Location: Children's Nutrition Research Center
2020 Annual Report
Objectives
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.
Progress Report
For Objective 1, our goal is to determine if vitamin D receptors in the ventromedial hypothalamus of the brain are critical for glucose regulation. This year we continued research on determining the role of vitamin D receptors in the brain on glucose levels. We were able to mate animals successfully in order to get breeding pairs that will give us the appropriate mouse groups. We anticipate being able to create the appropriate groups for testing when COVID-19 pandemic restrictions on animal research numbers and research effort are lifted. For Objective 2, in order to address all the sub-objectives of this project to study the effect of the hormone leptin and its receptor on glucose production from the liver, we have submitted and obtained approval from our institutional animal advisory committee to perform all of the proposed experiments. Transgenic animals required for the protocol were purchased and some of the pilot experiments were accomplished before the COVID-19 pandemic restrictions. Thus, we are well-placed to be able to meet our future goals. For Objective 3, we are studying the SIRT3 gene regulation of glucose production in the liver, we have conducted biochemical experiments to confirm the interaction between SIRT3 and pyruvate carboxylase, one of the key enzymes involved in the pathway for liver glucose synthesis. We have also been breeding mice with transgenic over-expression of SIRT3 and mice with genetic deletion of SIRT3 to study SIRT3’s specific role in regulating glucose production in vivo. Although the COVID-19 pandemic restrictions slowed down the pace for the generation of sufficient mice for the study, we will achieve our goal as we have partially resumed research activities.
Accomplishments
1. Resources for pediatricians who provide care for obese children. When caring for obese children, pediatric health care providers must be able to gather information on diet, sleep, TV time, exercise, family history, as well as other items during a short visit and offer recommendations. There are few concise resources to help providers gather and evaluate information; thus, researchers at Houston, Texas, reviewed the literature for pediatric obesity and published a concise curation of resources for pediatric providers to aid families with information on nutrition, time-constraint strategies, and harmful eating behaviors. This work will be useful to all pediatric healthcare providers who counsel families with obese children.
2. Vitamin D enhances insulin action in brain cells. Vitamin D is associated with type 2 diabetes, but mechanisms understanding why are not clear. Researchers in Houston, Texas, previously showed that the brain may be a key site for vitamin D action to regulate blood sugar levels. They now showed that in brain cells, vitamin D increases the ability of insulin to act within these cells. Additionally, they showed that a key insulin pathway, the PI3K pathway, was needed in order for vitamin D to have both rapid and long-acting effects in brain cells. This is significant because it gives further evidence of how vitamin D may act in the brain to regulate blood sugar levels and demonstrates that the vitamin D and insulin pathways are interdependent in the brain.
3. Impaired suppression of glucose production in lean type 2 diabetic condition. Most investigations about type 2 diabetes have focused on the obese population; however, there is a distinct sub-population of type 2 diabetes patients who are lean with normal body mass index. It is not known if glucose production by the liver is differently affected in these lean individuals with type 2 diabetes. Scientists in Houston, Texas, using a lean type 2 diabetes rat model demonstrated that glucose production from the liver did not decrease appropriately after animals had eaten. These findings provide insights for future research about how to achieve better blood glucose control among this distinct sub-population of type 2 diabetes patients who are lean with normal body mass index.
4. Metabolic abnormalities in children, adolescents and young adults with Barth syndrome. Barth syndrome is a rare metabolic and neuromuscular disorder that occurs primarily in males with mortality frequently occurring during infancy and adolescence due to factors associated with the heart, immune system, muscles, and overall growth. It is not known if fatty acid and glucose metabolism is altered during this condition in humans. Researchers in Houston, Texas, demonstrated that fat oxidation was severely blunted during exercise in children, and an inability to increase fat metabolism during moderate physical activity is partially compensated by elevations in glucose metabolism. The data from this study suggests that abnormalities in glucose and fat metabolism contribute to the Barth syndrome condition and this research provides insights and potential nutritional interventions for the treatment of this condition.
