Nancy F Butte1, Yan Liu2, Issa F Zakeri3, Robert P Mohney4, Nitesh Mehta2, V Saroja Voruganti5, Harald Göring6, Shelley A Cole6, Anthony G Comuzzie6. 1. USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX; nbutte@bcm.edu. 2. USDA/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX; 3. Department of Epidemiology and Biostatistics, Drexel University, Philadelphia, PA; 4. Metabolon Inc., Durham, NC; 5. Department of Nutrition and University of North Carolina at Chapel Hill Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC; and. 6. Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX.
Abstract
BACKGROUND: Metabolomics may unravel important biological pathways involved in the pathophysiology of childhood obesity. OBJECTIVES: We aimed to 1) identify metabolites that differ significantly between nonobese and obese Hispanic children; 2) collapse metabolites into principal components (PCs) associated with obesity and metabolic risk, specifically hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, and hyperuricemia; and 3) identify metabolites associated with energy expenditure and fat oxidation. DESIGN: This trial was a cross-sectional observational study of metabolomics by using gas chromatography-mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry analyses performed on fasting plasma samples from 353 nonobese and 450 obese Hispanic children. RESULTS: Branched-chained amino acids (BCAAs) (Leu, Ile, and Val) and their catabolites, propionylcarnitine and butyrylcarnitine, were significantly elevated in obese children. Strikingly lower lysolipids and dicarboxylated fatty acids were seen in obese children. Steroid derivatives were markedly higher in obese children as were markers of inflammation and oxidative stress. PC6 (BCAAs and aromatic AAs) and PC10 (asparagine, glycine, and serine) made the largest contributions to body mass index, and PC10 and PC12 (acylcarnitines) made the largest contributions to adiposity. Metabolic risk factors and total energy expenditure were associated with PC6, PC9 (AA and tricarboxylic acid cycle metabolites), and PC10. Fat oxidation was inversely related to PC8 (lysolipids) and positively related to PC16 (acylcarnitines). CONCLUSIONS: Global metabolomic profiling in nonobese and obese children replicates the increased BCAA and acylcarnitine catabolism and changes in nucleotides, lysolipids, and inflammation markers seen in obese adults; however, a strong signature of reduced fatty acid catabolism and increased steroid derivatives may be unique to obese children. Metabolic flexibility in fuel use observed in obese children may occur through the activation of alternative intermediary pathways. Insulin resistance, hyperleptinemia, hypertriglyceridemia, hyperuricemia, and oxidative stress and inflammation evident in obese children are associated with distinct metabolomic profiles.
BACKGROUND: Metabolomics may unravel important biological pathways involved in the pathophysiology of childhood obesity. OBJECTIVES: We aimed to 1) identify metabolites that differ significantly between nonobese and obese Hispanic children; 2) collapse metabolites into principal components (PCs) associated with obesity and metabolic risk, specifically hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, and hyperuricemia; and 3) identify metabolites associated with energy expenditure and fat oxidation. DESIGN: This trial was a cross-sectional observational study of metabolomics by using gas chromatography-mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry analyses performed on fasting plasma samples from 353 nonobese and 450 obese Hispanic children. RESULTS:Branched-chained amino acids (BCAAs) (Leu, Ile, and Val) and their catabolites, propionylcarnitine and butyrylcarnitine, were significantly elevated in obesechildren. Strikingly lower lysolipids and dicarboxylated fatty acids were seen in obesechildren. Steroid derivatives were markedly higher in obesechildren as were markers of inflammation and oxidative stress. PC6 (BCAAs and aromatic AAs) and PC10 (asparagine, glycine, and serine) made the largest contributions to body mass index, and PC10 and PC12 (acylcarnitines) made the largest contributions to adiposity. Metabolic risk factors and total energy expenditure were associated with PC6, PC9 (AA and tricarboxylic acid cycle metabolites), and PC10. Fat oxidation was inversely related to PC8 (lysolipids) and positively related to PC16 (acylcarnitines). CONCLUSIONS: Global metabolomic profiling in nonobese and obesechildren replicates the increased BCAA and acylcarnitine catabolism and changes in nucleotides, lysolipids, and inflammation markers seen in obese adults; however, a strong signature of reduced fatty acid catabolism and increased steroid derivatives may be unique to obesechildren. Metabolic flexibility in fuel use observed in obesechildren may occur through the activation of alternative intermediary pathways. Insulin resistance, hyperleptinemia, hypertriglyceridemia, hyperuricemia, and oxidative stress and inflammation evident in obesechildren are associated with distinct metabolomic profiles.
Authors: Sara F Michaliszyn; Lindsey A Sjaarda; Stephanie J Mihalik; Sojung Lee; Fida Bacha; Donald H Chace; Victor R De Jesus; Jerry Vockley; Silva A Arslanian Journal: J Clin Endocrinol Metab Date: 2012-09-13 Impact factor: 5.958
Authors: Stephanie J Mihalik; Bret H Goodpaster; David E Kelley; Donald H Chace; Jerry Vockley; Frederico G S Toledo; James P DeLany Journal: Obesity (Silver Spring) Date: 2010-01-28 Impact factor: 5.002
Authors: Stephanie J Mihalik; Sara F Michaliszyn; Javier de las Heras; Fida Bacha; SoJung Lee; Donald H Chace; Victor R DeJesus; Jerry Vockley; Silva A Arslanian Journal: Diabetes Care Date: 2012-01-20 Impact factor: 19.112
Authors: Brante P Sampey; Alex J Freemerman; Jimmy Zhang; Pei-Fen Kuan; Joseph A Galanko; Thomas M O'Connell; Olga R Ilkayeva; Michael J Muehlbauer; Robert D Stevens; Christopher B Newgard; Heather A Brauer; Melissa A Troester; Liza Makowski Journal: PLoS One Date: 2012-06-12 Impact factor: 3.240
Authors: Ele Ferrannini; Andrea Natali; Stefania Camastra; Monica Nannipieri; Andrea Mari; Klaus-Peter Adam; Michael V Milburn; Gabi Kastenmüller; Jerzy Adamski; Tiinamaija Tuomi; Valeriya Lyssenko; Leif Groop; Walter E Gall Journal: Diabetes Date: 2012-11-16 Impact factor: 9.461
Authors: So-Youn Shin; Eric B Fauman; Ann-Kristin Petersen; Jan Krumsiek; Rita Santos; Jie Huang; Matthias Arnold; Idil Erte; Vincenzo Forgetta; Tsun-Po Yang; Klaudia Walter; Cristina Menni; Lu Chen; Louella Vasquez; Ana M Valdes; Craig L Hyde; Vicky Wang; Daniel Ziemek; Phoebe Roberts; Li Xi; Elin Grundberg; Melanie Waldenberger; J Brent Richards; Robert P Mohney; Michael V Milburn; Sally L John; Jeff Trimmer; Fabian J Theis; John P Overington; Karsten Suhre; M Julia Brosnan; Christian Gieger; Gabi Kastenmüller; Tim D Spector; Nicole Soranzo Journal: Nat Genet Date: 2014-05-11 Impact factor: 38.330
Authors: Hye In Kim; Johannes Raffler; Wenyun Lu; Jung-Jin Lee; Deepti Abbey; Danish Saleheen; Joshua D Rabinowitz; Michael J Bennett; Nicholas J Hand; Christopher Brown; Daniel J Rader Journal: Am J Hum Genet Date: 2017-09-21 Impact factor: 11.025
Authors: M J Leal-Witt; M Ramon-Krauel; S Samino; M Llobet; D Cuadras; J C Jimenez-Chillaron; O Yanes; C Lerin Journal: Int J Obes (Lond) Date: 2017-08-17 Impact factor: 5.095
Authors: B Englich; G Herberth; U Rolle-Kampczyk; S Trump; S Röder; M Borte; G I Stangl; M von Bergen; I Lehmann; K M Junge Journal: Int J Obes (Lond) Date: 2017-05-10 Impact factor: 5.095
Authors: Wei Perng; Ellen C Francis; Harry A Smith; John Carey; Dongqing Wang; Katerina M Kechris; Dana Dabelea Journal: J Clin Endocrinol Metab Date: 2020-09-01 Impact factor: 5.958
Authors: Wei Perng; Brandy M Ringham; Harry A Smith; Gregory Michelotti; Katerina M Kechris; Dana Dabelea Journal: Diabetologia Date: 2019-11-13 Impact factor: 10.122
Authors: Christoph Saner; Brooke E Harcourt; Ahwan Pandey; Susan Ellul; Zoe McCallum; Kung-Ting Kao; Celia Twindyakirana; Anke Pons; Erin J Alexander; Richard Saffery; David P Burgner; Markus Juonala; Matthew A Sabin Journal: Metabolomics Date: 2019-05-03 Impact factor: 4.290