Research Article: Influence of long term administration of tofogliflozin on chronic inflammation of visceral adipose tissue in mice with obesity induced by a high-fat diet

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Kohsuke Shirakawa, Wataru Yano, Keisuke Inoue, Yoshinori Katsumata, Jin Endo, Motoaki Sano, Marcia B. Aguila.


We previously found that senescence of cluster of differentiation 4 (CD4) T cells is accelerated in the visceral adipose tissue (VAT) of mice with diet-induced obesity (DIO) due to a high-fat diet (HFD), and that these senescent-associated T cells cause chronic inflammation of visceral adipose tissue through secretion of osteopontin, provoking systemic insulin resistance. In this study, we examined whether the development of chronic inflammation and senescence-associated T cells in VAT of DIO mice was improved by long-term weight loss after switching to normal chow (NC) or by administration of a sodium glucose cotransporter 2 inhibitor (tofogliflozin). Wild-type mice were fed an HFD for 26 weeks from 4 weeks old. At 30 weeks of age, half of these DIO mice were switched to NC with or without 0.005% tofogliflozin for 38 weeks. The other mice remained on the HFD with or without 0.005% tofogliflozin for 38 weeks. When DIO mice were switched to NC, their weight decreased to that of mice kept on NC since weaning. After 38 weeks (68 weeks of age), chronic inflammation of the VAT subsided with disappearance of senescence-associated T cells. In the HFD groups, the carbohydrate intake per mouse was half or less of that in the NC group, and urinary glucose excretion by the effect of tofogliflozin was lower in the HFD mice than in the NC mice. Mice that remained on the HFD showed no improvement in chronic inflammation in VAT, possibly because urinary glucose excretion was not sufficiently promoted by tofogliflozin due to the low carbohydrate intake. Thus, no improvement in glucose metabolism or weight loss was observed in these mice.

Partial Text

Accumulation of visceral fat causes hypertension, diabetes mellitus, and dyslipidemia, leading to the development of cardiovascular disease, chronic kidney disease, or cancer over time [1–6]. These processes associated with the metabolic syndrome are also called the metabolic domino effect [7]. In addition to chronological aging, the acceleration of aging associated with the metabolic syndrome is called metabo-aging [7]. We previously found that senescence of immune cells is involved in the mechanism by which accumulation of visceral fat causes metabolic syndrome and/or metabo-aging [8].

When DIO mice fed an HFD until 30 weeks of age were switched to NC, their food intake calculated from two cages per group tended to decrease transiently and their weight also declined (Fig 1A and 1B). Although the calorie intakes rapidly returned to the same as those of HFD (Fig 1B and 1C), the body weight after weight loss was maintained. Adding 0.005% tofogliflozin to NC did not affect the food intake or body weight. When mice remained on the HFD, their body weight continued to increase until it reached a plateau around 50 weeks of age. Adding 0.005% tofogliflozin to the HFD did not affect the food intake or body weight of these mice until 50 weeks of age (Fig 1A and 1B).

Chronic inflammation of visceral fat induced by an HFD showed improvement with disappearance of senescence-associated T cells after long-term weight reduction. In our HFD mice with a small carbohydrate load, weight reduction and improvement in glucose metabolism by tofogliflozin were not observed, suggesting that SGLT2 inhibitor therapy is not effective unless there is a certain glucose load. Therefore, it may be difficult to observe the organ-protective effects of SGLT2 inhibitor therapy (inhibition of microalbuminuria, cardiac or renal hypertrophy, chronic inflammation of visceral fat) unless a model is devised in which the SGLT2 inhibitor significantly increases urinary glucose excretion, decreases blood glucose, improves glucose toxicity, and restores endogenous insulin secretion. Whether tofogliflozin could inhibit chronic inflammation of visceral fat in such a model warrants further investigation.




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