title: Dietary Betaine Supplementation Increases Fgf21 Levels to Improve Glucose Homeostasis and Reduce Hepatic Lipid Accumulation in Mice.
abstract: Identifying markers of human insulin resistance may permit development of new approaches for treatment and prevention of type 2 diabetes. To this end, we analyzed the fasting plasma metabolome in metabolically characterized human volunteers across a spectrum of insulin resistance. We demonstrate that plasma betaine levels are reduced in insulin-resistant humans and correlate closely with insulin sensitivity. Moreover, betaine administration to mice with diet-induced obesity prevents the development of impaired glucose homeostasis, reduces hepatic lipid accumulation, increases white adipose oxidative capacity, and enhances whole-body energy expenditure. In parallel with these beneficial metabolic effects, betaine supplementation robustly increased hepatic and circulating fibroblast growth factor (Fgf)21 levels. Betaine administration failed to improve glucose homeostasis and liver fat content in Fgf21(-/-) mice, demonstrating that Fgf21 is necessary for betaine's beneficial effects. Together, these data indicate that dietary betaine increases Fgf21 levels to improve metabolic health in mice and suggest that betaine supplementation merits further investigation as a supplement for treatment or prevention of type 2 diabetes in humans.
authors: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA.
authors: Asma
authors: A
authors: Ejaz
authors: Endocrinology Section, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Laura
authors: L
authors: Martinez-Guino
authors: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA.
authors: Allison B
authors: AB
authors: Goldfine
authors: Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors: Francesc
authors: F
authors: Ribas-Aulinas
authors: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain.
authors: Valeria
authors: V
authors: De Nigris
authors: Endocrinology Section, Hospital Sant Joan de Déu, Barcelona, Spain.
authors: Sílvia
authors: S
authors: Ribó
authors: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain.
authors: Alba
authors: A
authors: Gonzalez-Franquesa
authors: Diabetes and Obesity Laboratory, Institut d'Investigacions Biomèdiques August Pi Sunyer, Barcelona, Spain CIBERDEM, Barcelona, Spain Department of Physiological Sciences II, University of Barcelona, Barcelona, Spain.
authors: Pablo M
authors: PM
authors: Garcia-Roves
authors: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA.
authors: Elizabeth
authors: E
authors: Li
authors: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA Department of Biomedical Engineering, Boston University, Boston, MA.
authors: Jonathan M
authors: JM
authors: Dreyfuss
authors: Metabolon, Inc., Durham, NC.
authors: Walt
authors: W
authors: Gall
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors: Jason K
authors: JK
authors: Kim
authors: Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX.
authors: Teodoro
authors: T
authors: Bottiglieri
authors: Department of Biochemistry and Molecular Biology, Institute of Biomedicine, University of Barcelona, and CIBER Fisiopatología de la Obesidad y Nutrición, Barcelona, Spain.
authors: Francesc
authors: F
authors: Villarroya
authors: Massachusetts General Hospital and Harvard Medical School, Boston, MA.
authors: Robert E
authors: RE
authors: Gerszten
authors: Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA clerin@fsjd.org mary.elizabeth.patti@joslin.harvard.edu.
authors: Mary-Elizabeth
authors: ME
authors: Patti
authors: Endocrinology Section, Hospital Sant Joan de Déu, Barcelona, Spain clerin@fsjd.org mary.elizabeth.patti@joslin.harvard.edu.
authors: Carles
authors: C
authors: Lerin
mesh_terms: D000328:Adult; D000818:Animals; D001622:Betaine / Q000494:pharmacology*; D002478:Cells, Cultured; D019587:Dietary Supplements; D005234:Fatty Liver / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: C414620:fibroblast growth factor 21; D001622:Betaine; D005346:Fibroblast Growth Factors; D005947:Glucose