Background: In obesity, adipose tissue undergoes a remodeling process characterized by increased adipocyte size (hypertrophia) and number (hyperplasia). The 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 a hypertrophic growth that is accompanied by the development of inflammation and metabolic dysfunction. However, the molecular mechanisms underlying the fine-tuned regulation of adipose tissue expansion 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 inflammation (Low-INFL), showed reduced adipose tissue inflammation, as opposed to those developing the expected inflammatory response (Hi-INFL). We identified the discriminants between Low-INFL and Hi-INFL vWAT samples and explored their function in Adipose-Derived human Mesenchymal Stem Cells (AD-hMSCs) differentiated to adipocytes.

Results: vWAT proteomics allowed us to quantify 6051 proteins. Among the candidates that most differentiate Low-INFL from Hi-INFL vWAT, we found proteins involved in adipocyte function, including adiponectin and hormone sensitive lipase, suggesting that adipocyte differentiation is enhanced in Low-INFL, as compared to Hi-INFL. The chromatin modifier SET and MYND Domain Containing 3 (SMYD3), whose function in adipose tissue was so far unknown, was another top-scored hit. SMYD3 expression was significantly higher in Low-INFL vWAT, as confirmed by western blot analysis. Using AD-hMSCs in culture, we found that SMYD3 mRNA and protein levels decrease rapidly during the adipocyte differentiation. Moreover, SMYD3 knock-down before adipocyte differentiation resulted in reduced H3K4me3 and decreased cell proliferation, thus limiting the number of cells available for adipogenesis.

Conclusions: Our study describes an important role of SMYD3 as a newly discovered regulator of adipocyte precursor proliferation during the early steps of adipogenesis.