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Aim 1: To characterize the associations of IPMK, energy homeostasis and cardiovascular function during TRF in vivo. We will examine the temporal relationships of IPMK and its targets in liver, energy homeostasis, hemodynamics and cardiac parameters in ad libitum-fed (LD-fed) versus TRF (12 hour feeding) during the light (L-fed) or dark (D-fed) periods in C57BL/6J mice. This strain is genetically susceptible to diet-induced obesity and metabolic syndrome. We will investigate whether IPMK is causally involved in TRF by specifically deleting Ipmk in liver and examining metabolic phenotypes.
Aim 2: To determine the molecular mechanisms of IPMK in energy metabolism in vitro. We have demonstrated that IPMK is essential for regulating glucose via AMPK and potentially lipid homeostasis. Our new preliminary data showed that IPMK expression is markedly increased in TRF D-fed compared to LD-fed mice. Deletion of liver IPMK leads to a dramatic increase in the mature form of SREBP, and this change is associated with an increase in acetylated SREBP and a decrease in SIRT1 activity. Therefore, we hypothesize that an increase of IPMK during TRF will protect against metabolic stress caused by high fat diet. We will investigate the molecular mechanisms by which IPMK modulates lipid and glucose metabolism via AMPK-dependent and AMPK-independent pathways in hepatocytes, using a combination of genetic and pharmacological approaches.
The proposed studies in mice will advance our understanding of metabolic effects of TRF, how TRF in the dark versus light periods affects metabolic and cardiovascular functions, and the specific roles of IPMK and related signaling pathways. The experiments in Aim 1 will benefit from the Dr. Ahima's expertise in obesity, diabetes and metabolism, and the phenotyping of mice with Ipmk deletion in liver. Dr. Kim’s expertise in cellular and molecular biology, particularly in the areas of IPMK and AMPK signaling, will be beneficial in the experiments in Aim 2. We will be working together with the clinical and population researchers, and modify our experimental paradigm if necessary based on the outcomes of their studies. We will also perform biochemical analyses of biological samples obtained in the clinical studies (Clinical Project proposal). These collaboration will further bridge the gap between basic science and clinical/population studies. A better understanding of basic mechanisms underlying TRF will bridge the proposed clinical and population studies, provide novel insights into the relationship between feeding patterns and energy metabolism, and may potentially lead to the development of new preventive and therapeutic strategies for obesity, diabetes and associated diseases.
Basic Project PI: Rexford S. Ahima, MD, PhD