title: Elevated S-adenosylhomocysteine alters adipocyte functionality with corresponding changes in gene expression and associated epigenetic marks.
abstract: Maternal deficiencies in micronutrients affecting one-carbon metabolism before and during pregnancy can influence metabolic status and the degree of insulin resistance and obesity of the progeny in adulthood. Notably, maternal and progeny plasma S-adenosylhomocysteine (SAH) levels are both elevated after vitamin deficiency in pregnancy. Therefore, we investigated whether this key one-carbon cycle intermediate directly affects adipocyte differentiation and function. We found that expansion and differentiation of murine 3T3-L1 preadipocytes in the presence of SAH impaired both basal and induced glucose uptake as well as lipolysis compared with untreated controls. SAH did not alter preadipocyte factor 1 (Dlk1) or peroxisome proliferator-activated receptor-γ 2 (Pparγ2) but significantly reduced expression of CAAT enhancer-binding protein-α (Cebpα), Cebpβ, and retinoid x receptor-α (Rxrα) compared with untreated adipocytes. SAH increased Rxrα methylation on a CpG unit (chr2:27,521,057+, chr2:27,521,049+) and CpG residue (chr2:27,521,080+), but not Cebpβ methylation, relative to untreated adipocytes. Trimethylated histone H3-Lys27 occupancy was significantly increased on Cebpα and Rxrα promoters in SAH-treated adipocytes, consistent with the reduction in gene expression. In conclusion, SAH did not affect adipogenesis per se but altered adipocyte functionality through epigenetic mechanisms, such that they exhibited altered glucose disposal and lipolysis. Our findings implicate micronutrient imbalance in subsequent modulation of adipocyte function.
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand s.ngo@auckland.ac.nz.
authors.forename: Sherry
authors.initials: S
authors.lastname: Ngo
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Renelle
authors.initials: R
authors.lastname: O'Neill
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Chandrakanth
authors.initials: C
authors.lastname: Bhoothpur
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Peter
authors.initials: P
authors.lastname: Gluckman
authors.affiliation: Developmental Epigenetics Group, Liggins Institute, The University of Auckland, Auckland, New Zealand.
authors.forename: Allan
authors.initials: A
authors.lastname: Sheppard
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D050156:Adipogenesis / Q000187:drug effects / Q000235:genetics; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057486:Carbon Cycle; D019175:DNA Methylation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects*; D015870:Gene Expression / Q000187:drug effects*; D005819:Genetic Markers / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000494:pharmacology*
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D005819:Genetic Markers; D047495:PPAR gamma; D012435:S-Adenosylhomocysteine; D005947:Glucose