ZFAND3 Overexpression in the Mouse Liver Improves Glucose Tolerance and Hepatic Insulin Resistance

Kahori Shimizu; Yuya Ogiya; Kaede Yoshinaga; Hajime Kimura; Shotaro Michinaga; Moe Ono; Ayako Taketomi; Tomoyuki Terada; Fuminori Sakurai; Hiroyuki Mizuguchi; Koji Tomita; Toru Nishinaka

doi:10.1055/a-1400-2656

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2022; 130(04): 254-261
DOI: 10.1055/a-1400-2656

Article

ZFAND3 Overexpression in the Mouse Liver Improves Glucose Tolerance and Hepatic Insulin Resistance

Kahori Shimizu

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Yuya Ogiya

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Kaede Yoshinaga

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Hajime Kimura

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Shotaro Michinaga

²Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Moe Ono

³Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Ayako Taketomi

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Tomoyuki Terada

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Fuminori Sakurai

⁴Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

,

Hiroyuki Mizuguchi

⁴Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

⁵The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan

⁶Laboratory of Hepatocyte Differentiation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan

⁷Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.

,

Koji Tomita

³Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

,

Toru Nishinaka

¹Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan

› Author Affiliations

Abstract

Genome-wide association studies have identified more than 300 loci associated with type 2 diabetes mellitus; however, the mechanisms underlying their role in type 2 diabetes mellitus susceptibility remain largely unknown. Zinc finger AN1-type domain 3 (ZFAND3), known as testis-expressed sequence 27, is a type 2 diabetes mellitus-susceptibility gene. Limited information is available regarding the physiological role of ZFAND3 in vivo. This study aimed to investigate the association between ZFAND3 and type 2 diabetes mellitus. ZFAND3 was significantly upregulated in the liver of diabetic mice compared to wild-type mice. To overexpress ZFAND3, we generated a ZFAND3-expressing adenovirus (Ad) vector using an improved Ad vector exhibiting significantly lower hepatotoxicity (Ad-ZFAND3). Glucose tolerance was significantly improved in Ad-ZFAND3-treated mice compared to the control Ad-treated mice. ZFAND3 overexpression in the mouse liver also improved insulin resistance. Furthermore, gluconeogenic gene expression was significantly lower in primary mouse hepatocytes transduced with Ad-ZFAND3 than those transduced with the control Ad vector. The present results suggest that ZFAND3 improves glucose tolerance by improving insulin resistance and suppressing gluconeogenesis, serving as a potential novel therapeutic target for type 2 diabetes mellitus.

Key words

ZFAND3 - type 2 diabetes mellitus - adenovirus vector - glucose metabolism - genome-wide association studies

Full Text

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Supplementary Material