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Makino N, Maeda T, Oyama J, Higuchi Y, Mimori K. Improving insulin sensitivity via activation of PPAR-[gamma]/increases telomerase activity in the heart of OLETF rats. Am J Physiol Heart Circ Physiol 297: H2188-H2195, 2009. First published October 23, 2009; doi: 10.1152/ajpheart.00421.2009.--This study was conducted to examine telomere biology in terms of improving insulin sensitivity in a type 2 diabetic animal model: Otsuka Long-Evans Tokushima fatty (OLETF) rats. To improve insulin sensitivity, pioglitazone (PG; 10 mg x kg-1. day-1) was administrated to OLETF rats from 20 to 40 wk of age, and the effects of treatment were compared with those in untreated OLETF or control Long-Evans Tokushima Otsuka fatty rats. At the end of the study, the homeostasis model assessment of insulin resistance significantly increased in OLETF rats but decreased in OLETF rats treated with PG. No shortening of telomere length was observed in the heart tissue of OLETF rats, whereas telomerase activity was decreased in OLETF heart tissue. The mRNA expression of both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. The protein expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase was reduced in OLETF rats. On the other hand, myocardial matrix metalloproteinase-9 expression was elevated in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. However, protein and mRNA expression of Sirtl, a lifespan modulator, were attenuated in OLETF rat hearts, although they were enhanced in OLETF rats with PG treatement. Myocardial fibrosis was less extensive and diastolic dysfunction more greatly ameliorated in PG-treated OLETF rats than in OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisom proliferator-activated receptor-[gamma] may exert regulatory effects on cardiac telomere biology and may have desirable morphological and functional effects on the diabetic heart. telomere; pioglitazone; remodeling; diabetes; peroxisome proliferatot- activated receptor-gamma; Otsuka Long-Evans Tokushima fatty rats doi: 10.1152/ajpheart.00421.2009

A telomere is a repetitive DNA structure capping the chromosomal ends. Telomeres stabilize the chromosome structure and prevent harmful end-to-end recombinations. The telomere length of somatic cells can be determined as the terminal restriction fragment length provided by a genomic Southern blotting analysis, and the telomere length becomes shorter at each mitotic cycle due to an 'end-replication problem.' Therefore, older somatic cells, which have undergone more mitotic cycles, bear shorter telomeres. This telomere shortening is accelerated by various disease conditions. Parkinson's disease (PD) also yields telomere fragility, thus accelerating the telomere shortening of the circulating leukocytes. This study found that peripheral leukocytes of Japanese PD patients bear fewer short telomeres with constant subtelomeric methylation status in comparison with the healthy controls with increasing short telomeres and also increasing hypomethylated subtelomeres in short telomeres with aging. The correlation between the telomeric attrition and the subtelomeric methylated state in PD is herein discussed. Key Words: Subtelomere--Aging--DNA methylation--Parkinson's disease--Japanese.

Fatty acids stimulate lipid accumulation in parallel with increased expression of adipose differentiation-related protein (ADRP) in liver cells. Although it is generally considered that the fatty acid effect on ADRP expression is mediated by peroxisome proliferator-activated receptors (PPARs), we identified here an additional molecular mechanism using the NMuLi mouse liver nonparenchymal cell line, which expresses PPAR[gamma] and but not [alpha]. Oleic acid (OA) and specific ligands for PPAR[gamma] and -[delta] stimulated ADRP expression as well as the -2,090-bp ADRP promoter activity which encompasses the PPAR response element (PPRE) adjacent to an Ets/activator protein (AP)-1 site. When the AP-1 site was mutated, OA failed to stimulate the activity despite the presence of the PPRE, whereas ligands for PPAR[gamma] and -[delta] did stimulate it and so did a PPAR[alpha] ligand under the coexpression of PPAR[alpha]. DNA binding of AP-1 was stimulated by OA but not by PPAR ligands. Because we previously demonstrated that Pycnogenol (PYC), a French maritime pine bark extract, suppressed ADRP expression in macrophages partly by sappression of AP-1 activity, we tested the effect of PYC on NMuLi cells. PYC reduced the OA-induced ADRP expression along with suppression of lipid droplet formation. However, PYC neither suppressed the OA-stimulated ADRP promoter activity nor DNA binding of AP-1 but, instead, reduced the ADRP mRNA half-life. All these results indicate that the effect of OA on ADRP expression requires AP- 1 as well as PPRE, and PYC suppresses the ADRP expression in part by facilitating mRNA degradation. PYC, a widely used dietary supplement, could be beneficial for the prevention of excessive lipid accumulation such as hepatic steatosis. lipid droplet; hepatic steatosis; adipose differentiation-related protein; activator protein-1, peroxisome proliferator-activated receptor

Telomeres in somatic cells become shorter with aging, and the shortening is accelerated by pathophysiological conditions. Telomere shortening can be influenced by subtelomeric DNA methylation. The telomere length and subtelomeric methylation status in peripheral leukocytes were compared in healthy controls and sarcoidosis patients. The sarcoidosis patients revealed shorter telomeres and a faster attrition of telomere shortening in comparison with healthy controls. Both healthy controls and sarcoidosis patients showed that long telomeres (>9.4 kb) decrease and short telomeres ( Key Words: Sarcoidosis--DNA methylation--Subtelomere--Telomere--Aging.

Background. The telomeres of somatic cells become shorter with individual aging. However. no significant change in subtelomeric methylation of somatic cells with aging has yet been reported. Methods. Telomere lengths of the peripheral blood cells of 148 normal Japanese were analyzed by Southern blotting using methylation-sensitive and -insensitive isoschizomers. Results. With aging, long telomeres decrease and short telomeres increase, and the contents of the telomeres with methylated subtelomere increase in long telomeres, thus leading us to postulate that telomeres with less methylated subtelomeres tend to become shortened faster. Conclusions. A telomere length distribution analysis with methylation-sensitive and -insensitive isoschizomer seems to be a useful tool to assess the subtelomeric methylation status of the somatic cell population. The subtelomeric methylation of peripheral blood cells is also indicated to be an indicator for aging-associated genomic changes. Key Words: Telomere--Aging--DNA methylation--Japanese.