Short-term high-fat feeding induces islet macrophage infiltration and β-cell replication independently of insulin resistance in mice

Short-term high-fat consumption stimulates mouse islet beta-cell replication through unknown mechanisms. Resident macrophages (M Phi s) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes M Phi infiltration in pancreatic islets and that M Phi s serve as a regulator of beta-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced beta-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an M Phi-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet beta-cell replication, oxidative stress, and M Phi infiltration were examined. Short-term HFD promoted an increase in body and epididymal fat pad weight and blood glucose levels, along with an increased fasting serum insulin concentration. beta-Cell replication, islet M Phi infiltration, and the percentage of inducible NO synthase positive M Phi s in the islets increased significantly in mice fed the HFD. Immunofluorescence staining for 8-oxo-2'-deoxyguanosine or activated caspase-3 revealed no significant induction of DNA damage or apoptosis, respectively. In addition, no change in stromal-derived factor 1-expressing cells was found induced by HFD. Despite continuous elevation of nonfasting blood glucose and fasting serum insulin levels, depletion of M Phi s through treatments of clodronate abrogated HFD-induced beta-cell replication. These findings demonstrated that HFD-induced M Phi infiltration is responsible for beta-cell replication. This study suggests the existence of M Phi-mediated mechanisms in beta-cell replication that are independent of insulin resistance.