MMPC :: MICROMouse Program Application Abstract

MICROMouse Program Application Abstract

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A novel AMPK-interacting protein in cardiac metabolism and function

Brian Iritani (Seattle, WA)

MICROMouse Program

Type II diabetes, obesity, and metabolic syndrome, are diseases of energy imbalance, which greatly increase the risk of developing cardiovascular diseases. Proper energy balance is normally regulated by AMP-activated protein kinase (AMPK). When activated by nutrient deficit or cellular stresses such as glucose deprivation or hypoxia, AMPK stimulates glucose uptake and lipid oxidation to produce energy, while turning off energy consuming anabolic pathways, including glucose and lipid production. Drugs that activate AMPK such as metformin and thiazolidinediones are a mainstay in the treatment of type-II diabetes, reinforcing the importance of targeting the AMPK pathway as a potential therapy to control metabolic disorders. However, a better understanding of the downstream cellular pathways and targets of AMPK, could result in more specific therapies, which have fewer side effects. Using a chemical mutagenesis strategy in mice, we have identified a novel strain of mice that contains a deletion in the Fnip1 gene, resulting in the absence of Folliculin interacting protein-1 (Fnip1). While the normal functions of Fnip1 are unknown, Fnip1 physically interacts with AMPK, and inhibition of AMPK results in a reduction in Fnip1 expression. Interestingly, mice deficient in Fnip1 (Fnip1d/d) phenocopy humans with mutations in AMPK subunits, including hypertropic cardiomyopathy and increased skeletal muscle mitochondrial biogenesis. The Broad Objective of this proposal is to dissect the roles of Fnip1 in cardiac metabolism and function. Our Specific Aims are: (1) To define the alterations in cardiac morphology and function which occur following loss of Fnip1. We will utilize echocardiography, electrocardiography, ultrasound, and histology to define the morphological and functional changes in cardiac muscle in Fnip1d/d and +/+ mice. (2) To determine if loss of Fnip1 alters AMPK-dependent signaling pathways and metabolism in cardiac tissue. We will assess AMPK-regulated metabolic pathways, including glucose uptake, glycogen deposition, fatty acid production, and mitochondrial biogenesis in cardiac tissue from Fnip1d/d and +/+ mice.

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