{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:13:15Z","timestamp":1779894795328,"version":"3.53.1"},"reference-count":130,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T00:00:00Z","timestamp":1639958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001775","name":"University of Technology Sydney","doi-asserted-by":"publisher","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}],"id":[{"id":"10.13039\/501100001775","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UTS Start-up Grant 2018","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP\/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin\u2019s therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP\/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL\/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg\/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K\/AKT intracellular pathway and the PACAP\/VIP system were evaluated by real-time qPCR and\/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP\/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K\/AKT and PACAP\/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP\/VIP system homeostasis. Data also suggests that the PI3K\/AKT pathway, at least in part, mediates some of metformin\u2019s beneficial effects.<\/jats:p>","DOI":"10.3390\/ijms222413660","type":"journal-article","created":{"date-parts":[[2021,12,20]],"date-time":"2021-12-20T08:43:32Z","timestamp":1639989812000},"page":"13660","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Metformin Treatment Attenuates Brain Inflammation and Rescues PACAP\/VIP Neuropeptide Alterations in Mice Fed a High-Fat Diet"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4165-4276","authenticated-orcid":false,"given":"Mawj","family":"Mandwie","sequence":"first","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyn","family":"Karunia","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6636-2555","authenticated-orcid":false,"given":"Aram","family":"Niaz","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin A.","family":"Keay","sequence":"additional","affiliation":[{"name":"Laboratory of Neural Structure and Function, School of Medical Science (Neuroscience), University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8260-8890","authenticated-orcid":false,"given":"Giuseppe","family":"Musumeci","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Biotechnological Sciences, Anatomy, Histology and Movement Sciences Section, School of Medicine, University of Catania, 95125 Catania, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Rennie","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6244-3929","authenticated-orcid":false,"given":"Kristine","family":"McGrath","sequence":"additional","affiliation":[{"name":"School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghaith","family":"Al-Badri","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7037-759X","authenticated-orcid":false,"given":"Alessandro","family":"Castorina","sequence":"additional","affiliation":[{"name":"Laboratory of Cellular and Molecular Neuroscience (LCMN), School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW 2007, Australia"},{"name":"Laboratory of Neural Structure and Function, School of Medical Science (Neuroscience), University of Sydney, Sydney, NSW 2006, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/ijo.2016.183","article-title":"High fat induces acute and chronic inflammation in the hypothalamus: Effect of high-fat diet, palmitate and tnf-alpha on appetite-regulating npy neurons","volume":"41","author":"Dalvi","year":"2017","journal-title":"Int. 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