Location: Children's Nutrition Research Center
Project Number: 3092-51000-065-002-S
Project Type: Non-Assistance Cooperative Agreement
Start Date: Apr 1, 2019
End Date: Mar 31, 2024
Objective:
Objective 1: Determine if vitamin D receptors in the VMH of the brain are critical for glucose regulation.
Objective 2: In wild type (WT) and transgenic animals lacking functional leptin signaling (leptin knockout (KO), leptin receptor KO and leptin receptor agonist/antagonist treated WT mice) determine whether:
Objective 2A: Leptin is involved in the regulation of gluconeogenesis
Objective 2B: Regulation of gluconeogenesis through the leptin dependent mechanism operates via the leptin receptor
Objective 2C: Leptin agonist and small doses of hypoglycin-A or B reduces the rates of gluconeogenesis
Objective 3: Investigate the role of the mitochondrial deacetylase SIRT3 in regulation of pyruvate carboxylase and the gluconeogenesis pathway.
Subobjective 3A: To investigate SIRT3 regulation of pyruvate carboxylase
Subobjective 3B: To investigate SIRT3 regulation of gluconeogenesis in mouse models
Approach:
One of the most significant abnormalities underlying type 2 diabetes is continued production of glucose by the liver (gluconeogenesis). Thus, understanding the mechanisms by which gluconeogenesis is regulated is paramount to effectively treating type 2 diabetes. In this project, researchers are investigating three mechanisms that are likely involved in glucose regulation by the liver. Scientists will determine if vitamin D receptors in a specific area of the brain, the ventromedial hypothalamus (VMH), are important for glucose control. We will create a preponderance of data to support the role of the vitamin D receptor in the VMH irrespective of the limitations of each model. We will determine the role of leptin and the leptin receptor in hepatic gluconeogenesis and investigate the nutritional significance of certain small molecules in reducing glucose production via gluconeogeneic pathway. Researchers will also determine the mechanisms of SIRT3, a mitochondrial protein, to regulate gluconeogenesis. Together, these projects will advance our understanding of how the liver regulates glucose production using neural, hormonal, and intracellular mechanisms, and increase the overall body of knowledge.
