Growing interest in IP6K1

JUPITER, Fla.—The U.S. Centers for Disease Control and Prevention estimate that as of 2014, 29.1 million people—9.3 percent of the population—had diabetes, and obesity rates for children and adults are at 17 and 36 percent, respectively. As those numbers continue to climb, the search continues for therapeutic approaches to help patients manage their weight and insulin levels.

And in the midst of that research, a new target has emerged. The protein in question, IP6K1, was examined in a trio of studies led by Anutosh Chakraborty, an assistant professor at the Florida campus of The Scripps Research Institute (TSRI), and the results were published in The International Journal of Biochemistry & Cell Biology, Molecular Metabolism and The Journal of Clinical Investigation.

“The ubiquitously expressed enzyme IP6K1 primarily generates the signaling ‘inositol pyrophosphates’ in the body. Inositol pyrophosphates bind or pyrophosphorylate their target proteins. IP6K1 also regulates some other proteins by direct binding. As a result, IP6K1 regulates various cellular processes including energy metabolism. IP6K1 promotes energy accumulation, especially in fat cells,” explains Chakraborty. “Moreover, IP6K1 reduces insulin’s efficacy in high-fat-fed mice. Therefore, mice with global or fat cell-specific deletion of IP6K1 are protected from diet-induced obesity (DIO), insulin resistance and fatty liver. Accordingly, the IP6K inhibitor TNP [N2-(m-Trifluorobenzyl), N6-(p-nitrobenzyl)purine] protects mice from these metabolic aberrations. In addition, the compound promotes weight loss and restores insulin sensitivity, when dosed to mice that are already DIO.”

Given these results, some of the greatest interest related to IP6K1 is in blocking it with inhibitors such as TNP. Energy expenditure—specifically fat energy—follows the process of lipolysis, which breaks down stored fat or triglycerides into free fatty acids and glycerol for cells to use as energy. When IP6K1 is deleted, it affects its interaction with another protein and enhances the breakdown of fats. When IP6K1 was deleted in the fat cells of animal models, the animals saw enhanced energy expenditure as well as protection from DIO and insulin resistance.

“In addition, the compound facilitates weight loss and improves metabolic parameters when used in animals that are already obese,” Chakraborty noted in a press release.

Despite its promise, however, Chakraborty admits TNP “has several shortcomings,” and as such, “research is ongoing to overcome these obstacles, which will generate novel IP6K inhibitors with higher efficacy and minimum side effects. Testing these compounds in rodents and higher primates will be the next step.”

Given its effect on fat breakdown and insulin resistance, it’s unknown whether or not IP6K1’s activity is altered in obese or diabetic individuals, but Chakraborty tells DDNews his lab is working to answer that question.

As for how the deletion of this protein can protect against insulin resistance, Chakraborty notes that “Protein kinases Akt/PKB and AMPK maintain insulin sensitivity. In addition, AMPK enhances energy expenditure, which reduces energy storage. IP6K1 inhibits Akt and AMPK via distinct mechanisms, which promote insulin resistance and weight gain. Moreover, adipocyte-specific IP6K1-KO mice exhibit increased plasma levels of adiponectin, which is an insulin sensitizing cytokine secreted from the adipose tissue. Therefore, IP6K1 exerts pleiotropic inhibitory effects on the insulin signaling pathway.”

“Obesity is a global epidemic. In the U.S., 34.9 percent of adults are obese, of which 9.3 percent also have type 2 diabetes (T2D). Obesity/T2D leads to various other life-threatening diseases, such as heart diseases, stroke and neurodegeneration. Although lifestyle interventions are effective for weight control, a significant number of patients exhibit inadequate long-term responses. Thus, anti-obesity pharmacotherapy is essential. Unfortunately, current anti-obesity medications are only partly effective. Therefore, new drugs, with long-term efficacy and without substantial side-effects, are urgently needed, especially for patients who are refractory to current treatments,” says Chakraborty.