Significant alteration of liver metabolites by AAV8.Urocortin 2 gene transfer in mice with insulin resistance.

Abstract

INTRODUCTION:

Urocortin 2 (Ucn2) is a 38-amino acid peptide of the corticotropin-releasing factor family. Intravenous (IV) delivery of an adeno-associated virus vector serotype 8 encoding Ucn2 (AAV8.Ucn2) increases insulin sensitivity and glucose disposal in mice with insulin resistance.

OBJECTIVE:

To determine the effects of Ucn2 on liver metabolome.

METHODS:

Six-week-old C57BL6 mice were divided into normal chow (CHOW)-fed and high fat diet (HFD)-fed groups. The animals received saline, AAV8 encoding no gene (AAV8.Empt) or AAV8.Ucn2 (2x1013 genome copy/kg, IV injection). Livers were isolated from CHOW-fed and HFD-fed mice and analyzed by untargeted metabolomics. Group differences were statistically analyzed.

RESULTS:

In CHOW-fed mice, AAV8.Ucn2 gene transfer (vs. saline) altered the metabolites in glycolysis, pentose phosphate, glycogen synthesis, glycogenolysis, and choline-folate-methionine signaling pathways. In addition, AAV8.Ucn2 gene transfer increased amino acids and peptides, which were associated with reduced protein synthesis. In insulin resistant (HFD-induced) mice, HFD (vs CHOW) altered 448 (112 increased and 336 decreased) metabolites and AAV8.Ucn2 altered 239 metabolites (124 increased and 115 reduced) in multiple pathways. There are 61 metabolites in 5 super pathways showed interactions between diet and AAV8.Ucn2 treatment. Among them, AAV8.Ucn2 gene transfer reversed HFD effects on 13 metabolites. Finally, plasma Ucn2 effects were determined using a 3-group comparison of HFD-fed mice that received AAV8.Ucn2, AAV.Empt or saline, where 18 metabolites that altered by HFD (15 increased and 3 decreased), but restored levels to that seen in CHOW-fed mice by increased plasma Ucn2.

CONCLUSIONS:

Metabolomics study revealed that AAV8.Ucn2 gene transfer, through increased plasma Ucn2, provided counter-HFD effects in restoring hepatic metabolites to normal levels, which could be the underlying mechanisms for Ucn2 effects on increasing glucose disposal and reducing insulin assistance.

• Authors: Young Chul Kim, Agnieszka D Truax, Dimosthenis Giamouridis, N Chin Lai, Tracy Guo, H Kirk Hammond, Mei Hua Gao
• Journal: PloS one (PLoS One) Vol. 14 Issue 12 Pg. e0224428 ( 2019) ISSN: 1932-6203 [Electronic] United States
• PMID: 31790421 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Urocortins
• Glucose

Topics

• Animals
• Dependovirus (genetics)
• Gene Transfer Techniques
• Genetic Vectors (genetics)
• Glucose (metabolism)
• Homeostasis (genetics)
• Insulin Resistance (genetics)
• Liver (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Urocortins (genetics)