1H NMR-based metabolomic study on resistance to diet-induced obesity in AHNAK knock-out mice

Il Yong Kim, Jeeyoun Jung, Mi Jang, Yun Gyong Ahn, Jae Hoon Shin, Ji Won Choi, Mi Ra Sohn, Sun Mee Shin, Dae Gil Kang, Ho Sub Lee, Yun Soo Bae, Do Hyun Ryu, Je Kyung Seong, Geum Sook Hwang

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32 Scopus citations

Abstract

AHNAK is a giant protein of approximately 700kDa identified in human neuroblastomas and skin epithelial cells. Recently, we found that AHNAK knock-out (AHNAK-/-) mice have a strong resistance to high-fat diet-induced obesity. In this study, we applied 1H NMR-based metabolomics with multivariate statistical analysis to compare the altered metabolic patterns detected in urine from high-fat diet (HFD) fed wild-type and AHNAK-/- mice and investigate the mechanisms underlying the resistance to high-fat diet-induced obesity in AHNAK-/- mice. In global profiling, principal components analysis showed a clear separation between the chow diet and HFD groups; wild-type and AHNAK-/- mice were more distinctly separated in the HFD group compared to the chow diet group. Based on target profiling, the urinary metabolites of HFD-fed AHNAK-/- mice gave higher levels of methionine, putrescine, tartrate, urocanate, sucrose, glucose, threonine, and 3-hydroxyisovalerate. Furthermore, two-way ANOVAs indicated that diet type, genetic type, and their interaction (gene×diet) affect the metabolite changes differently. Most metabolites were affected by diet type, and putrescine, threonine, urocanate, and tartrate were also affected by genetic type. In addition, cis-aconitate, succinate, glycine, histidine, methylamine (MA), phenylacetylglycine (PAG), methionine, putrescine, uroconate, and tartrate showed interaction effects. Through the pattern changes in urinary metabolites of HFD-fed AHNAK-/- mice, our data suggest that the strong resistance to HFD-induced obesity in AHNAK-/- mice comes from perturbations of amino acids, such as methionine, putrescine, threonine, and histidine, which are related to fat metabolism. The changes in metabolites affected by microflora such as PAG and MA were also observed. In addition, resistance to obesity in HFD-fed AHNAK-/- mice was not related to an activated tricarboxylic acid cycle. These findings demonstrate that 1H NMR-based metabolic profiling of urine is suitable for elucidating possible biological pathways perturbed by functional loss of AHNAK on HFD feeding and could elucidate the mechanism underlying the resistance to high-fat diet-induced obesity in AHNAK-/- mice.

Original languageEnglish
Pages (from-to)428-434
Number of pages7
JournalBiochemical and Biophysical Research Communications
Volume403
Issue number3-4
DOIs
StatePublished - 17 Dec 2010

Bibliographical note

Funding Information:
This research was supported grants from National Research Foundation of Korea funded by the Korean Ministry of Education, Science and Technology ( 2009-008146 and PGA048) and Korea Basic Science Institute to Hwang GS; grant by Basic Science Research Program (No. R13-2008-028-01000-0 ) of the National Research Foundation of Korea funded by the Ministry of Education Science and Technology of Korea to Lee HS,; Research of New Drug Target Discovery by the Ministry of Education, Science and Technology of Korea to Seong J.K. (No. 20100020468 ) and Bae Y.S. (No. 20090093987 ).

Keywords

  • AHNAK
  • H NMR
  • High-fat diet
  • Metabolic profiling
  • Metabolomics

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