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- Title
CycloZ Improves Hyperglycemia and Lipid Metabolism by Modulating Lysine Acetylation in KK-Ay Mice.
- Authors
Jongsu Jeon; Dohyun Lee; Bobae Kim; Bo-Yoon Park; Chang Joo Oh; Min-Ji Kim; Jae-Han Jeon; In-Kyu Lee; Onyu Park; Seoyeong Baek; Chae Won Lim; Dongryeol Ryu; Sungsoon Fang; Auwerx, Johan; Kyong-Tai Kim; Hoe-Yune Jung
- Abstract
Background: CycloZ, a combination of cyclo-His-Pro and zinc, has anti-diabetic activity. However, its exact mode of action remains to be elucidated. Methods: KK-Ay mice, a type 2 diabetes mellitus (T2DM) model, were administered CycloZ either as a preventive intervention, or as a therapy. Glycemic control was evaluated using the oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels. Liver and visceral adipose tissues (VATs) were used for histological evaluation, gene expression analysis, and protein expression analysis. Results: CycloZ administration improved glycemic control in KK-Ay mice in both prophylactic and therapeutic studies. Lysine acetylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, liver kinase B1, and nuclear factor-κB p65 was decreased in the liver and VATs in CycloZ-treated mice. In addition, CycloZ treatment improved mitochondrial function, lipid oxidation, and inflammation in the liver and VATs of mice. CycloZ treatment also increased the level of ß-nicotinamide adenine dinucleotide (NAD+), which affected the activity of deacetylases, such as sirtuin 1 (Sirt1). Conclusion: Our findings suggest that the beneficial effects of CycloZ on diabetes and obesity occur through increased NAD+ synthesis, which modulates Sirt1 deacetylase activity in the liver and VATs. Given that the mode of action of an NAD+ booster or Sirt1 deacetylase activator is different from that of traditional T2DM drugs, CycloZ would be considered a novel therapeutic option for the treatment of T2DM.
- Subjects
PGC-1 protein; LIPID metabolism; TYPE 2 diabetes; GLYCOSYLATED hemoglobin; GLUCOSE tolerance tests
- Publication
Diabetes & Metabolism Journal, 2023, Vol 47, Issue 5, p653
- ISSN
2233-6079
- Publication type
Article
- DOI
10.4093/dmj.2022.0244