The epidemic of DM has increased in the last decades and is the leading cause of decreased life expectancy. AT adapts to nutrient excess by balancing hypertrophy and hyperplasia that contribute to AT expansion. Unhealthy AT expansion seen in a person with diabetes is characterized by decreased preadipocyte (PA) content, and increased adipocyte size. AT macrophages (ATM) contribute to unhealthy AT expansion by blocking adipogenesis, promoting adipocyte hypertrophy, fibrosis and insulin resistance (IR). Many of the cellular and molecular mechanisms by which adipocyte numbers and size is regulated by ATMs in vivo are still unknown, especially in human obesity. This study focused on the hypotheses that ATM expression of F13A1, a tissue transglutaminase enzyme shown to regulate fibrin networks during tissue growth: 1) modulates abundance of preadipocyte (PA) populations during obesity and DM states, and 2) contributes to adipocyte hypertrophic states and potential metabolic dysfunction. The premise for these studies was based on evidence that F13A1 is increased in Visceral AT (VAT) of DM individuals compared to non-DM and that it is produced by a tissue remodeling ATM subset increased in DM. We utilized nondiabetic (NDM) and DM human secondary PA treated with F13A1 and assessed the following: 1) F13A1 expression requirement for the inhibition of healthy PA expansion in obesity, and 2) the mechanisms by which its function leads to arrested proliferation. Results showed that F13A1 impairs PA proliferation through its exerted effects on PA ECM fibronectin crosslink leading to: 1) downregulation of downstream gene proliferative signaling pathways and 2) defaulted adipocyte differentiation with hypertrophic profiles as an antagonistic response to decreased proliferation. These studies have advanced our understanding of ATM-derived F13A1 as a potential immunotherapeutic target to improve AT function.
D.M. Elizondo: None. L.M. Geletka: None. C.G. Flesher: None. C.N. Lumeng: None.
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK101357)