The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling
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 re...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-05-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/13/5/868 |
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| author | Sandip Mukherjee Molee Chakraborty Jake Haubner Glen Ernst Michael DePasquale Danielle Carpenter James C. Barrow Anutosh Chakraborty |
| author_facet | Sandip Mukherjee Molee Chakraborty Jake Haubner Glen Ernst Michael DePasquale Danielle Carpenter James C. Barrow Anutosh Chakraborty |
| author_sort | Sandip Mukherjee |
| collection | DOAJ |
| description | 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−activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO <i>WT</i> 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. |
| first_indexed | 2024-03-11T03:53:30Z |
| format | Article |
| id | doaj.art-2695fa91a3a24772ab51b42c8d89cc7f |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-11T03:53:30Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-2695fa91a3a24772ab51b42c8d89cc7f2023-11-18T00:40:22ZengMDPI AGBiomolecules2218-273X2023-05-0113586810.3390/biom13050868The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin SignalingSandip Mukherjee0Molee Chakraborty1Jake Haubner2Glen Ernst3Michael DePasquale4Danielle Carpenter5James C. Barrow6Anutosh Chakraborty7Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USALieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USALieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USALieber Institute for Brain Development and Department of Pharmacology, Johns Hopkins University School of Medicine, 855 North Wolfe Street Suite 300, Baltimore, MD 21205, USADepartment of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USAObesity 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−activity relationship (SAR) studies identified LI-2242 as a potent IP6K inhibitor compound. Here, we tested the efficacy of LI-2242 in DIO <i>WT</i> 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.https://www.mdpi.com/2218-273X/13/5/868IP6K1LI-2242obesityinsulin resistanceNAFLD |
| spellingShingle | Sandip Mukherjee Molee Chakraborty Jake Haubner Glen Ernst Michael DePasquale Danielle Carpenter James C. Barrow Anutosh Chakraborty The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling Biomolecules IP6K1 LI-2242 obesity insulin resistance NAFLD |
| title | The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling |
| title_full | The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling |
| title_fullStr | The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling |
| title_full_unstemmed | The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling |
| title_short | The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling |
| title_sort | ip6k inhibitor li 2242 ameliorates diet induced obesity hyperglycemia and hepatic steatosis in mice by improving cell metabolism and insulin signaling |
| topic | IP6K1 LI-2242 obesity insulin resistance NAFLD |
| url | https://www.mdpi.com/2218-273X/13/5/868 |
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