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.
Highlights
Nutrition in pregnancy has been shown to affect various aspects of fetal growth and development [1]
In this study we investigate the effect of nicotinamide, in combination with excess fatty acids, on SIRT1 activity and the adipogenic response potential of human umbilical cord-derived mesenchymal stem cells, which represent a fetal stem cell population
The present study tested the hypothesis that SIRT1 may be involved in micronutrient-induced enhancement of adipogenic differentiation of human mesenchymal stem cells (MSCs)
Summary
Nutrition in pregnancy has been shown to affect various aspects of fetal growth and development [1]. A maternal high-fat diet (HFD) during pregnancy increases newborn adiposity in both rodents and in non-human primates [2,3,4]. In addition to increased macronutrient content, modulation of adipogenesis may occur through pathways involving micronutrients that can interact directly with proteins involved in promoting adipose tissue accretion. Evidence from cell culture models suggests that niacin may be one such “obesogenic” micronutrient, where bone marrow-derived mesenchymal stem cells (MSCs) treated with nicotinamide (NAM), the amide form of niacin, demonstrated increased adipogenesis in vitro [5]. Niacin treatment has recently been linked to increased risk of new onset diabetes in a large meta-analysis of clinical trials [6]. The mechanism by which niacin induces a greater adipogenic response and metabolic dysfunction is unclear
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