{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T04:55:10Z","timestamp":1791521710659,"version":"4.3.4"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T00:00:00Z","timestamp":1655337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"publisher","award":["AA022937 AA026865 AA027697"],"award-info":[{"award-number":["AA022937 AA026865 AA027697"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["HL122507 HL156986"],"award-info":[{"award-number":["HL122507 HL156986"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["S10 OD026980"],"award-info":[{"award-number":["S10 OD026980"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:p>Obesity is associated with insulin resistance, glucose intolerance, inflammation, and altered neuronal activity in brain regions controlling metabolic functions including food intake, energy expenditure, and glucose homeostasis, such as the hypothalamus. In this study, we tested the hypothesis that inhibiting inflammation with minocycline could reduce adverse metabolic consequences associated with high-fat diet (HFD)-induced obesity in mice and sought to determine if metabolic improvements were associated with reduced hypothalamic microglia activity. Male C57Bl\/6J mice were placed on 60% HFD for 12\u00a0weeks, with minocycline (40\u00a0mg\/kg, p.o.) or normal tap water given during the last 6\u00a0weeks of diet. Age-matched mice maintained on control diet were used as an additional comparator group. Metabolic function was assessed during the last week of treatment. Ramified (resting) and non-ramified (active) microglia were quantified in the hypothalamus following immunohistochemical staining of ionized calcium-binding adaptor 1 (Iba-1) and further assessed by RNAseq. In HFD fed mice, minocycline attenuated body mass and adiposity without altering food intake suggesting enhanced energy expenditure. Minocycline also attenuated hyperinsulinemia and improved insulin sensitivity in HFD mice. Increased microglial activation and autophagy gene network changes were observed in the paraventricular nucleus (PVN) of the hypothalamus of HFD mice, which was prevented by minocycline treatment. Contrary to PVN findings, there were no significant effects of either HFD or minocycline on microglia activation in the hypothalamic arcuate nucleus or central amygdala. Together, these findings suggest that minocycline improves HFD-induced weight gain and insulin resistance in part by reducing inflammatory processes in the PVN, a key hypothalamic region regulating metabolic function.<\/jats:p>","DOI":"10.3389\/fphys.2022.933706","type":"journal-article","created":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T10:13:38Z","timestamp":1655374418000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Minocycline Reduces Hypothalamic Microglia Activation and Improves Metabolic Dysfunction in High Fat Diet-Induced Obese Mice"],"prefix":"10.3389","volume":"13","author":[{"given":"Caitlin R.","family":"Coker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aneesh","family":"Singal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah S.","family":"Bingaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anirban","family":"Paul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy C.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuval","family":"Silberman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,6,16]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11970","DOI":"10.1523\/JNEUROSCI.0624-12.2012","article-title":"Food Intake Adaptation to Dietary Fat Involves PSA-dependent Rewiring of the Arcuate Melanocortin System in Mice","volume":"32","author":"Benani","year":"2012","journal-title":"J. Neurosci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1111\/j.1749-6632.2011.06388.x","article-title":"Hypothalamic Inflammation: a Double-Edged Sword to Nutritional Diseases","volume":"1243","author":"Cai","year":"2011","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e45250","DOI":"10.1371\/journal.pone.0045250","article-title":"The Neuron-Astrocyte-Microglia Triad in Normal Brain Ageing and in a Model of Neuroinflammation in the Rat Hippocampus","volume":"7","author":"Cerbai","year":"2012","journal-title":"PLoS One"},{"key":"B37","doi-asserted-by":"publisher","first-page":"100043","DOI":"10.1016\/j.bioflm.2021.100043","article-title":"Do Results Obtained With RNA-Sequencing Require Independent Verification?","volume":"3","author":"Coenye","year":"2021","journal-title":"Biofilm"},{"key":"B4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.alcohol.2020.03.007","article-title":"Access Schedules Mediate the Impact of High Fat Diet on Ethanol Intake and Insulin and Glucose Function in Mice","volume":"86","author":"Coker","year":"2020","journal-title":"Alcohol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/J.PHYSBEH.2014.01.016","article-title":"Obesity Induces Neuroinflammation Mediated by Altered Expression of the Renin-Angiotensin System in Mouse Forebrain Nuclei","volume":"136","author":"de Kloet","year":"2014","journal-title":"Physiology Behav."},{"key":"B6","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1111\/jnc.13607","article-title":"Neuroinflammation: the Devil Is in the Details","volume":"139","author":"DiSabato","year":"2016","journal-title":"J. Neurochem."},{"key":"B7","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1016\/J.MOLMET.2017.01.010","article-title":"Astrocyte IKK\u03b2\/NF-\u03baB Signaling Is Required for Diet-Induced Obesity and Hypothalamic Inflammation","volume":"6","author":"Douglass","year":"2017","journal-title":"Mol. Metab."},{"key":"B36","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1038\/s41598-017-01617-3","article-title":"Benchmarking of RNA-Sequencing Analysis Workflows Using Whole-Transcriptome RT-qPCR Expression Data","volume":"7","author":"Everaert","year":"2017","journal-title":"Sci Rep."},{"key":"B8","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1152\/PHYSIOLGENOMICS.00073.2018","article-title":"Disparate Effects of Antibiotics on Hypertension","volume":"50","author":"Galla","year":"2018","journal-title":"Physiol. Genomics"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1002\/eji.201847807","article-title":"The Role of the Gut Microbiota and Microbial Metabolites in Neuroinflammation","volume":"50","author":"Haase","year":"2020","journal-title":"Eur. J. Immunol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.bbi.2019.09.001","article-title":"Modulation of High Fat Diet-Induced Microbiome Changes, but Not Behaviour, by Minocycline","volume":"82","author":"Hasebe","year":"2019","journal-title":"Brain, Behav. Immun."},{"key":"B35","doi-asserted-by":"publisher","first-page":"S627","DOI":"10.4103\/2230-8210.105581","article-title":"PVN Pathways Controlling Energy Homeostasis","volume":"16","author":"Hill","year":"2012","journal-title":"Indian J. Endocrinol. Metab."},{"key":"B11","doi-asserted-by":"publisher","first-page":"378","DOI":"10.3389\/fnagi.2018.00378","article-title":"A Critical Role of Autophagy in Regulating Microglia Polarization in Neurodegeneration","volume":"10","author":"Jin","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-based Genome Alignment and Genotyping with HISAT2 and HISAT-Genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.bbadis.2013.05.017","article-title":"Cellular and Molecular Players in Adipose Tissue Inflammation in the Development of Obesity-Induced Insulin Resistance","volume":"1842","author":"Lee","year":"2014","journal-title":"Biochimica Biophysica Acta (BBA) - Mol. Basis Dis."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41398-020-0774-1","article-title":"Minocycline-induced Microbiome Alterations Predict Cafeteria Diet-Induced Spatial Recognition Memory Impairments in Rats","volume":"10","author":"Leigh","year":"2020","journal-title":"Transl. PsychiatryPsychiatry"},{"key":"B15","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1038\/nature09782","article-title":"Autophagy in Immunity and Inflammation","volume":"469","author":"Levine","year":"2011","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"FeatureCounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"B17","doi-asserted-by":"publisher","first-page":"W199","DOI":"10.1093\/nar\/gkz401","article-title":"WebGestalt 2019: Gene Set Analysis Toolkit with Revamped UIs and APIs","volume":"47","author":"Liao","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B18","doi-asserted-by":"publisher","first-page":"e0126714","DOI":"10.1371\/journal.pone.0126714","article-title":"Long-term Over-expression of Neuropeptide Y in Hypothalamic Paraventricular Nucleus Contributes to Adipose Tissue Insulin Resistance Partly via the Y5 Receptor","volume":"10","author":"Long","year":"2015","journal-title":"PLoS One"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e132760","DOI":"10.1172\/jci.insight.132760","article-title":"Glucose in the Hypothalamic Paraventricular Nucleus Regulates GLP-1 Release","volume":"5","author":"Ma","year":"2020","journal-title":"JCI Insight"},{"key":"B20","doi-asserted-by":"publisher","first-page":"4288","DOI":"10.1093\/nar\/gks042","article-title":"Differential Expression Analysis of Multifactor RNA-Seq Experiments with Respect to Biological Variation","volume":"40","author":"McCarthy","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"B21","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1016\/J.AMJCARD.2021.07.004","article-title":"Potential of Minocycline for Treatment of Resistant Hypertension","volume":"156","author":"Pepine","year":"2021","journal-title":"Am. J. Cardiol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.bcp.2018.01.024","article-title":"Hypothalamic Inflammation and Malfunctioning Glia in the Pathophysiology of Obesity and Diabetes: Translational Significance","volume":"153","author":"Rahman","year":"2018","journal-title":"Biochem. Pharmacol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.ynstr.2016.03.001","article-title":"The Microbiome: A Key Regulator of Stress and Neuroinflammation","volume":"4","author":"Rea","year":"2016","journal-title":"Neurobiol. Stress"},{"key":"B24","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor Package for Differential Expression Analysis of Digital Gene Expression Data","volume":"26","author":"Robinson","year":"2009","journal-title":"Bioinformatics"},{"key":"B25","doi-asserted-by":"publisher","first-page":"604179","DOI":"10.3389\/fimmu.2020.604179","article-title":"The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology","volume":"11","author":"Rutsch","year":"2020","journal-title":"Front. Immunol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"2677","DOI":"10.3892\/mmr.2015.3735","article-title":"Minocycline Attenuates Pain by Inhibiting Spinal Microglia Activation in Diabetic Rats","volume":"12","author":"Sun","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"B27","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1016\/J.YFRNE.2009.10.002","article-title":"Hypothalamic Inflammation and Energy Homeostasis: Resolving the Paradox","volume":"31","author":"Thaler","year":"2010","journal-title":"Front. Neuroendocrinol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1172\/JCI59660","article-title":"Obesity Is Associated with Hypothalamic Injury in Rodents and Humans","volume":"122","author":"Thaler","year":"2012","journal-title":"J. Clin. Invest."},{"key":"B29","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1146\/annurev-physiol-021014-071656","article-title":"Hypothalamic Inflammation in the Control of Metabolic Function","volume":"77","author":"Valdearcos","year":"2015","journal-title":"Annu. Rev. Physiol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1016\/j.cmet.2017.05.015","article-title":"Microglial Inflammatory Signaling Orchestrates the Hypothalamic Immune Response to Dietary Excess and Mediates Obesity Susceptibility","volume":"26","author":"Valdearcos","year":"2017","journal-title":"Cell. Metab."},{"key":"B31","doi-asserted-by":"publisher","first-page":"18","DOI":"10.21307\/ane-2017-033","article-title":"Energy Dense Diet Tiggers Changes in Gut Microbiota, Reorganization of Gut brain Vagal Communication and Increases Body Fat Accumulation","volume":"77","author":"Vaughn","year":"2017","journal-title":"Acta Neurobiol. Exp. (Wars)."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1016\/j.bbrc.2015.07.097","article-title":"One-day High-Fat Diet Induces Inflammation in the Nodose Ganglion and Hypothalamus of Mice","volume":"464","author":"Waise","year":"2015","journal-title":"Biochem. Biophysical Res. Commun."},{"key":"B33","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1186\/s13293-019-0251-9","article-title":"Sex Differences in Metabolic Effects of Angiotensin-(1-7) Treatment in Obese Mice","volume":"10","author":"White","year":"2019","journal-title":"Biol. Sex. Differ."},{"key":"B34","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1242\/dmm.009464","article-title":"High-fat Diet Exposure Induces IgG Accumulation in Hypothalamic Microglia","volume":"5","author":"Yi","year":"2012","journal-title":"DMM Dis. Model. Mech."}],"container-title":["Frontiers in Physiology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.933706\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,16]],"date-time":"2022-06-16T10:13:43Z","timestamp":1655374423000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphys.2022.933706\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,16]]},"references-count":37,"alternative-id":["10.3389\/fphys.2022.933706"],"URL":"https:\/\/doi.org\/10.3389\/fphys.2022.933706","relation":{},"ISSN":["1664-042X"],"issn-type":[{"value":"1664-042X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,16]]},"article-number":"933706"}}