title: 1H NMR-based metabolomic study on resistance to diet-induced obesity in AHNAK knock-out mice.
abstract: AHNAK is a giant protein of approximately 700 kDa 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 (1)H 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 (1)H 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.
authors.affiliation: Laboratory of Developmental Biology and Genomics, College of Veterinary Medicine, BK21 Program for Veterinary Science, Research Institute for Veterinary Science, Seoul National University, Seoul 151-742, Republic of Korea.
authors.forename: Il Yong
authors.initials: IY
authors.lastname: Kim
authors.forename: Jeeyoun
authors.initials: J
authors.lastname: Jung
authors.forename: Mi
authors.initials: M
authors.lastname: Jang
authors.forename: Yun Gyong
authors.initials: YG
authors.lastname: Ahn
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Shin
authors.forename: Ji Won
authors.initials: JW
authors.lastname: Choi
authors.forename: Mi Ra
authors.initials: MR
authors.lastname: Sohn
authors.forename: Sun Mee
authors.initials: SM
authors.lastname: Shin
authors.forename: Dae-Gil
authors.initials: DG
authors.lastname: Kang
authors.forename: Ho-Sub
authors.initials: HS
authors.lastname: Lee
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.forename: Do Hyun
authors.initials: DH
authors.lastname: Ryu
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.forename: Geum-Sook
authors.initials: GS
authors.lastname: Hwang
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D004032:Diet / Q000009:adverse effects*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects*; D009682:Magnetic Resonance Spectroscopy; D008565:Membrane Proteins / Q000235:genetics*; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics*; D009765:Obesity / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*
chemical_list: C489572:Ahnak protein, mouse; D004041:Dietary Fats; D008565:Membrane Proteins; D009363:Neoplasm Proteins