher mRNA expression of genes involved in lipid metabolism, like fatty acid carbohydrate and lipid metabolism, vascular endothelial functions, and pancreatic transporters, enzymes of 6-oxidation, and others, providing an explanation for the beta-cell functions (Tobin and Freedman 2006). Up to now three diverse PPARs higher lipolytic activity in women during exercise (Maher et al. 2010). Further have been identified: subtype PPARalpha, gamma, and delta (Reddy 2004). examples for higher expressed genes are hormone sensitive lipase (HSL) (Roepstorff PPARalpha is highly expressed in the liver and skeletal muscle and modulates et al. 2006),