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

  • Exp Clin Endocrinol Diabetes. 2022 Apr;130(4):254-261. doi: 10.1055/a-1400-2656.
Kahori Shimizu  1 ,  Yuya Ogiya  1 ,  Kaede Yoshinaga  1 ,  Hajime Kimura  1 ,  Shotaro Michinaga  2 ,  Moe Ono  3 ,  Ayako Taketomi  1 ,  Tomoyuki Terada  1 ,  Fuminori Sakurai  4 ,  Hiroyuki Mizuguchi  4  5  6  7 ,  Koji Tomita  3 ,  Toru Nishinaka  1
Affiliations
  • 1. Laboratory of Biochemistry, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan.
  • 2. Laboratory of Pharmacology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan.
  • 3. Laboratory of Molecular Biology, Faculty of Pharmacy, Osaka Ohtani University, Osaka, Japan.
  • 4. Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
  • 5. The Center for Advanced Medical Engineering and Informatics, Osaka University, Osaka, Japan.
  • 6. Laboratory of Hepatocyte Differentiation, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan.
  • 7. Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Osaka, Japan.
PMID: 33782927 DOI: 10.1055/a-1400-2656
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.

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