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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE273735 | GEO | 2025/03/14

REPOSITORIES: GEO

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Project description:Abstract Background In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The individual ability to tip the balance toward the hyperplastic growth, with recruitment of new fat cells through adipogenesis, seems to be critical for a healthy adipose tissue expansion, as opposed to the development of inflammation and detrimental metabolic consequences. However, the molecular mechanisms underlying this fine-tuned regulation are far from being understood. Methods We analyzed by mass spectrometry-based proteomics visceral white adipose tissue (vWAT) samples collected from C57BL6 mice fed with a HFD for 8 weeks. A subset of these mice, called low responders (LowR HFD), showed a low susceptibility to the onset of adipose tissue inflammation, as opposed to their HFD counterpart. We identified the discriminants between LowR HFD and HFD vWAT samples and explored their function in Adipose Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes. Results We quantified 6051 proteins. Among the candidates that most differentiate LowR HFD from HFD vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in LowR HFD, as compared to HFD. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was totally unknown, was another top-scored hit. SMYD3 expression was significantly higher in LowR HFD vWAT, as confirmed by western blot analysis. In vitro, we found that SMYD3 mRNA and protein levels decrease rapidly along the differentiation process of AD-hMSCs. Moreover, SMYD3 knock-down at the beginning of adipocyte differentiation resulted in reduced cell proliferation and, at longer term, reduced lipid accumulation in adipocytes. Conclusions Our study describes for the first time the role of SMYD3 as a regulator of adipocyte proliferation during the early steps of adipogenesis.

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

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