{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T19:15:13Z","timestamp":1789067713046,"version":"build-2803163510"},"reference-count":57,"publisher":"American Diabetes Association","issue":"11","license":[{"start":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/journals\/pages\/license"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["PJT-183901"],"award-info":[{"award-number":["PJT-183901"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,11,1]]},"abstract":"<jats:sec>\n                    <jats:title\/>\n                    <jats:p>An acute increase of lipids in the upper small intestine (USI) of rodents and humans triggers lipid-sensing pathways to reduce food intake. However, USI lipid sensing does not reduce feeding in high-fat (HF) fed conditions, and the underlying mechanism remains elusive. Here, we report that HF feeding in male rats impaired USI lipid infusion to stimulate glucose-dependent insulinotropic polypeptide (GIP) secretion and decrease refeeding, and the defects of USI lipid sensing were restored by metformin. Next, we found that infusion of GIP receptor (GIPR) agonist in the nucleus of the solitary tract (NTS), but not mediobasal hypothalamus or area postrema, resulted in decreased refeeding in chow-fed rats. The anorectic effect of NTS GIPR agonist remained intact in HF rats and was inhibited by a genetic knockdown of GIPR. Finally, an inhibition of NTS GIPR also negated the ability of USI lipid sensing with metformin to decrease refeeding despite an increase in plasma GIP levels in HF rats. Thus, USI lipid sensing in HF rats is enhanced by metformin to trigger an endocrine GIP to NTS GIPR axis to reduce food intake, thereby unveiling small intestinal lipid-sensing pathways as potential targets to enhance GIP action and reduce weight in obesity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Article Highlights<\/jats:title>\n                    <jats:p>High-fat (HF) feeding in rats impairs upper small intestine (USI) lipid sensing to increase plasma glucose-dependent insulinotropic polypeptide (GIP) levels and reduce feeding. Metformin enhances USI lipids to increase GIP and reduce feeding in HF-fed rats. GIP activates the GIP receptor (GIPR) in the nucleus of the solitary tract (NTS), which reduces food intake in HF-fed rats. GIPR in the NTS is required for small intestinal lipids with metformin to reduce feeding.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.2337\/db25-0100","type":"journal-article","created":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T17:06:09Z","timestamp":1753203969000},"page":"1906-1917","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":4,"title":["Metformin Boosts Intestinal Lipid Sensing via GIP to Suppress Feeding"],"prefix":"10.2337","volume":"74","author":[{"given":"Rachel","family":"Kuah","sequence":"first","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto 2 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa T.","family":"Wang","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto 2 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Back","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa J.W.","family":"Li","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto 2 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyla","family":"Bruce","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Institute of Medical Science, University of Toronto 3 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N.","family":"LoChoy","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline L.","family":"Beaudry","sequence":"additional","affiliation":[{"name":"Department of Nutritional Sciences, University of Toronto 4 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel R.","family":"Barros","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto 2 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Yang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2908-3324","authenticated-orcid":false,"given":"Tony K.T.","family":"Lam","sequence":"additional","affiliation":[{"name":"Toronto General Hospital Research Institute, University Health Network 1 , Toronto, Ontario, Canada"},{"name":"Department of Physiology, University of Toronto 2 , Toronto, Ontario, Canada"},{"name":"Institute of Medical Science, University of Toronto 3 , Toronto, Ontario, Canada"},{"name":"Department of Medicine, University of Toronto 5 , Toronto, Ontario, Canada"},{"name":"Banting and Best 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