Exercise-induced cardiac hypertrophy has been recently identified to be regulated in a sex-specific manner. In parallel, women exhibit enhanced exercise-mediated lipolysis compared with men, which might be linked to cardiac responses. The aim of the present study was to assess if previously reported sex-dependent differences in the cardiac hypertrophic response during exercise are associated with differences in cardiac energy substrate availability/utilization. Female and male C57BL/6J mice were challenged with active treadmill running for 1.5 h/day (0.25 m/s) over 4 wk. Mice underwent cardiac and metabolic phenotyping including echocardiography, small-animal PET, peri-exercise indirect calorimetry, and analysis of adipose tissue (AT) lipolysis and cardiac gene expression. Female mice exhibited increased cardiac hypertrophic responses to exercise compared with male mice, measured by echocardiography [percent increase in left ventricular mass (LVM): female: 22.2 ± 0.8%, male: 9.0 ± 0.2%; P < 0.05]. This was associated with increased plasma free fatty acid (FFA) levels and augmented AT lipolysis in female mice after training, whereas FFA levels from male mice decreased. The respiratory quotient during exercise was significantly lower in female mice indicative for preferential utilization of fatty acids. In parallel, myocardial glucose uptake was reduced in female mice after exercise, analyzed by PET {injection dose (ID)/LVM [%ID/g]: 36.8 ± 3.5 female sedentary vs. 28.3 ± 4.3 female training; P < 0.05}, whereas cardiac glucose uptake was unaltered after exercise in male counterparts. Cardiac genes involved in fatty acid uptake/oxidation in females were increased compared with male mice. Collectively, our data demonstrate that sex differences in exercise-induced cardiac hypertrophy are associated with changes in cardiac substrate availability and utilization.

Expression of selected genes coding for proteins with defined cellular functions was analysed in human cell lines derived from normal colonic mucosa, non‐mucinous colonic carcinomas and mucinous colonic carcinomas. Altered expression of 10 genes in colon carcinoma cells was found by using a cDNA array; 6 of these alterations (60%) were confirmed by Northern blotting or semi‐quantitative reverse transcription‐polymerase chain reaction (RT‐PCR). Among these 6 genes, 3 transcription factors as well as the topoisomerase II α and the mitosis inhibitor WEE1Hu gene were significantly suppressed in the tumour cell lines. In addition, the gene coding for the cell cycle inhibitor p21 was overexpressed only in cell lines derived from mucinous carcinomas. The significant suppression of the kinase WEE1Hu gene in carcinoma cells of both phenotypes and the tendency of the mucinous phenotype to overexpress p21 protein were confirmed in human colon carcinoma tissues. Our data show that the cDNA array method permits a correct identification of changes in gene expression with a relatively high accuracy. The different expression of the p21 gene in the non‐mucinous and mucinous carcinoma cells supports the hypothesis that these phenotypes may develop along different genetic pathways. The detection of WEE1Hu gene suppression in colon carcinoma cells and tissues suggests its potential role in tumourigenesis. Int. J. Cancer 82:868–874, 1999. © 1999 Wiley‐Liss, Inc.

OBJECTIVE-The angiotensin type 1 receptor blocker (ARB) and peroxisome proliferator-activated receptor (PPAR) ␥ modulator telmisartan has been recently demonstrated to reduce plasma triglycerides in nondiabetic and diabetic hypertensive patients. The present study investigates the molecular mechanisms of telmisartans hypolipidemic actions, in particular its effect on the PPAR␣ pathway.RESEARCH DESIGN AND METHODS-Regulation of PPAR␣ target genes by telmisartan was studied by real-time PCR and Western immunoblotting in vitro and in vivo in liver/skeletal muscle of mice with diet-induced obesity. Activation of the PPAR␣ ligand binding domain (LBD) was investigated using transactivation assays.RESULTS-Telmisartan significantly induced the PPAR␣ target genes carnitine palmitoyl transferase 1A (CPT1A) in human HepG2 cells and acyl-CoA synthetase long-chain family member 1 (ACSL1) in murine AML12 cells in the micromolar range. Telmisartan-induced CPT1A stimulation was markedly reduced after small interfering RNA-mediated knockdown of PPAR␣. Telmisartan consistently activated the PPAR␣-LBD as a partial PPAR␣ agonist. Despite high in vitro concentrations required for PPAR␣ activation, telmisartan (3 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ) potently increased ACSL1 and CPT1A expression in liver from dietinduced obese mice associated with a marked decrease of hepatic and serum triglycerides. Muscular CPT1B expression was not affected. Tissue specificity of telmisartan-induced PPAR␣ target gene induction may be the result of previously reported high hepatic concentrations of telmisartan.CONCLUSIONS-The present study identifies the ARB/PPAR␥ modulator telmisartan as a partial PPAR␣ agonist. As a result of its particular pharmacokinetic profile, PPAR␣ activation by telmisartan seems to be restricted to the liver. Hepatic PPAR␣ activation may provide an explanation for telmisartan's antidyslipidemic actions observed in recent clinical trials.