title: Short-term high-fat feeding induces islet macrophage infiltration and β-cell replication independently of insulin resistance in mice.
abstract: Short-term high-fat consumption stimulates mouse islet β-cell replication through unknown mechanisms. Resident macrophages (MΦs) are capable of secreting various factors involved in islet development and tissue remodeling. We hypothesized that a short-term high-fat diet (HFD) promotes MΦ infiltration in pancreatic islets and that MΦs serve as a regulator of β-cell replication. To test these hypotheses and dissect mechanisms involved in HFD-induced β-cell replication, adult C57BL/6J mice were fed a HFD for 7 days with or without administration of clodronate-containing liposomes, an MΦ-depleting agent. Mouse body and epididymal fat pad weights, and nonfasting blood glucose and fasting serum insulin levels were measured, and pancreatic islet β-cell replication, oxidative stress, and MΦ 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. β-Cell replication, islet MΦ infiltration, and the percentage of inducible NO synthase positive MΦs 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 MΦs through treatments of clodronate abrogated HFD-induced β-cell replication. These findings demonstrated that HFD-induced MΦ infiltration is responsible for β-cell replication. This study suggests the existence of MΦ-mediated mechanisms in β-cell replication that are independent of insulin resistance.
authors: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York; Department of Surgery, Columbia University Medical Center, New York, New York.
authors: David C
authors: DC
authors: Woodland
authors: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York; Department of Surgery, Columbia University Medical Center, New York, New York; The Second Clinical Medicine College, Jilin University, Changchun, Jilin Province, China.
authors: Wei
authors: W
authors: Liu
authors: Touro College of Osteopathic Medicine, New York, New York; and.
authors: Jacky
authors: J
authors: Leong
authors: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York; Department of Surgery, Columbia University Medical Center, New York, New York.
authors: Mallory L
authors: ML
authors: Sears
authors: The Second Clinical Medicine College, Jilin University, Changchun, Jilin Province, China.
authors: Ping
authors: P
authors: Luo
authors: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York; Department of Surgery, Columbia University Medical Center, New York, New York; xc2248@cumc.columbia.edu.
authors: Xiaojuan
authors: 0000-0002-2109-1277
authors: X
authors: Chen
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division; D004002:Clodronic Acid / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004822:Epididymis / Q000166:cytology / Q000187:drug effects; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000187:drug effects*; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D007328:Insulin; D004002:Clodronic Acid; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: HFD; macrophage; β-cell replication