Global Metabolic Profiling of Plasma Shows that Three-Year Mild-Caloric Restriction Lessens an Age-Related Increase in Sphingomyelin and Reduces L-leucine and L-phenylalanine in Overweight and Obese Subjects

Minjoo Kim, Sang-Hyun Lee, Jong Ho Lee, Minjoo Kim, Sang-Hyun Lee, Jong Ho Lee

Abstract

The effect of weight loss from long-term, mild-calorie diets (MCD) on plasma metabolites is unknown. This study was to examine whether MCD-induced weight reduction caused changes in the extended plasma metabolites. Overweight and obese subjects aged 40-59 years consumed a MCD (approximately 100 kcal/day deficit, n=47) or a weight-maintenance diet (control, n=47) in a randomized, controlled design with a three-year clinical intervention period and plasma samples were analyzed by using UPLC-LTQ-Orbitrap mass spectrometry. The three-year MCD intervention resulted in weight loss (-8.87%) and significant decreases in HOMA-IR and TG. The three-year follow-up of the MCD group showed reductions in the following 13 metabolites: L-leucine; L-phenylalanine; 9 lysoPCs; PC (18:0/20:4); and SM (d18:0/16:1). The three-year MCD group follow-up identified increases in palmitic amide, oleamide, and PC (18:2/18:2). Considering the age-related alterations in the identified metabolites, the MCD group showed a greater decrease in L-leucine, L-phenylalanine, and SM (d18:0/16:1) compared with those of the control group. Overall, the change (Δ) in BMI positively correlated with the ΔTG, ΔHOMA-IR, ΔL-leucine, and ΔSM (d18:0/16:1). The ΔHOMA-IR positively correlated with ΔTG, ΔL-leucine, ΔL-phenylalanine, and ΔSM (d18:0/16:1). The weight loss resulting from three-year mild-caloric restriction lessens the age-related increase in SM and reduces L-leucine and L-phenylalanine in overweight and obese subjects. These changes were coupled with improved insulin resistance (ClinicalTrials.gov: NCT02081898).

Keywords: BMI; L-leucine; L-phenylalanine; mild-calorie diet; sphingomyelin.

Figures

Figure 1.
Figure 1.
Non-targeted metabolic pattern analysis. (A) Score plots from PLS-DA models for the control at the baseline (n=47) and the MCD at the baseline (n=47). (B) The score plots from PLS-DA models for the control at the three-year follow-up (n=47) and the MCD at the three-year follow-up (n=47). (C, D) S-plots for covariance [p] and reliability correlations [p(corr)] from PLS-DA models.
Figure 2.
Figure 2.
L-leucine, L-phenylalanine, and SM (d18:0/16:1) at the baseline (□) and three-year follow-up (▢) in control and MCD individuals. Normalized peak intensities ± SE; the changes are different from baseline values. *q<0.05, **q<0.01, ***q<0.001 compared with baseline values in each group. †q<0.05, ††q<0.01, †††q<0.001 compared between two groups at the three-year follow-up.
Figure 3.
Figure 3.
Correlation matrix of changes (Δ) in metabolites and conventional risk factors in all subjects. The supervised hierarchical clustering plot shows that the 20 most important metabolites stratify the samples according to conventional risk factors. Correlations were obtained by deriving a Spearman correlation coefficient. Metabolites are listed on the left side of the heat map, with conventional risk factors listed across the top. Red is a positive correlation and blue is a negative correlation.

References

    1. The World Health Organization Western Pacific Region; The International Association for the Study of Obesity; The International Obesity Task Force. The Asia-Pacific Perspective: Redefining Obesity and Its Treatment. Sydney, Australia: Health Communications Australia Pty Limited; 2000
    1. Yuan JM, Ross RK, Gao YT, Yu MC (1998). Body weight and mortality: a prospective evaluation in a cohort of middle-aged men in Shanghai, China. Int J Epidemiol, 27:824-32.
    1. Zhou BF (2002). Effect of body mass index on all-cause mortality and incidence of cardiovascular diseases--report for meta-analysis of prospective studies open optimal cut-off points of body mass index in Chinese adults. Biomed Environ Sci, 15:245-52.
    1. Gu D, He J, Duan X, Reynolds K, Wu X, Chen J, et al. (2006). Body weight and mortality among men and women in China. JAMA, 295:776-83.
    1. Gu Y, Zhao A, Huang F, Zhang Y, Liu J, Wang C, et al. (2013). Very low carbohydrate diet significantly alters the serum metabolic profiles in obese subjects. J Proteome Res, 12:5801-11.
    1. Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. (2009). A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab, 9:311-26.
    1. Kim JY, Park JY, Kim OY, Ham BM, Kim HJ, Kwon DY, et al. (2010). Metabolic profiling of plasma in overweight/obese and lean men using ultra performance liquid chromatography and Q-TOF mass spectrometry (UPLC-Q-TOF MS). J Proteome Res, 9:4368-75.
    1. Pietiläinen KH, Naukkarinen J, Rissanen A, Saharinen J, Ellonen P, Keränen H, et al. (2008). Global transcript profiles of fat in monozygotic twins discordant for BMI: pathways behind acquired obesity. PLoS Med, 5:e51.
    1. Adams SH (2011). Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state. Adv Nutr, 2:445-56.
    1. Gibney MJ, Walsh M, Brennan L, Roche HM, German B, van Ommen B (2005). Metabolomics in human nutrition: opportunities and challenges. Am J Clin Nutr, 82:497-503.
    1. Huffman KM, Shah SH, Stevens RD, Bain JR, Muehlbauer M, Slentz CA, et al. (2009). Relationships between circulating metabolic intermediates and insulin action in overweight to obese, inactive men and women. Diabetes Care, 32:1678-83.
    1. Tai ES, Tan ML, Stevens RD, Low YL, Muehlbauer MJ, Goh DL, et al. (2010). Insulin resistance is associated with a metabolic profile of altered protein metabolism in Chinese and Asian-Indian men. Diabetologia, 53:757-67.
    1. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, et al. (2011). Metabolite profiles and the risk of developing diabetes. Nat Med, 17:448-53.
    1. Würtz P, Soininen P, Kangas AJ, Rönnemaa T, Lehtimäki T, Kähönen M, et al. (2013). Branched-chain and aromatic amino acids are predictors of insulin resistance in young adults. Diabetes Care, 36:648-55.
    1. Würtz P, Mäkinen VP, Soininen P, Kangas AJ, Tukiainen T, Kettunen J, et al. (2012). Metabolic signatures of insulin resistance in 7,098 young adults. Diabetes Care, 61:1372-80.
    1. Stancáková A, Civelek M, Saleem NK, Soininen P, Kangas AJ, Cederberg H, et al. (2012). Hyperglycemia and a common variant of GCKR are associated with the levels of eight amino acids in 9,369 Finnish men. Diabetes, 61:1895-902.
    1. Perez-Cornago A, Brennan L, Ibero-Baraibar I, Hermsdorff HH, O'Gorman A, Zulet MA, et al. (2014). Metabolomics identifies changes in fatty acid and amino acid profiles in serum of overweight older adults following a weight loss intervention. J Physiol Biochem, 70:593-602.
    1. Jung S, Kim OY, Kim M, Song J, Lee S-H, Lee JH (2014). Age-related increase in alanine aminotransferase correlates with elevated levels of plasma amino acids, decanoylcarnitine, Lp-PLA2 activity, oxidative stress, and arterial stiffness. J Proteome Res, 13:3467-75.
    1. Kim M, Jung S, Lee S-H, Lee JH (2015). Association between arterial stiffness and serum L-octanoylcarnitine and lactosylceramide in overweight middle-aged subjects: 3-year follow-up study. PLoS One, 10:e0119519.
    1. Choi E-K, Song J-M, Kim E-K (2005). Assessment of daily steps, activity coefficient, body composition, resting energy expenditure and daily energy expenditure in female university students. J Korean Diet Assoc, 11:159-69.
    1. Wilensky RL, Shi Y, Mohler ER 3rd, Hamamdzic D, Burgert ME, Li J, Postle A, et al. (2008). Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med, 14:1059-66.
    1. Cazzola R, Rondanelli M, Trotti R, Cestaro B (2011). Effects of weight loss on erythrocyte membrane composition and fluidity in overweight and moderately obese women. J Nutr Biochem, 22:388-92.
    1. Nilsson A, Duan RD (2006). Absorption and lipoprotein transport of sphingomyelin. J Lipid Res, 47:154-71.
    1. Samad F, Hester KD, Yang G, Hannun YA, Bielawski J (2006). Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes, 55:2579-87.
    1. Weir JM, Wong G, Barlow CK, Greeve MA, Kowalczyk A, Almasy L, et al. (2013). Plasma lipid profiling in a large population-based cohort. J Lipid Res, 54:2898-908.
    1. Nelson JC, Jiang XC, Tabas I, Tall A, Shea S (2006). Plasma sphingomyelin and subclinical atherosclerosis: findings from the multi-ethnic study of atherosclerosis. Am J Epidemiol, 163:903-12.
    1. Shah SH, Crosslin DR, Haynes CS, Nelson S, Turer CB, Stevens RD, et al. (2012). Branched-chain amino acid levels are associated with improvement in insulin resistance with weight loss. Diabetologia, 55:321-30.
    1. Krebs M, Krssak M, Bernroider E, Anderwald C, Brehm A, Meyerspeer M, et al. (2002). Mechanism of amino acid-induced skeletal muscle insulin resistance in humans. Diabetes, 51:599-605.
    1. Nilsson M, Holst JJ, Björck IM (2007). Metabolic effects of amino acid mixtures and whey protein in healthy subjects: studies using glucose-equivalent drinks. Am J Clin Nutr, 85:996-1004.
    1. van Loon LJ, Saris WH, Verhagen H, Wagenmakers AJ (2000). Plasma insulin responses after ingestion of different amino acid or protein mixtures with carbohydrate. Am J Clin Nutr, 72:96-105.
    1. She P, Van Horn C, Reid T, Hutson SM, Cooney RN, Lynch CJ (2007). Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism. Am J Physiol Endocrinol Metab, 293:E1552-63.
    1. Hanamatsu H, Ohnishi S, Sakai S, Yuyama K, Mitsutake S, Takeda H, et al. (2014). Altered levels of serum sphingomyelin and ceramide containing distinct acyl chains in young obese adults. Nutr Diabetes, 4:e141.
    1. Olson K, Hendricks B, Murdock DK (2012). The Triglyceride to HDL Ratio and Its Relationship to Insulin Resistance in Pre- and Postpubertal Children: Observation from the Wausau SCHOOL Project. Cholesterol, 2012:794252.
    1. Howard BV (1999). Insulin resistance and lipid metabolism. Am J Cardiol, 84:28J-32J.
    1. Eckel RH, Grundy SM, Zimmet PZ (2005). The metabolic syndrome. Lancet, 365:1415-28.
    1. Fielding BA, Humphreys SM, Allman RF, Frayn KN (1993). Mono-, di- and triacylglycerol concentrations in human plasma: effects of heparin injection and of a high-fat meal. Clin Chim Acta, 216:167-73.
    1. Schlitt A, Blankenberg S, Yan D, von Gizycki H, Buerke M, Werdan K, et al. (2006). Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease. Nutr Metab, 3:5.
    1. Mamtani M, Meikle PJ, Kulkarni H, Weir JM, Barlow CK, Jowett JB, et al. (2014). Plasma dihydroceramide species associate with waist circumference in Mexican American families. Obesity, 22:950-6.
    1. Schwab U, Seppänen-Laakso T, Yetukuri L, Agren J, Kolehmainen M, Laaksonen DE, et al. (2008). Triacylglycerol fatty acid composition in diet-induced weight loss in subjects with abnormal glucose metabolism--the GENOBIN study. PLoS One, 3:e2630.
    1. Hojjati MR, Li Z, Zhou H, Tang S, Huan C, Ooi E, et al. (2005). Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice. J Biol Chem, 280:10284-9.
    1. De Guzman JM, Ku G, Fahey R, Youm YH, Kass I, Ingram DK, et al. (2013). Chronic caloric restriction partially protects against age-related alteration in serum metabolome. Age, 35:1091-104.
    1. Kougias P, Chai H, Lin PH, Lumsden AB, Yao Q, Chen C (2006). Lysophosphatidylcholine and secretory phospholipase A2 in vascular disease: mediators of endothelial dysfunction and atherosclerosis. Med Sci Monitor, 12:RA5-16.
    1. Stafforini DM, Sheller JR, Blackwell TS, Sapirstein A, Yull FE, McIntyre TM, et al. (2006). Release of free F2-isoprostanes from esterified phospholipids is catalyzed by intracellular and plasma platelet-activating factor acetylhydrolases. J Biol Chem, 281:4616-23.
    1. Kono N, Inoue T, Yoshida Y, Sato H, Matsusue T, Itabe H, et al. (2008). Protection against oxidative stress-induced hepatic injury by intracellular type II platelet-activating factor acetylhydrolase by metabolism of oxidized phospholipids in vivo. J Biol Chem, 283:1628-36.
    1. Rimm EB, Giovannucci EL, Stampfer MJ, Colditz GA, Litin LB, Willett WC (1992). Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol, 135:1114-26.
    1. Hu FB, Rimm E, Smith-Warner SA, Feskanich D, Stampfer MJ, Ascherio A, et al. (1999). Reproducibility and validity of dietary patterns assessed with a food-frequency questionnaire. Am J Clin Nutr, 69:243-9.
    1. Dai W, Yin P, Zeng Z, Kong H, Tong H, Xu Z, et al. (2014). Nontargeted Modification-Specific Metabolomics Study Based on Liquid Chromatography-High-Resolution Mass Spectrometry. Anal Chem, 86:9146-53.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera