The IP6K Inhibitor LI-2242 Ameliorates Diet-Induced Obesity, Hyperglycemia, and Hepatic Steatosis in Mice by Improving Cell Metabolism and Insulin Signaling

• Published in: Biomolecules (Basel, Switzerland) Switzerland), 2023-05, Vol.13 (5), p.868
• Main Authors: Mukherjee, Sandip, Chakraborty, Molee, Haubner, Jake, Ernst, Glen, DePasquale, Michael, Carpenter, Danielle, Barrow, James C, Chakraborty, Anutosh
• Format: Article
• Language: English
• Subjects: Adipocytes; Adipose tissue; Animals; Body composition; Body fat; Body weight; Care and treatment; Chemical inhibitors; Diet; Diphosphates - metabolism; Energy metabolism; Fatty liver; Food; Glucagon; Glucose; Health aspects; Hepatocytes; High-throughput screening; Hyperglycemia; Hyperglycemia - metabolism; Hyperinsulinemia; Inositol; Inositol - metabolism; Insulin; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; IP6K1; Kinases; Laboratories; LI-2242; Lipid Metabolism; Lipids; Lipogenesis; Liver - metabolism; Liver diseases; Medical research; Metabolism; Mice; Mice, Inbred C57BL; Mitochondria; NAFLD; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Obesity - etiology; Obesity - genetics; Oxygen consumption; Phosphates; Physiological aspects; Plasma; Public health; Risk factors; Steatosis; World health
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom13050868

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 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.