{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:38:01Z","timestamp":1786358281074,"version":"build-2736575974"},"reference-count":94,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,9]],"date-time":"2026-08-09T00:00:00Z","timestamp":1786233600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005825","name":"USDA-NIFA Evans Allen project","doi-asserted-by":"publisher","award":["ARX01-6012"],"award-info":[{"award-number":["ARX01-6012"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Peripheral \u03b3-aminobutyric acid (GABA) signaling is emerging as a context-dependent contributor to metabolic regulation. Long recognized as the principal inhibitory neurotransmitter in the central nervous system, GABA\u2019s role as an important signal in peripheral tissues is recently getting attention. This expanded view raises a central question: why do GABA-sensitive pathways support regulation in some metabolic settings, yet reinforce dysfunction in others? In obesity and type 2 diabetes mellitus (T2DM), nutrient excess, insulin resistance, and chronic inflammation remodel the cellular environments in which GABA is produced, sensed, and metabolized. As a result, GABA signaling may shift from adaptive regulation that maintains tissue function to compensatory responses that attempt to limit metabolic stress, and ultimately to maladaptive outputs that reinforce disease progression. Here, we review the biochemical basis, sources, receptor systems, and extracellular regulation of peripheral GABA signaling. We then examine how GABA-sensitive pathways are organized across metabolic tissues and remodeled in obesity and T2DM, with emphasis on islet endocrine dysfunction, hepatic GABA output, and adipose\u2013immune\u2013microbiota interactions. We further consider how this framework informs pathway-specific therapeutic strategies and the barriers to translation. We propose that peripheral GABA signaling is neither inherently protective nor harmful. Its metabolic consequence depends on the source of GABA, the responding tissue environment, and the stage of metabolic disease.<\/jats:p>","DOI":"10.3390\/ijms27167141","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T10:23:50Z","timestamp":1786357430000},"page":"7141","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Peripheral GABA Signaling in Metabolic Adaptation and Maladaptation"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4857-3882","authenticated-orcid":false,"given":"Tolulope Peter","family":"Saliu","sequence":"first","affiliation":[{"name":"Department of Life, Earth and Environmental Sciences, West Texas A&M University, Canyon, TX 79016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6611-126X","authenticated-orcid":false,"given":"Adedeji O.","family":"Adetunji","sequence":"additional","affiliation":[{"name":"Department of Agriculture, University of Arkansas at Pine Bluff, Pine Bluff, AR 71602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johnson O.","family":"Ogunsile","sequence":"additional","affiliation":[{"name":"Molecular Targets and Therapeutics Center, Institute of Virology, Helmholtz Munich, 85764 Neuherberg, Germany"},{"name":"Division of Clinical Pharmacology, Faculty of Medicine IV, Ludwig-Maximilians-University of Munich (LMU), 80337 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9180-5979","authenticated-orcid":false,"given":"Hannah O.","family":"Popoola","sequence":"additional","affiliation":[{"name":"Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6807-7248","authenticated-orcid":false,"given":"Chinyere Mary-Cynthia","family":"Ikele","sequence":"additional","affiliation":[{"name":"Department of Biology, New Mexico State University, Las Cruces, NM 88003, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9490-9041","authenticated-orcid":false,"given":"Sierra N.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Life, Earth and Environmental Sciences, West Texas A&M University, Canyon, TX 79016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Oriakhi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Diaz","sequence":"additional","affiliation":[{"name":"Department of Life, Earth and Environmental Sciences, West Texas A&M University, Canyon, TX 79016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2623-9592","authenticated-orcid":false,"given":"Stephen P.","family":"Karaganis","sequence":"additional","affiliation":[{"name":"Department of Life, Earth and Environmental Sciences, West Texas A&M University, Canyon, TX 79016, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1007\/BF00237558","article-title":"The action of \u03b3-aminobutyric acid on cortical neurones","volume":"3","author":"Schwartz","year":"1967","journal-title":"Exp. 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