Yuichiro Nishida1, Kazutoshi Nishijima2, Yosuke Yamada3, Hiroaki Tanaka4, Akiko Matsumoto5, Jianglin Fan6, Yoichi Uda7, Hajime Tomatsu7, Hiroyuki Yamamoto7, Kenjiro Kami7, Shuji Kitajima8, Keitaro Tanaka9. 1. Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan. ynishida@cc.saga-u.ac.jp. 2. Center for Animal Resources and Collaborative Study, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan. 3. National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Tokyo, Japan. 4. Laboratory of Exercise Physiology, Faculty of Health and Sports Science, Fukuoka University, Fukuoka, Japan. 5. Department of Environmental Medicine, Faculty of Medicine, Saga University, Saga, Japan. 6. Department of Molecular Pathology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Yamanashi, Japan. 7. Human Metabolome Technologies, Inc, Tsuruoka, Japan. 8. Division of Biological Resources and Development, Analytical Research Center for Experimental Sciences, Saga University, Saga, Japan. 9. Department of Preventive Medicine, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Abstract
INTRODUCTION: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. OBJECTIVES: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. METHODS: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. RESULTS: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). CONCLUSION: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression.
INTRODUCTION: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. OBJECTIVES: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. METHODS: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. RESULTS: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). CONCLUSION: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression.
Authors: S Kitajima; M Morimoto; E Liu; T Koike; Y Higaki; Y Taura; K Mamba; K Itamoto; T Watanabe; K Tsutsumi; N Yamada; J Fan Journal: Diabetologia Date: 2004-06-25 Impact factor: 10.122
Authors: Elena S F Berman; Tracy Swibas; Wendy M Kohrt; Vicki A Catenacci; Seth A Creasy; Edward L Melanson; John R Speakman Journal: Eur J Clin Nutr Date: 2019-08-19 Impact factor: 4.016