{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T01:02:58Z","timestamp":1767834178387,"version":"3.49.0"},"reference-count":53,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T00:00:00Z","timestamp":1684540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Saint Louis University (SLU)","award":["NIH-R01DK132162"],"award-info":[{"award-number":["NIH-R01DK132162"]}]},{"name":"Saint Louis University (SLU)","award":["NIH-U01 MH112658"],"award-info":[{"award-number":["NIH-U01 MH112658"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Obesity and nonalcoholic fatty liver disease (NAFLD) are global health concerns, and thus, drugs for the long-term treatment of these diseases are urgently needed. We previously discovered that the inositol pyrophosphate biosynthetic enzyme IP6K1 is a target in diet-induced obesity (DIO), insulin resistance, and NAFLD. Moreover, high-throughput screening (HTS) assays and structure\u2212activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO WT C57\/BL6J mice. LI-2242 (20 mg\/kg\/BW daily, i.p.) reduced body weight in DIO mice by specifically reducing the accumulation of body fat. It also improved glycemic parameters and reduced hyperinsulinemia. LI-2242-treated mice displayed reduced the weight of various adipose tissue depots and an increased expression of metabolism- and mitochondrial-energy-oxidation-inducing genes in these tissues. LI-2242 also ameliorated hepatic steatosis by reducing the expression of genes that enhance lipid uptake, lipid stabilization, and lipogenesis. Furthermore, LI-2242 enhances the mitochondrial oxygen consumption rate (OCR) and insulin signaling in adipocytes and hepatocytes in vitro. In conclusion, the pharmacologic inhibition of the inositol pyrophosphate pathway by LI-2242 has therapeutic potential in obesity and NAFLD.<\/jats:p>","DOI":"10.3390\/biom13050868","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T02:28:42Z","timestamp":1684722522000},"page":"868","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling"],"prefix":"10.3390","volume":"13","author":[{"given":"Sandip","family":"Mukherjee","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Molee","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jake","family":"Haubner","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glen","family":"Ernst","sequence":"additional","affiliation":[{"name":"Lieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"DePasquale","sequence":"additional","affiliation":[{"name":"Lieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5115-9300","authenticated-orcid":false,"given":"James C.","family":"Barrow","sequence":"additional","affiliation":[{"name":"Lieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anutosh","family":"Chakraborty","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat. 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