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Trem2 deletion in mice (Trem2<jats:sup>\u2212\/\u2212<\/jats:sup>) evokes adipose tissue dysfunction, but its role in worsening obesity\u2010induced metabolic dysfunction has not been resolved. Here we aimed to determine the causal role of Trem2 in regulating glucose homeostasis and insulin sensitivity in mice. Nine\u2010week\u2010old male and female littermate wild\u2010type (WT) and Trem2<jats:sup>\u2212\/\u2212<\/jats:sup> mice were fed a low\u2010 or high\u2010fat diet for 18\u00a0weeks and phenotyped for metabolic function. Diet\u2010induced weight gain was similar between genotypes, irrespective of sex. Consistent with previous reports, we find that loss of Trem2 causes massive adipocyte hypertrophy and an attenuation in the lipid\u2010associated macrophage transcriptional response to obesity. In contrast to published data, we find that loss of Trem2 does not worsen metabolic function in obese mice. No differences in intraperitoneal glucose tolerance (ipGTT), oral GTT or mixed meal substrate control, including postprandial glucose, non\u2010esterified fatty acids, insulin or triglycerides, were found between WT and Trem2<jats:sup>\u2212\/\u2212<\/jats:sup> animals. Similarly, no phenotypic differences existed when animals were challenged with stressors on metabolic demand (i.e. acute exercise or environmental temperature modulation). Collectively, we report a disassociation between adipose tissue remodelling caused by loss of Trem2 and whole\u2010body metabolic homeostasis in obese mice. The complementary nature of experiments conducted gives credence to the conclusion that loss of Trem2 is unlikely to worsen glucose homeostasis in mice.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15246-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1113\/jp283684","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T15:58:37Z","timestamp":1661961517000},"page":"4485-4501","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Exon 2\u2010mediated deletion of Trem2 does not worsen metabolic function in diet\u2010induced obese mice"],"prefix":"10.1113","volume":"600","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5276-0592","authenticated-orcid":false,"given":"Nathan C.","family":"Winn","sequence":"first","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elysa M.","family":"Wolf","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie N.","family":"Garcia","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa H.","family":"Hasty","sequence":"additional","affiliation":[{"name":"Department of Molecular Physiology and Biophysics Vanderbilt University  Nashville TN USA"},{"name":"VA Tennessee Valley Healthcare System  Nashville TN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,20]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90617.2008"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.55.02.06.db05-0686"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1242\/dmm.006239"},{"issue":"3","key":"e_1_2_5_5_1","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1152\/jappl.1978.45.3.425","article-title":"Glycogen depletion in exercising rats infused with glucose, lactate, or pyruvate","volume":"45","author":"Bagby G. 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