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Here, we questioned whether WL-induced rapid restoration of normoglycemia is mediated by the resolution of hypothalamic microgliosis in mid-aged mice. Mid-aged (1 year) mice were fed normal chow (NC) or a high-fat diet (HFD, 8 weeks), and WL was induced by a 2-week switch back to NC. Key findings were compared to young (7 weeks) mice. Mid-aged WL mice lost within 2 weeks 54% of their excess body weight, somewhat less than young mice (68%). Whole-hypothalamus RNA sequencing revealed\u2009~\u20094 times more differentially expressed genes (DEGs) in mid-aged than in young mice (2419 vs. 670, respectively). Nevertheless, in both ages, WL did not reverse but rather aggravated the transcriptomic response to HFD in\u2009~\u200980% of DEGs, uncovering downregulated metabolic (oxidative phosphorylation, thermogenesis) and neurodegenerative pathways, particularly in mid-age. Consistently, in the arcuate nucleus (ARC), HFD-induced increase in microglial number and volume further increased in weight-losing mid-aged mice. Consistently, only in mid-aged mice, WL further increased HFD-induced mean single-microglial volume in ARC, corresponding to increased pNF\u03baB-(p-p65) nuclear staining. Despite aggravated hypothalamic and microglial changes, mid-aged mice fully normalized impaired glucose tolerance by early WL. Adipose tissue inflammation was not resolved in mid-aged WL mice, and adipose tissue crown-like-structure density correlated with ARC microglial cell volume (Rho(\u03c1)\u2009=\u20090.691,\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.001). In conclusion, in mid-aged mice, obesity-induced hypothalamic and microglial changes were aggravated during the early response to WL. The resolution of these obesity-induced changes is not required for the normalization of glucose intolerance.\n                  <\/jats:p>","DOI":"10.1007\/s11357-025-01933-x","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T20:47:42Z","timestamp":1760734062000},"page":"5329-5342","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Weight loss aggravates obesity-induced hypothalamic inflammation in mid-aged mice"],"prefix":"10.1007","volume":"48","author":[{"given":"Alon","family":"Zemer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia","family":"Haim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Tsitrina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vered","family":"Chalifa-Caspi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Habib","family":"Muallem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Pincu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G. 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