Targeting colonic macrophages improves glycemic control in high-fat diet-induced obesity

• DOI: 10.1038/s42003-022-03305-z
• Publication Date: 2022-04-19T10:03:39Z
• Authors: Theresa V. Rohm; Lena Keller; Angela J. T. Bosch; Shefaa AlAsfoor; Zora Baumann; Amandine Thomas; Sophia J. Wiedemann; Laura Steiger; Elise Dalmas; Josua Wehner; Leila Rachid; Catherine Mooser; Bahtiyar Yilmaz; Nerea Fernandez T...; Annaise J. Jauch; Stephan Wueest; Daniel Konrad; Sandrine Henri; Jan H. Niess; Petr Hruz; Stephanie C. Gana...; Julien Roux; Daniel T. Meier; Claudia Cavelti-W...
• Keywords: Blood Glucose; 0301 basic medicine; QH301-705.5; Colon; [SDV]Life Sciences [q-bio]; 10265 Clinic for Endocrinology and Diabetology; 610; 610 Medicine & health; 1100 General Agricultural and Biological Sciences; Glycemic Control; Diet, High-Fat; Article; Mice; 03 medical and health sciences; 1300 General Biochemistry, Genetics and Molecular Biology; 616; Animals; Obesity; Biology (General); Monocytes and macrophages; 2. Zero hunger; 0303 health sciences; Macrophages; TOR Serine-Threonine Kinases; 2701 Medicine (miscellaneous); Type 2 diabetes; Metabolic syndrome; 3. Good health; [SDV] Life Sciences [q-bio]; 10036 Medical Clinic; Mucosal immunology; Insulin Resistance

AbstractThe 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.