The effect of Notch signaling in macrophages on metabolic diseases

Abstract

Obesity is a chronic metabolic disease that accompanies hypertension, heart disease and type 2 diabetes. Furthermore, lipid accumulation in the adipose tissue can cause inflammation and lead to insulin resistance. Therefore, effective molecular mechanism and pharmacotherapeutic drugs need to be urgently developed to treat obesity. Although immune cells, such as macrophages, in the adipose tissue are expected to play an important role in homeostatic regulation, the mechanism by which lipids shape the phenotype of adipose tissue macrophages in diet-induced obesity remains unknown. The association between the Notch signaling system, which regulates various cell functions, and the inflammatory state is supported by many studies. Notch signaling is regulated by inflammatory signals. Hairy and enhancer of split-1 (Hes1) is a representative targets of the Notch signaling system. Hes1 negatively modulates macrophage Toll-Like Receptor (TLR) responses, suggesting that it is involved in autoimmune and inflammatory disorders. Therefore, I hypothesized that there is an association between Hes1, macrophages, and adipose tissues in relation to obesity and inflammation. In this paper, I confirmed an increase in Notch signaling factors in the immune cells of obese mice. When Hes1 macrophage-specific knock-out mice were fed a high-fat diet, the conditional knockout (cKO) mice gained less weight and exhibited reduced blood sugar levels. Moreover, the IL-10 expression level in bone marrow-derived macrophages (BMDMs) of the cKO mice was increased when they were in contact with adipocytes. IL-10 suppressed adipogenesis and lipid accumulation in adipocytes. I also found that tschimganidine, a terpenoid from the Umbelliferae family, inhibited Notch signaling factors and Hes1 in macrophages. Treatment with tschimganidine reduced lipid accumulation and adipogenesis accompanied by reduced expression levels of adipogenesis and lipid accumulation-related factors through AMP-activated protein kinase (AMPK) activation. These results suggest that, Hes1 in macrophages plays an important role in the adipose tissue and appears to affect metabolic diseases. Hes1 may thus be a therapeutic target for obesity and metabolic diseases. Moreover, tschimganidine, an inhibitor of Hes1, may act as an anti-obesity agent that can impede adipogenesis and improve glucose homeostasis.