Abstract
The influence of sex on the 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 involved in the regulation of lipid and carbohydrate metabolism. Given a high prevalence of those metabolic disorders, and thus a broad use of PPAR agonists, the present review will discuss distinct aspects of sex-specific differences in antiobesity treatment using those groups of PPAR ligands.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- BMI:
-
Body mass index
- CAD:
-
Coronary artery disease
- ER:
-
Estrogen receptor
- NHR:
-
Nuclear hormone receptor
- PPAR:
-
Peroxisome proliferator-activated receptor
- RXR:
-
Retinoid acid receptor
- T2DM:
-
Type 2 diabetes mellitus
- TZD:
-
Thiazolidinediones
References
Amoruso A, Bardelli C, Fresu LG, Palma A, Vidali M, Ferrero V, Ribichini F, Vassanelli C, Brunelleschi S (2009) Enhanced peroxisome proliferator-activated receptor-gamma expression in monocyte/macrophages from coronary artery disease patients and possible gender differences. J Pharmacol Exp Ther 331:531–538
Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M (2010) Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 12:716–721
Auboeuf D, Rieusset J, Fajas L, Vallier P, Frering V, Riou JP, Staels B, Auwerx J, Laville M, Vidal H (1997) Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes 46:1319–1327
Barbieri M, Bonafe M, Rizzo MR, Ragno E, Olivieri F, Marchegiani F, Franceschi C, Paolisso G (2004) Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity. Exp Gerontol 39:1095–1100
Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR (1998) Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes 47:1806–1808
Beconi M, Mao A, Creighton M, Hop CE, Chiu SH, Eydelloth R, Franklin R, Tang F, Yu N, Vincent S (2003) Species and gender differences in the formation of an active metabolite of a substituted 2,4-thiazolidinedione insulin sensitizer. Xenobiotica 33:767–787
Ben Ali S, Ben Yahia F, Sediri Y, Kallel A, Ftouhi B, Feki M, Elasmi M, Haj-Taieb S, Souheil O, Sanhagi H et al (2009) Gender-specific effect of Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma-2 gene on obesity risk and leptin levels in a Tunisian population. Clin Biochem 42:1642–1647
Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435
Bilik D, McEwen LN, Brown MB, Pomeroy NE, Kim C, Asao K, Crosson JC, Duru OK, Ferrara A, Hsiao VC et al (2010) Thiazolidinediones and fractures: evidence from translating research into action for diabetes. J Clin Endocrinol Metab 95:4560–4565
Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES (2005) Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol 45:185–197
Blaak E (2001) Gender differences in fat metabolism. Curr Opin Clin Nutr Metab Care 4:499–502
Brun RP, Tontonoz P, Forman BM, Ellis R, Chen J, Evans RM, Spiegelman BM (1996) Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev 10:974–984
Campbell SE, Mehan KA, Tunstall RJ, Febbraio MA, Cameron-Smith D (2003) 17beta-estradiol upregulates the expression of peroxisome proliferator-activated receptor alpha and lipid oxidative genes in skeletal muscle. J Mol Endocrinol 31:37–45
Carlson LA, Rossner S (1975) Editorial: results of the coronary drug project–an interpretation. Atherosclerosis 22:317–323
Carter SL, Rennie C, Tarnopolsky MA (2001) Substrate utilization during endurance exercise in men and women after endurance training. Am J Physiol 280:E898–E907
Cavailles V, Dauvois S, L’Horset F, Lopez G, Hoare S, Kushner PJ, Parker MG (1995) Nuclear factor RIP140 modulates transcriptional activation by the estrogen receptor. EMBO J 14:3741–3751
Chaput E, Saladin R, Silvestre M, Edgar AD (2000) Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun 271:445–450
Ciana P, Biserni A, Tatangelo L, Tiveron C, Sciarroni AF, Ottobrini L, Maggi A (2007) A novel peroxisome proliferator-activated receptor responsive element-luciferase reporter mouse reveals gender specificity of peroxisome proliferator-activated receptor activity in liver. Mol Endocrinol 21:388–400
Claudel T, Staels B, Kuipers F (2005) The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. Arterioscler Thromb Vasc Biol 25:2020–2030
Costet P, Legendre C, More J, Edgar A, Galtier P, Pineau T (1998) Peroxisome proliferator-activated receptor alpha-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem 273:29577–29585
Crisafulli C, Bruscoli S, Esposito E, Mazzon E, Di Paola R, Genovese T, Bramanti P, Migliorati G, Cuzzocrea S (2009) PPAR-alpha contributes to the anti-inflammatory activity of 17beta-estradiol. J Pharmacol Exp Ther 331:796–807
Cutolo M, Brizzolara R, Atzeni F, Capellino S, Straub RH, Puttini PC (2010) The immunomodulatory effects of estrogens: clinical relevance in immune-mediated rheumatic diseases. Ann N Y Acad Sci 1193:36–42
Dayspring TD, Pokrywka G (2010) Impact of triglycerides on lipid and lipoprotein biology in women. Gend Med 7:189–205
de Aloysio D, Gambacciani M, Meschia M, Pansini F, Bacchi Modena A, Bolis PF, Massobrio M, Maiocchi G, Peruzzi E (1999) The effect of menopause on blood lipid and lipoprotein levels. The Icarus Study Group. Atherosclerosis 147:147–153
De Bosscher K, Vanden Berghe W, Haegeman G (2006) Cross-talk between nuclear receptors and nuclear factor kappaB. Oncogene 25:6868–6886
Dedoussis GV, Theodoraki EV, Manios Y, Yiannakouris N, Panagiotakos D, Papoutsakis C, Skenderi K, Zampelas A (2007) The Pro12Ala polymorphism in PPARgamma2 gene affects lipid parameters in Greek primary school children: a case of gene-to-gender interaction. Am J Med Sci 333:10–15
Dedoussis GV, Vidra N, Butler J, Papoutsakis C, Yannakoulia M, Hirschhorn JN, Lyon HN (2009) Peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphism and risk for pediatric obesity. Clin Chem Lab Med 47:1047–1050
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287
Deeg MA, Tan MH (2008) Pioglitazone versus rosiglitazone: effects on lipids, lipoproteins, and apolipoproteins in head-to-head randomized clinical studies. PPAR Res 2008:520465
Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B (1999) Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 274:32048–32054
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688
Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384:39–43
Djouadi F, Weinheimer CJ, Saffitz JE, Pitchford C, Bastin J, Gonzalez FJ, Kelly DP (1998) A gender-related defect in lipid metabolism and glucose homeostasis in peroxisome proliferator- activated receptor alpha- deficient mice. J Clin Invest 102:1083–1091
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD et al (2005) Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366:1279–1289
Fairweather D, Frisancho-Kiss S, Rose NR (2008) Sex differences in autoimmune disease from a pathological perspective. Am J Pathol 173:600–609
Ferre P (2004) The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 53(Suppl 1):S43–S50
Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM (1995) 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83:803–812
Forman BM, Chen J, Evans RM (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 94:4312–4317
Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, Krikov M, Bhanot S, Barros R, Morani A et al (2008) Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4:e1000108
Frick MH, Syvanne M, Nieminen MS, Kauma H, Majahalme S, Virtanen V, Kesaniemi YA, Pasternack A, Taskinen MR (1997) Prevention of the angiographic progression of coronary and vein-graft atherosclerosis by gemfibrozil after coronary bypass surgery in men with low levels of HDL cholesterol. Lopid Coronary Angiography Trial (LOCAT) Study Group. Circulation 96:2137–2143
Fruchart JC (2001) Peroxisome proliferator-activated receptor-alpha activation and high-density lipoprotein metabolism. Am J Cardiol 88:24N–29N
Fujita Y, Yamada Y, Kusama M, Yamauchi T, Kamon J, Kadowaki T, Iga T (2003) Sex differences in the pharmacokinetics of pioglitazone in rats. Comp Biochem Physiol C Toxicol Pharmacol 136:85–94
Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF (2004) Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol 44:499–523
Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V et al (2006) Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 368:1096–1105
Ginsberg HN, Elam MB, Lovato LC, Crouse JR 3rd, Leiter LA, Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J et al (2010) Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 362:1563–1574
Glass CK (2006) Going nuclear in metabolic and cardiovascular disease. J Clin Invest 116:556–560
Guan HP, Ishizuka T, Chui PC, Lehrke M, Lazar MA (2005) Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev 19:453–461
Guerre-Millo M, Gervois P, Raspe E, Madsen L, Poulain P, Derudas B, Herbert JM, Winegar DA, Willson TM, Fruchart JC et al (2000) Peroxisome proliferator-activated receptor alpha activators improve insulin sensitivity and reduce adiposity. J Biol Chem 275:16638–16642
Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK (2010) Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 95:592–600
Hofbauer KG (2002) Molecular pathways to obesity. Int J Obes Relat Metab Disord 26(Suppl 2):S18–S27
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP, Komajda M, McMurray JJ (2009) Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet 373:2125–2135
Hsieh YC, Frink M, Choudhry MA, Bland KI, Chaudry IH (2007) Metabolic modulators following trauma sepsis: sex hormones. Crit Care Med 35:S621–S629
Jalouli M, Carlsson L, Ameen C, Linden D, Ljungberg A, Michalik L, Eden S, Wahli W, Oscarsson J (2003) Sex difference in hepatic peroxisome proliferator-activated receptor alpha expression: influence of pituitary and gonadal hormones. Endocrinology 144:101–109
Jepsen K, Hermanson O, Onami TM, Gleiberman AS, Lunyak V, McEvilly RJ, Kurokawa R, Kumar V, Liu F, Seto E et al (2000) Combinatorial roles of the nuclear receptor corepressor in transcription and development. Cell 102:753–763
Kahn SE, Haffner SM, Viberti G, Herman WH, Lachin JM, Kravitz BG, Yu D, Paul G, Holman RR, Zinman B (2010) Rosiglitazone decreases C-reactive protein to a greater extent relative to glyburide and metformin over 4 years despite greater weight gain: observations from a Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 33:177–183
Kamei Y, Ohizumi H, Fujitani Y, Nemoto T, Tanaka T, Takahashi N, Kawada T, Miyoshi M, Ezaki O, Kakizuka A (2003) PPARgamma coactivator 1beta/ERR ligand 1 is an ERR protein ligand, whose expression induces a high-energy expenditure and antagonizes obesity. Proc Natl Acad Sci USA 100:12378–12383
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T, Glasziou P et al (2005) Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366:1849–1861
Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W (1993) Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 90:2160–2164
Keller H, Givel F, Perroud M, Wahli W (1995) Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements. Mol Endocrinol 9:794–804
Kiens B, Roepstorff C, Glatz JF, Bonen A, Schjerling P, Knudsen J, Nielsen JN (2004) Lipid-binding proteins and lipoprotein lipase activity in human skeletal muscle: influence of physical activity and gender. J Appl Physiol 97:1209–1218
Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW (1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54:254–260
Kitson AP, Stroud CK, Stark KD (2010) Elevated production of docosahexaenoic acid in females: potential molecular mechanisms. Lipids 45:209–224
Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359
Koskinen P, Kovanen PT, Tuomilehto J, Manninen V (1992) Gemfibrozil also corrects dyslipidemia in postmenopausal women and smokers. Arch Intern Med 152:90–96
Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11:779–791
Lazarenko OP, Rzonca SO, Hogue WR, Swain FL, Suva LJ, Lecka-Czernik B (2007) Rosiglitazone induces decreases in bone mass and strength that are reminiscent of aged bone. Endocrinology 148:2669–2680
Lecka-Czernik B (2010) PPARs in bone: the role in bone cell differentiation and regulation of energy metabolism. Curr Osteoporos Rep 8:84–90
Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ (1995) Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol 15:3012–3022
Lefebvre P, Chinetti G, Fruchart JC, Staels B (2006) Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116:571–580
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE (2007) Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 298:1180–1188
Loke YK, Singh S, Furberg CD (2009) Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180:32–39
Lonard DM, O’Malley BW (2006) The expanding cosmos of nuclear receptor coactivators. Cell 125:411–414
Lopez GN, Webb P, Shinsako JH, Baxter JD, Greene GL, Kushner PJ (1999) Titration by estrogen receptor activation function-2 of targets that are downstream from coactivators. Mol Endocrinol 13:897–909
Maher AC, Fu MH, Isfort RJ, Varbanov AR, Qu XA, Tarnopolsky MA (2009) Sex differences in global mRNA content of human skeletal muscle. PLoS One 4:e6335
Maher AC, Akhtar M, Vockley J, Tarnopolsky MA (2010) Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men. PLoS One 5:e12025
Mancini FP, Lanni A, Sabatino L, Moreno M, Giannino A, Contaldo F, Colantuoni V, Goglia F (2001) Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett 491:154–158
Mandard S, Muller M, Kersten S (2004) Peroxisome proliferator-activated receptor alpha target genes. Cell Mol Life Sci 61:393–416
Mannucci E, Monami M, Di Bari M, Lamanna C, Gori F, Gensini GF, Marchionni N (2010) Cardiac safety profile of rosiglitazone: a comprehensive meta-analysis of randomized clinical trials. Int J Cardiol 143:135–140
Manttari M, Huttunen JK, Koskinen P, Manninen V, Tenkanen L, Heinonen OP, Frick MH (1990) Lipoproteins and coronary heart disease in the Helsinki Heart Study. Eur Heart J 11(Suppl H):26–31
Masugi J, Tamori Y, Mori H, Koike T, Kasuga M (2000) Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. Biochem Biophys Res Commun 268:178–182
Mattevi VS, Zembrzuski VM, Hutz MH (2007) Effects of a PPARG gene variant on obesity characteristics in Brazil. Braz J Med Biol Res 40:927–932
McKenna NJ, O’Malley BW (2002) Combinatorial control of gene expression by nuclear receptors and coregulators. Cell 108:465–474
Morini E, Tassi V, Capponi D, Ludovico O, Dallapiccola B, Trischitta V, Prudente S (2008) Interaction between PPARgamma2 variants and gender on the modulation of body weight. Obesity (Silver Spring) 16:1467–1470
Nerbrand C, Nyberg P, Nordstrom L, Samsioe G (2002) Effects of a lipid lowering fibrate and hormone replacement therapy on serum lipids and lipoproteins in overweight postmenopausal women with elevated triglycerides. Maturitas 42:55–62
Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356:2457–2471
Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH et al (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98:5306–5311
Palmer CN, Hsu MH, Griffin KJ, Raucy JL, Johnson EF (1998) Peroxisome proliferator activated receptor-alpha expression in human liver. Mol Pharmacol 53:14–22
Patel J, Anderson RJ, Rappaport EB (1999) Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diabetes Obes Metab 1:165–172
Pejic RN, Lee DT (2006) Hypertriglyceridemia. J Am Board Fam Med 19:310–316
Phatak HM, Yin DD (2006) Factors associated with the effect-size of thiazolidinedione (TZD) therapy on HbA(1c): a meta-analysis of published randomized clinical trials. Curr Med Res Opin 22:2267–2278
Picard F, Auwerx J (2002) PPAR(gamma) and glucose homeostasis. Annu Rev Nutr 22:167–197
Reddy JK (2004) Peroxisome proliferators and peroxisome proliferator-activated receptor alpha: biotic and xenobiotic sensing. Am J Pathol 164:2305–2321
Ribalta J, Halkes CJ, Salazar J, Masana L, Cabezas MC (2005) Additive effects of the PPARgamma, APOE, and FABP-2 genes in increasing daylong triglycerides of normolipidemic women to concentrations comparable to those in men. Clin Chem 51:864–871
Rivellese AA, Riccardi G, Vaccaro O (2010) Cardiovascular risk in women with diabetes. Nutr Metab Cardiovasc Dis 20:474–480
Roepstorff C, Donsmark M, Thiele M, Vistisen B, Stewart G, Vissing K, Schjerling P, Hardie DG, Galbo H, Kiens B (2006) Sex differences in hormone-sensitive lipase expression, activity, and phosphorylation in skeletal muscle at rest and during exercise. Am J Physiol 291:E1106–E1114
Rogers NH, Perfield JW 2nd, Strissel KJ, Obin MS, Greenberg AS (2009) Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology 150:2161–2168
Ross R, Aru J, Freeman J, Hudson R, Janssen I (2002) Abdominal adiposity and insulin resistance in obese men. Am J Physiol 282:E657–E663
Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G et al (1999) Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 341:410–418
Ruotolo G, Ericsson CG, Tettamanti C, Karpe F, Grip L, Svane B, Nilsson J, de Faire U, Hamsten A (1998) Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT). J Am Coll Cardiol 32:1648–1656
Schernthaner G, Chilton RJ (2010) Cardiovascular risk and thiazolidinediones–what do meta-analyses really tell us? Diabetes Obes Metab 12:1023–1035
Semple RK, Chatterjee VK, O’Rahilly S (2006) PPAR gamma and human metabolic disease. J Clin Invest 116:581–589
Singh S, Loke YK, Furberg CD (2007) Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. JAMA 298:1189–1195
Singh V, Sharma R, Kumar A, Deedwania P (2010) Low high-density lipoprotein cholesterol: current status and future strategies for management. Vasc Health Risk Manag 6:979–996
Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC (1998) Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 98:2088–2093
Straus DS, Glass CK (2007) Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 28:551–558
Sundseth SS, Waxman DJ (1992) Sex-dependent expression and clofibrate inducibility of cytochrome P450 4A fatty acid omega-hydroxylases. Male specificity of liver and kidney CYP4A2 mRNA and tissue-specific regulation by growth hormone and testosterone. J Biol Chem 267:3915–3921
Syvanne M, Taskinen MR, Nieminen, Manninen V, Kesaniemi YA, Pasternack A, Nawrocki JW, Haber H, and Frick MH (1997) A study to determine the response of coronary atherosclerosis to raising low high density lipoprotein cholesterol with a fibric-acid derivative in men after coronary bypass surgery. The rationale, design, and baseline characteristics of the LOCAT Study. Lopid Coronary Angiography Trial. Control Clin Trials 18:93–119
Tarnopolsky MA (2008) Sex differences in exercise metabolism and the role of 17-beta estradiol. Med Sci Sports Exerc 40:648–654
Tobin JF, Freedman LP (2006) Nuclear receptors as drug targets in metabolic diseases: new approaches to therapy. Trends Endocrinol Metab 17:284–290
Tsuboyama-Kasaoka N, Takahashi M, Kim H, Ezaki O (1999) Up-regulation of liver uncoupling protein-2 mRNA by either fish oil feeding or fibrate administration in mice. Biochem Biophys Res Commun 257:879–885
Vaccaro O, Mancini FP, Ruffa G, Sabatino L, Colantuoni V, Riccardi G (2000) Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study. Int J Obes Relat Metab Disord 24:1195–1199
Vaccaro O, Boemi M, Cavalot F, De Feo P, Miccoli R, Patti L, Rivellese AA, Trovati M, Ardigo D, Zavaroni I (2008) The clinical reality of guidelines for primary prevention of cardiovascular disease in type 2 diabetes in Italy. Atherosclerosis 198:396–402
Vakkilainen J, Steiner G, Ansquer JC, Aubin F, Rattier S, Foucher C, Hamsten A, Taskinen MR (2003) Relationships between low-density lipoprotein particle size, plasma lipoproteins, and progression of coronary artery disease: the Diabetes Atherosclerosis Intervention Study (DAIS). Circulation 107:1733–1737
Vlckova V, Cornelius V, Kasliwal R, Wilton L, Shakir S (2010) Hypoglycaemia with pioglitazone: analysis of data from the Prescription-Event Monitoring study. J Eval Clin Pract 16:1124–1128
Wan Y, Chong LW, Evans RM (2007) PPAR-gamma regulates osteoclastogenesis in mice. Nat Med 13:1496–1503
Wang X, Kilgore MW (2002) Signal cross-talk between estrogen receptor alpha and beta and the peroxisome proliferator-activated receptor gamma1 in MDA-MB-231 and MCF-7 breast cancer cells. Mol Cell Endocrinol 194:123–133
Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans RM (2003) Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113:159–170
Wang Y, Fang F, Wong CW (2010) Troglitazone is an estrogen-related receptor alpha and gamma inverse agonist. Biochem Pharmacol 80:80–85
Wei W, Wang X, Yang M, Smith LC, Dechow PC, Sonoda J, Evans RM, Wan Y (2010) PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. Cell Metab 11:503–516
Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR (1997) Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 241:270–274
Yepuru M, Eswaraka J, Kearbey JD, Barrett CM, Raghow S, Veverka KA, Miller DD, Dalton JT, Narayanan R (2010) Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice. J Biol Chem 285:31292–31303
Yki-Jarvinen H (2004) Thiazolidinediones. N Engl J Med 351:1106–1118
Yoon M, Jeong S, Nicol CJ, Lee H, Han M, Kim JJ, Seo YJ, Ryu C, Oh GT (2002) Fenofibrate regulates obesity and lipid metabolism with sexual dimorphism. Exp Mol Med 34:481–488
Yusuf S, Hawken S, Ounpuu S, Bautista L, Franzosi MG, Commerford P, Lang CC, Rumboldt Z, Onen CL, Lisheng L et al (2005) Obesity and the risk of myocardial infarction in 27,000 participants from 52 countries: a case-control study. Lancet 366:1640–1649
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer-Verlag Berlin Heidelberg
About this chapter
Cite this chapter
Benz, V., Kintscher, U., Foryst-Ludwig, A. (2013). Sex-Specific Differences in Type 2 Diabetes Mellitus and Dyslipidemia Therapy: PPAR Agonists. In: Regitz-Zagrosek, V. (eds) Sex and Gender Differences in Pharmacology. Handbook of Experimental Pharmacology, vol 214. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-30726-3_18
Download citation
DOI: https://doi.org/10.1007/978-3-642-30726-3_18
Published:
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-30725-6
Online ISBN: 978-3-642-30726-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)