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Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.<\/jats:p>","DOI":"10.1210\/endrev\/bnaa032","type":"journal-article","created":{"date-parts":[[2020,12,15]],"date-time":"2020-12-15T12:26:19Z","timestamp":1608035179000},"page":"101-132","source":"Crossref","is-referenced-by-count":283,"title":["Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation"],"prefix":"10.1210","volume":"42","author":[{"given":"Brent A","family":"McLean","sequence":"first","affiliation":[{"name":"Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chi Kin","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan E","family":"Campbell","sequence":"additional","affiliation":[{"name":"The Department of Medicine, Division of Endocrinology, Department of Pharmacology and Cancer Biology, Duke Molecular Physiology Institute, Duke University, Durham, NC, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8641-8568","authenticated-orcid":false,"given":"David J","family":"Hodson","sequence":"additional","affiliation":[{"name":"Institute of Metabolism and Systems Research (IMSR), University of Birmingham, and Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Trapp","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular and Metabolic Neuroscience, Department of Neuroscience, Physiology & Pharmacology, UCL, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6688-8127","authenticated-orcid":false,"given":"Daniel J","family":"Drucker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, University of Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,12,15]]},"reference":[{"issue":"3","key":"2021121110231533700_CIT0001","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1210\/jc.2015-3449","article-title":"Evolving concepts and translational relevance of enteroendocrine cell biology","volume":"101","author":"Drucker","year":"2016","journal-title":"J Clin Endocrinol Metab."},{"issue":"5924","key":"2021121110231533700_CIT0002","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1038\/304368a0","article-title":"Exon duplication and divergence in the human preproglucagon gene","volume":"304","author":"Bell","year":"1983","journal-title":"Nature."},{"issue":"6","key":"2021121110231533700_CIT0003","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1210\/endo-115-6-2176","article-title":"Pre-proglucagon messenger ribonucleic acid: nucleotide and encoded 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