Dietary oleic acid drives obesogenic adipogenesis via modulation of LXR⍺ signaling

Dietary fat composition has changed substantially as the obesity epidemic has spread. Adipocyte hyperplasia is a major mechanism of fat mass expansion in obesity, but how dietary fats contribute to obesogenic adipocyte hyperplasia is unknown. Here we employed various dietary strategies, including an unbiased dietary screen, to determine the effect of dietary fat composition on adipocyte hyperplasia in mice. We identified oleic acid (OA) as the only dietary fatty acid that induces adipogenesis and obesogenic hyperplasia at physiologic levels. OA induced differentiation via AKT2 signaling, a hallmark of obesogenic hyperplasia. We also demonstrate that reduction of LXR signaling in APCs is necessary for OA-stimulated adipogenesis. Furthermore, blocking LXRa phosphorylation at S196 results in APC hyperproliferation upon HFD feeding, suggesting that LXRa phosphorylation inhibits HFD-stimulated proliferation. As OA is associated with numerous health effects, our findings that OA is a unique physiologic metabolic regulator underscores the importance of understanding the mechanisms by which OA effects metabolic health.