Depot-Specific Changes in Fat Metabolism with Aging in a Type 2 Diabetic Animal Model

Abstract

Visceral fat accretion is a hallmark of aging and is associated with aging-induced metabolic dysfunction. PPARγ agonist was reported to improve insulin sensitivity by redistributing fat from visceral fat to subcutaneous fat. The purpose of this study was to investigate the underlying mechanisms by which aging affects adipose tissue remodeling in a type 2 diabetic animal model and through which PPARγ activation modulates aging-related fat tissue distribution. At the ages of 21, 31 and 43 weeks, OLETF rats as an animal model of type 2 diabetes were evaluated for aging-related effects on adipose tissue metabolism in subcutaneous and visceral fat depots. During aging, the ratio of visceral fat weight to subcutaneous fat weight (V/S ratio) increased. Aging significantly increased the mRNA expression of genes involved in lipogenesis such as lipoprotein lipase, fatty acid binding protein aP2, lipin 1, and diacylglycerol acyltransferase 1, which were more prominent in visceral fat than subcutaneous fat. The mRNA expression of adipose triglyceride lipase, which is involved in basal lipolysis and fatty acid recycling, was also increased, more in visceral fat compared to subcutaneous fat during aging. The mRNA levels of the genes associated with lipid oxidation were increased, whereas the mRNA levels of genes associated with energy expenditure showed no significant change during aging. PPARγ agonist treatment in OLETF rats resulted in fat redistribution with a decreasing V/S ratio and improved glucose intolerance. The genes involved in lipogenesis decreased in visceral fat of the PPARγ agonist-treated rats. During aging, fat distribution was changed by stimulating lipid uptake and esterification in visceral fat rather than subcutaneous fat, and by altering the lipid oxidation.

Fig 1

The effect of aging on the weight of subcutaneous fat/visceral fat ratio (A), OGTT (B), AUC during OGTT (C), adipocyte size distribution of subcutaneous fat (D) and visceral fat (E), and PPARγ2 mRNA levels (F). (*P <0.05 vs. the same deposit in the untreated OLETF rats, ^†P<0.05 vs. subcutaneous fat in the same group.)

Fig 2. The effects of aging on the genes involved in adipose fatty acid uptake, esterification and triacylglycerol synthesis.

The effects of aging on the gene expression were analyzed by 2-way ANOVA (*P <0.05 vs. OLETF rats at 21 weeks of age). The effects of rosiglitazone on the metabolic genes in each fat depot were evaluated among the different groups at 21 weeks (†P <0.05 vs. the same deposit in OLETF rats at 21 weeks; RGZ, rosiglitazone treated).

Fig 3. The effects of aging on the genes involved in glycerol and fatty acid recycling.

The effects of aging on the gene expression were analyzed by 2-way ANOVA (*P <0.05 vs. OLETF rats at 21 weeks of age). The effects of rosiglitazone on the metabolic genes in each fat depot were evaluated among the different groups at 21 weeks (†P <0.05 vs. the same deposit in OLETF rats at 21 weeks; RGZ, rosiglitazone treated).

Fig 4. The effects of aging on the genes involved in fatty acid oxidation and energy expenditure.

The effects of aging on the gene expression were analyzed by 2-way ANOVA (*P <0.05 vs. OLETF rats at 21 weeks of age). The effects of rosiglitazone on the metabolic genes in each fat depot were evaluated among the different groups at 21 weeks (†P <0.05 vs. the same deposit in OLETF rats at 21 weeks; RGZ, rosiglitazone treated).