Lipoprotein Lipase Maintains Microglial Innate Immunity in Obesity
Yuanqing Gao,
Andrés Vidal-Itriago,
Martin J. Kalsbeek,
Clarita Layritz,
Cristina García-Cáceres,
Robby Zachariah Tom,
Thomas O. Eichmann,
Frédéric M. Vaz,
Riekelt H. Houtkooper,
Nicole van der Wel,
Arthur J. Verhoeven,
Jie Yan,
Andries Kalsbeek,
Robert H. Eckel,
Susanna M. Hofmann,
Chun-Xia Yi
Affiliations
Yuanqing Gao
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands
Andrés Vidal-Itriago
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands
Martin J. Kalsbeek
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands
Clarita Layritz
Helmholtz Diabetes Center & German Center for Diabetes Research, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich, Germany
Cristina García-Cáceres
Helmholtz Diabetes Center & German Center for Diabetes Research, Helmholtz Zentrum München & Division of Metabolic Diseases, Technische Universität München, Munich, Germany
Robby Zachariah Tom
Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München, Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Munich, Germany
Thomas O. Eichmann
Institute of Molecular Biosciences, University of Graz, Austria
Frédéric M. Vaz
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, the Netherlands
Riekelt H. Houtkooper
Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, the Netherlands
Nicole van der Wel
Cellular Imaging Core Facility, Academic Medical Center, University of Amsterdam, the Netherlands
Arthur J. Verhoeven
Department of Medical Biochemistry, Academic Medical Centre, University of Amsterdam, the Netherlands
Jie Yan
Department of Forensic Science, School of Basic Medical Science, Central South University, Changsha, Hunan, China
Andries Kalsbeek
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands
Robert H. Eckel
Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Aurora, CO, USA
Susanna M. Hofmann
Institute for Diabetes and Regeneration Research & Helmholtz Diabetes Center, Helmholtz Zentrum München, Medizinische Klinik und Poliklinik IV, Klinikum der LMU, Munich, Germany
Chun-Xia Yi
Department of Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, the Netherlands
Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism.
