{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T06:00:35Z","timestamp":1792216835171,"version":"4.4.0"},"reference-count":22,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Food Science Institute Foundation","award":["25K21072"],"award-info":[{"award-number":["25K21072"]}]},{"name":"JSPS KAKENHI","award":["25K21072"],"award-info":[{"award-number":["25K21072"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Overweight and obesity are currently a worldwide problem, with undesirable health consequences, such as type 2 diabetes. Therefore, much attention has been paid to preventing obesity through diet. Free fatty acids (FFAs) serve as signaling molecules in many biological processes, leading to increased energy expenditure and insulin secretion. Short-chain fatty acids (SCFAs) such as acetic, propionic and butyric acid are bioactive metabolites produced by gut microbes, and their beneficial effects on host metabolism are well studied. However, the effects of hexanoic acid on metabolism are poorly understood. Methods: Male C57BL\/6J mice were fed a normal chow diet, a high-fat diet (HFD), an HFD containing 5% butyric acid or an HFD containing 5% hexanoic acid for 4 weeks, and the effects of hexanoic acid on their lipid and glucose metabolisms were examined. Results: Dietary supplementation of hexanoic acid or butyric acid for 4 weeks prevented HFD-induced obesity and fat accumulation in the white adipose tissues. Both FFAs also suppressed the elevated plasma non-esterified fatty acid (NEFA) levels and hepatic triglyceride content in the mice fed an HFD. In addition, butyric acid and hexanoic acid decreased the elevated expression of genes involved in fatty acid biosynthesis in the white adipose tissues under HFD conditions. Hyperinsulinemia induced by HFD feeding was attenuated by oral intake of butyric acid or hexanoic acid, whereas hyperglycemia under HFD feeding was improved only through oral administration of hexanoic acid. Hexanoic acid increased plasma glucagon-like peptide-1 (GLP-1) levels and the expression of genes associated with gluconeogenesis. The intraperitoneal glucose tolerance test (IPGTT) and the insulin tolerance test (ITT) revealed that the oral administration of hexanoic acid significantly enhanced glucose tolerance and insulin sensitivity. Conclusions: This study highlights the importance of hexanoic acid in improving lipid and glucose metabolisms. Hexanoic acid, as well as butyric acid, is a remarkable FFA with anti-obesity properties. Furthermore, hexanoic acid is more potent in maintaining glucose homeostasis than butyric acid. Thus, our findings provide insight into the development of functional foods which could prevent obesity-related diseases such as type 2 diabetes.<\/jats:p>","DOI":"10.3390\/nu17172868","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T15:31:21Z","timestamp":1756999881000},"page":"2868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Hexanoic Acid Improves Metabolic Health in Mice Fed High-Fat Diet"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-1213","authenticated-orcid":false,"given":"Takako","family":"Ikeda","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2567-7022","authenticated-orcid":false,"given":"Kumika","family":"Takii","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuna","family":"Omichi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Nishimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoka","family":"Matsunaga","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ami","family":"Kawauchi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ikuo","family":"Kimura","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neurobiology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"},{"name":"Department of Molecular Endocrinology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","unstructured":"NCD Risk Factor Collaboration (NCD-RisC) (2024). Worldwide trends in underweight and obesity from 1990 to 2022: A pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults. Lancet, 403, 1027\u20131050."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Wici\u0144ski, M., Fajkiel-Madajczyk, A., Kurant, Z., Liss, S., Szyperski, P., Szambelan, M., Gromadzki, B., Rupniak, I., S\u0142upski, M., and Sadowska-Krawczenko, I. (2024). Ashwagandha\u2019s multifaceted effects on human health: Impact on vascular endothelium, inflammation, lipid Metabolism, and cardiovascular outcomes. Nutrients, 16.","DOI":"10.3390\/nu16152481"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ikeda, T., Nishida, A., Yamano, M., and Kimura, I. (2022). Short-chain fatty acid receptors and gut microbiota as therapeutic targets in metabolic, immune, and neurological diseases. Pharmacol. Ther., 239.","DOI":"10.1016\/j.pharmthera.2022.108273"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Lin, H.V., Frassetto, A., Kowalik, E.J., Nawrocki, A.R., Lu, M.M., Kosinski, J.R., Hubert, J.A., Szeto, D., Yao, X., and Forrest, G. (2012). Butyrate and propionate protect against diet induced obesity and regulate gut hormones via free fatty acid receptor 3-independent mechanisms. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035240"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"van de Heijning, B.J.M., Oosting, A., Kegler, D., and van der Beek, E.M. (2017). An increased dietary supply of medium-chain fatty acids during early weaning in rodents prevents excessive fat accumulation in adulthood. Nutrients, 9.","DOI":"10.3390\/nu9060631"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Folwaczny, A., Waldmann, E., Altenhofer, J., Henze, K., and Parhofer, K.G. (2021). Postprandial lipid metabolism in normolipidemic subjects and patients with mild to moderate hypertriglyceridemia: Effects of test meals containing saturated fatty acids, mono-unsaturated fatty acids, or medium-chain fatty acids. Nutrients, 13.","DOI":"10.3390\/nu13051737"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"283","DOI":"10.5650\/jos.56.283","article-title":"Dietary medium- and long-chain triacylglycerols accelerate diet-induced thermogenesis in humans","volume":"56","author":"Ogawa","year":"2007","journal-title":"J. Oleo. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jbiotec.2014.04.010","article-title":"A biosynthetic pathway for hexanoic acid production in Kluyveromyces marxianus","volume":"182","author":"Cheon","year":"2014","journal-title":"J. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"11312","DOI":"10.1074\/jbc.M211609200","article-title":"The Orphan G protein-coupled receptors GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids","volume":"278","author":"Brown","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1007\/s11745-010-3465-5","article-title":"Inhibition of insulin and t3-induced fatty acid synthase by hexanoate","volume":"45","author":"Akpa","year":"2010","journal-title":"Lipids"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9575","DOI":"10.1096\/fj.202000455R","article-title":"Propionic acid and not caproic acid, attenuates nonalcoholic steatohepatitis and improves (cerebro) vascular functions in obese Ldlr-\/-. Leiden mice","volume":"34","author":"Tengeler","year":"2020","journal-title":"FASEB J."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Shimizu, H., Masujima, Y., Ushiroda, C., Mizushima, R., Taira, S., Ohue-Kitano, R., and Kimura, I. (2019). Dietary short-chain fatty acids intake improves the hepatic metabolic condition via FFAR3. Sci. Rep., 9.","DOI":"10.1038\/s41598-019-53242-x"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ohue-Kitano, R., Nonaka, H., Nishida, A., Masujima, Y., Takahashi, D., Ikeda, T., Uwamizu, A., Tanaka, M., Kohjima, M., and Igarashi, M. (2023). Medium-chain fatty acids suppress lipotoxicity-induced hepatic fibrosis via the immunomodulating receptor GPR84. JCI Insight, 8.","DOI":"10.1172\/jci.insight.165469"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1509","DOI":"10.2337\/db08-1637","article-title":"Butyrate improves insulin sensitivity and increases energy expenditure in mice","volume":"58","author":"Gao","year":"2009","journal-title":"Diabetes"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"288","DOI":"10.3109\/09637486.2016.1153611","article-title":"Medium-chain fatty acid reduces lipid accumulation by regulating expression of lipid-sensing genes in human liver cells with steatosis","volume":"67","author":"Wang","year":"2016","journal-title":"Int. J. Food Sci. Nutr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.febslet.2007.11.057","article-title":"Inflammation and insulin resistance","volume":"582","author":"Luca","year":"2008","journal-title":"FEBS Lett."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.cell.2013.12.016","article-title":"Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits","volume":"156","author":"Goncalves","year":"2014","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/nrendo.2011.126","article-title":"Targeting gut microbiota in obesity: Effects of prebiotics and probiotics","volume":"7","author":"Delzenne","year":"2011","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1093\/advances\/nmx009","article-title":"Butyrate: A double-edged sword forhealth?","volume":"9","author":"Liu","year":"2018","journal-title":"Adv. Nutr."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Wang, Q., Huang, Y., Meng, K., Zhang, H., Han, Y., Zhang, R., Han, X., Liu, G., Cai, H., and Yang, P. (2025). Probiotic potentials and protective effects of Ligilactobacillus animalis LA-1 against high-fat diet-induced obesity in mice. Nutrients, 17.","DOI":"10.3390\/nu17142346"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Deuren, T., Smolders, L., Hartog, A., Bouwman, F.G., Blaak, E.E., and Canfora, E.E. (2023). Butyrate and hexanoate-enriched triglycerides increase postprandrial systemic butyrate and hexanoate in men with overweight\/obesity: A double-blind placebo-controlled randomized crossover trial. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.1066950"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2868\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:39:36Z","timestamp":1760035176000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/17\/2868"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":22,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["nu17172868"],"URL":"https:\/\/doi.org\/10.3390\/nu17172868","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.02.20.639216","asserted-by":"object"}]},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,4]]}}}