1. Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity
- Author
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Rohm, Theresa V, Keller, Lena, Bosch, Angela J T, AlAsfoor, Shefaa, Baumann, Zora, Thomas, Amandine, Wiedemann, Sophia J, Steiger, Laura, Dalmas, Elise, Wehner, Josua, Rachid, Leila, Mooser, Catherine, Yilmaz, Bahtiyar, Fernandez Trigo, Nerea, Jauch, Annaise J, Wueest, Stephan, Konrad, Daniel, Henri, Sandrine, Niess, Jan Hendrik, Hruz, Petr, Ganal-Vonarburg, Stephanie C, Roux, Julien, Meier, Daniel T, Cavelti-Weder, Claudia, University Hospital Basel [Basel], University of Basel (Unibas), Bern University Hospital [Berne] (Inselspital), Universität Bern [Bern] (UNIBE), Pediatric Heart Center, University Children’s Hospital Zürich, Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), St. Clara Hospital and University Hospital Basel, Universität Zürich [Zürich] = University of Zurich (UZH), University of Zurich, Cavelti-Weder, Claudia, DBMR, University of Bern, and DUMENIL, Anita
- Subjects
Blood Glucose ,Colon ,[SDV]Life Sciences [q-bio] ,10265 Clinic for Endocrinology and Diabetology ,Medicine (miscellaneous) ,610 Medicine & health ,1100 General Agricultural and Biological Sciences ,Glycemic Control ,Diet, High-Fat ,General Biochemistry, Genetics and Molecular Biology ,Mice ,1300 General Biochemistry, Genetics and Molecular Biology ,Animals ,Obesity ,Monocytes and macrophages ,Macrophages ,TOR Serine-Threonine Kinases ,2701 Medicine (miscellaneous) ,Type 2 diabetes ,Metabolic syndrome ,[SDV] Life Sciences [q-bio] ,10036 Medical Clinic ,Mucosal immunology ,Insulin Resistance ,General Agricultural and Biological Sciences ,610 Medizin und Gesundheit - Abstract
The obesity epidemic continues to worsen worldwide. However, the mechanisms initiating glucose dysregulation in obesity remain poorly understood. We assessed the role that colonic macrophage subpopulations play in glucose homeostasis in mice fed a high-fat diet (HFD). Concurrent with glucose intolerance, pro-inflammatory/monocyte-derived colonic macrophages increased in mice fed a HFD. A link between macrophage numbers and glycemia was established by pharmacological dose-dependent ablation of macrophages. In particular, colon-specific macrophage depletion by intrarectal clodronate liposomes improved glucose tolerance, insulin sensitivity, and insulin secretion capacity. Colonic macrophage activation upon HFD was characterized by an interferon response and a change in mitochondrial metabolism, which converged in mTOR as a common regulator. Colon-specific mTOR inhibition reduced pro-inflammatory macrophages and ameliorated insulin secretion capacity, similar to colon-specific macrophage depletion, but did not affect insulin sensitivity. Thus, pharmacological targeting of colonic macrophages could become a potential therapy in obesity to improve glycemic control.
- Published
- 2022
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