{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:33:28Z","timestamp":1790984008427,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003092","name":"Dutch Diabetes Research Foundation","doi-asserted-by":"publisher","award":["C.-X.Y., Diabetes Fonds, 2015.82.1826"],"award-info":[{"award-number":["C.-X.Y., Diabetes Fonds, 2015.82.1826"]}],"id":[{"id":"10.13039\/501100003092","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity and type 2 diabetes mellitus (T2DM) are highly prevalent disorders, associated with insulin resistance and chronic inflammation. The brain is key for energy homeostasis and contains many insulin receptors. Microglia, the resident brain immune cells, are known to express insulin receptors (InsR) and to be activated by a hypercaloric environment. The aim of this study was to evaluate whether microglial insulin signaling is involved in the control of systemic energy homeostasis and whether this function is sex-dependent. We generated a microglia-specific knockout of the InsR gene in male and female mice and exposed them to control or obesogenic dietary conditions. Following 10 weeks of diet exposure, we evaluated insulin tolerance, energy metabolism, microglial morphology and phagocytic function, and neuronal populations. Lack of microglial InsR resulted in increased plasma insulin levels and insulin resistance in obese female mice. In the brain, loss of microglial InsR led to a decrease in microglial primary projections in both male and female mice, irrespective of the diet. In addition, in obese male mice lacking microglial InsR the number of proopiomelanocortin neurons was decreased, compared to control diet, while no differences were observed in female mice. Our results demonstrate a sex-dependent effect of microglial InsR-signaling in physiology and obesity, and stress the importance of a heterogeneous approach in the study of diseases such as obesity and T2DM.<\/jats:p>","DOI":"10.3390\/ijms23062933","type":"journal-article","created":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T12:35:37Z","timestamp":1646742937000},"page":"2933","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5069-3330","authenticated-orcid":false,"given":"Irina V.","family":"Milanova","sequence":"first","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Laboratory of Endocrinology, 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9606-8453","authenticated-orcid":false,"given":"Andries","family":"Kalsbeek","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Laboratory of Endocrinology, Amsterdam University Medical Centers, Amsterdam Gastroenterology Endocrinology Metabolism (AGEM), 1105 AZ Amsterdam, The Netherlands"},{"name":"Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, 1105 BA Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1184-4615","authenticated-orcid":false,"given":"Chun-Xia","family":"Yi","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, University of 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