title: Nicotinamide Promotes Adipogenesis in Umbilical Cord-Derived Mesenchymal Stem Cells and Is Associated with Neonatal Adiposity: The Healthy Start BabyBUMP Project.
abstract: The cellular mechanisms whereby excess maternal nutrition during pregnancy increases adiposity of the offspring are not well understood. However, nicotinamide (NAM), a fundamental micronutrient that is important in energy metabolism, has been shown to regulate adipogenesis through inhibition of SIRT1. Here we tested three novel hypotheses: 1) NAM increases the adipogenic response of human umbilical cord tissue-derived mesenchymal stem cells (MSCs) through a SIRT1 and PPARγ pathway; 2) lipid potentiates the NAM-enhanced adipogenic response; and 3) the adipogenic response to NAM is associated with increased percent fat mass (%FM) among neonates. MSCs were derived from the umbilical cord of 46 neonates born to non-obese mothers enrolled in the Healthy Start study. Neonatal %FM was measured using air displacement plethysmography (Pea Pod) shortly after birth. Adipogenic differentiation was induced for 21 days in the 46 MSC sets under four conditions, +NAM (3mM)/-lipid (200 μM oleate/palmitate mix), +NAM/+lipid, -NAM/+lipid, and vehicle-control (-NAM/-lipid). Cells incubated in the presence of NAM had significantly higher PPARγ protein (+24%, p <0.01), FABP4 protein (+57%, p <0.01), and intracellular lipid content (+51%, p <0.01). Lipid did not significantly increase either PPARγ protein (p = 0.98) or FABP4 protein content (p = 0.82). There was no evidence of an interaction between NAM and lipid on adipogenic response of PPARγ or FABP4 protein (p = 0.99 and p = 0.09). In a subset of 9 MSC, SIRT1 activity was measured in the +NAM/-lipid and vehicle control conditions. SIRT1 enzymatic activity was significantly lower (-70%, p <0.05) in the +NAM/-lipid condition than in vehicle-control. In a linear model with neonatal %FM as the outcome, the percent increase in PPARγ protein in the +NAM/-lipid condition compared to vehicle-control was a significant predictor (β = 0.04, 95% CI 0.01-0.06, p <0.001). These are the first data to support that chronic NAM exposure potentiates adipogenesis in human MSCs in-vitro, and that this process involves PPARγ and SIRT1.
authors.affiliation: Department of Epidemiology, Colorado School of Public Health (CSPH), Aurora, Colorado, United States of America.
authors.forename: Allison L B
authors.initials: AL
authors.lastname: Shapiro
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine (UC-SOM), Aurora, Colorado, United States of America.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Boyle
authors.affiliation: Department of Epidemiology, CSPH, Aurora, Colorado, United States of America.
authors.forename: Dana
authors.initials: D
authors.lastname: Dabelea
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine (UC-SOM), Aurora, Colorado, United States of America.
authors.forename: Zachary W
authors.initials: ZW
authors.lastname: Patinkin
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine (UC-SOM), Aurora, Colorado, United States of America.|Department of Biochemistry & Molecular Genetics, UC-SOM, Aurora, Colorado, United States of America.
authors.forename: Becky
authors.initials: B
authors.lastname: De la Houssaye
authors.affiliation: Department of Biostatistics & Informatics, CSPH, Aurora, Colorado, United States of America.
authors.forename: Brandy M
authors.initials: BM
authors.lastname: Ringham
authors.affiliation: Department of Biostatistics & Informatics, CSPH, Aurora, Colorado, United States of America.
authors.forename: Deborah H
authors.initials: DH
authors.lastname: Glueck
authors.affiliation: Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, UC-SOM, Aurora, Colorado, United States of America.|Department of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine UC-SOM, Aurora, Colorado, United States of America.
authors.forename: Linda A
authors.initials: LA
authors.lastname: Barbour
authors.affiliation: Department of Epidemiology, CSPH, Aurora, Colorado, United States of America.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Norris
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine (UC-SOM), Aurora, Colorado, United States of America.|Department of Biochemistry & Molecular Genetics, UC-SOM, Aurora, Colorado, United States of America.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D050156:Adipogenesis / Q000187:drug effects*; D050154:Adiposity / Q000187:drug effects*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007231:Infant, Newborn / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000187:drug effects*; D009536:Niacinamide / Q000494:pharmacology*; D047495:PPAR gamma / Q000378:metabolism; D010991:Plethysmography; D016133:Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000378:metabolism; D014470:Umbilical Cord / Q000166:cytology / Q000187:drug effects*
chemical_list: D047495:PPAR gamma; D009536:Niacinamide; C447939:SIRT1 protein, human; D056564:Sirtuin 1