{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T17:47:33Z","timestamp":1785433653692,"version":"3.56.0"},"reference-count":41,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK 119135"],"award-info":[{"award-number":["DK 119135"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["DK 59630"],"award-info":[{"award-number":["DK 59630"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Breakthrough T1D","award":["3-SRA-2023-1361-S-B"],"award-info":[{"award-number":["3-SRA-2023-1361-S-B"]}]},{"award":["3-SRA-2023-1361-S-B"],"award-info":[{"award-number":["3-SRA-2023-1361-S-B"]}],"id":[{"id":"https:\/\/ror.org\/00vqxjy61","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Apolipoprotein A-IV (ApoA-IV) is a glycoprotein secreted by the small intestine to regulate lipid metabolism and satiety. Its role in insulin-independent glucose homeostasis remains largely unknown. In this study, we demonstrate that intestinal ApoA-IV overexpression significantly attenuates diet-induced obesity and hyperglycemia following severe \u03b2-cell loss. Over a 20-week high-fat diet challenge, ApoA-IV transgenic (ApoA-IV-Tg) mice maintained significantly lower adiposity than wild-type controls, driven by elevated energy expenditure and fatty acid oxidation rather than reduced caloric intake. Beyond weight maintenance, ApoA-IV maintained excellent systemic glycemic control and enhanced peripheral insulin sensitivity. Most notably, ApoA-IV significantly attenuated hyperglycemia following streptozotocin (STZ)-induced \u03b2-cell ablation, maintaining glucose stability despite severe insulin deficiency. Mechanistically, this protection results from a blunted glucagon response and the subsequent suppression of the hepatic pCREB-G6Pase gluconeogenic signaling pathway. In vitro evidence confirms that ApoA-IV directly inhibits pancreatic \u03b1-cell glucagon secretion through an LDL receptor-related protein 1 (LRP1)-dependent pathway, reinforced by the precise co-localization of LRP1 and glucagon in pancreatic islets. Furthermore, ApoA-IV-Tg mice were protected from the STZ-induced corticosterone surge and systemic lipolysis. Collectively, these findings establish the ApoA-IV\u2013LRP1 signaling axis as a potent metabolic switch, providing a promising insulin-independent strategy for managing obesity and diabetes.<\/jats:p>","DOI":"10.3390\/cells15131229","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:04:49Z","timestamp":1783411489000},"page":"1229","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The ApoA-IV\u2013LRP1 Signaling Axis: A Novel Insulin-Independent Pathway for the Suppression of Diabetic Hyperglucagonemia"],"prefix":"10.3390","volume":"15","author":[{"given":"Min","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xenia","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Wei","family":"Ko","sequence":"additional","affiliation":[{"name":"Chroma Medicine, 201 Brookline Ave, Suite 1101, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maureen","family":"Fitzgerald","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Physiology, & Neurobiology, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0252-0267","authenticated-orcid":false,"given":"Chunmin C.","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Tso","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1016\/j.ajcnut.2025.07.033","article-title":"Global, Regional, and National Burden of High Sugar-Sweetened Beverages Consumption, 1990\u20132021, with Projections up to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021","volume":"122","author":"Nascimento","year":"2025","journal-title":"Am. 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