Preservation of β cell mass by targeting fatty acid oxidation in islet macrophages : mechanisms and therapeutic interventions

Abstract

Obesity is now considered as an international epidemic. It contributes to the increased incidences of metabolic complications, including diabetes mellitus, liver disease and cardiovascular dysfunction. Macrophage induced chronic inflammation is thought to be one of the primary causes for the development of such dysfunctions in different tissues. Type 2 diabetes is characterized with gradual loss of tissue insulin sensitivity and also loss of beta cell mass and insulin secretion. The resident macrophages in the pancreatic islets are thought to play critical roles in obesity-induced islet inflammation and beta cell dysfunction. However, the detailed relationship between islet-resident macrophage and beta cell function, and their possible cross-talk with each other remain poorly understood. Classically, the polarization state of macrophage is classified to either classically activated pro-inflammatory M1 macrophage, or alternatively activated anti-inflammatory M2 macrophage. On the other hand, M1 macrophage was characterized with increased level of glycolysis, while M2 macrophage was found to have increased fatty acid oxidation (FAO). So there has been increasing interest in the possible regulatory effect of the metabolism and metabolites to the function and polarization of macrophage. Carnitine palmitoyltransferase I (CPT1) is an enzyme located in the inner membrane of the mitochondria, it is essential for the transportation process of the long chain fatty acid into the mitochondria matrix, and serves as a rate-limiting enzyme to the fatty acid oxidation. In this study, we used macrophage-specific Cpt1a knockout (LysM-Cre+, Cpt1aflox/flox, MKO) mice model to investigate the function and underlying mechanism of islet-resident macrophage in beta cell function and proliferation. Cpt1a expression in macrophage was found to respond positively to both fatty acid treatment in vitro and high fat diet (HFD) fed mice in vivo. The successful ablation of Cpt1a in macrophage was confirmed by both quantitative polymerase chain reaction and western blot. Wild-type(WT) and MKO mice were found to have no difference in body weights, body compositions and respiratory profiles under both standard chow diet (STC) and HFD feeding. While glucose tolerance was found to be improved in the MKO mice. Insulin secretion was improved in the MKO mice, while insulin sensitivity was unchanged comparing with WT control group. Through histological evaluation and insulin content test, the expanded beta cell mass was confirmed in the MKO mice under HFD feeding. Furthermore, beta cell in the MKO mice islets were found to have increased proliferation level through EdU (ethynyldeoxyuridine) proliferation assay and immunofluorescence staining of Ki67. In addition, bone marrow derived macrophages from MKO mice could induce beta cell proliferation in isolated islets in vitro. And islet-resident macrophages from WT and MKO mice were isolated through flow cytometry cell sorting for transcriptional analysis. In sum, our results discovered that under the state of Cpt1a deficient induced inhibition of fatty acid oxidation, both islet resident macrophage and isolated bone marrow macrophage in vitro could induce beta cell proliferation. These results provide potential new method for the treatment of diabetes mellitus.