Department of Pediatrics/ Neonatology
University of Colorado Denver
Mechanisms For Obesity-Induced Insulin Resistance
Fetal Programming of Skeletal Muscle Metabolism
1. K12 RFA-OD-004 Building Interdisciplinary Careers in Women’s Health (BIRCWH): Jul 2008- Jul 2011. Fetal Programming of Skeletal Muscle Metabolism. Direct Cost: $82,455; Effort: 9cal mo
2. NIDDK P30DK57516 University of Colorado-Denver Diabetes and Endocrinology Research Center Pilot and Feasibility Award: April 2009-April 2010. Essential Role of p85alpha PI 3-Kinase in Obesity-Induced Inflammation. Direct Cost: $47,600
Description of Research
Insulin resistance in obesity leads to a greater risk of developing many metabolic diseases. The mechanisms that trigger the progression of obesity-induced insulin resistance are not fully understood. My research focuses on two aspects of understanding obesity induced insulin resistance; 1) to investigate possible fetal programming of insulin resistance in skeletal muscle and 2) to identify the role of p85a PI 3-Kinase in macrophage, adipose tissue, and their interactive effects on obesity-induced inflammation and insulin resistance. Project 1: The profound inter-generational impact of maternal obesity is being increasingly recognized as the single greatest pregnancy risk for both mother and infant. A growing body of data has shown that obesity prior to and during pregnancy, which affects ~30% of women, may have adverse long-term metabolic effects on the offspring. Since skeletal muscle is the primary site of insulin-mediated glucose disposal and fatty acid utilization, this project focuses on determining the effect of maternal obesity and/or maternal high fat, high calorie diet on in utero re-programming of energy metabolism in fetal skeletal muscle and identifying the molecular mechanisms that lead to this increased susceptibility to metabolic diseases in the offspring using a unique non-human primate model (Japanese Macaque). Project 2: Infiltration of immune cells, in particular bone-marrow derived macrophages, into an expanded fat cell mass is an important aspect of obesity. These infiltrating macrophages appear to be necessary for the initiation and propagation of inflammation. Using a transgenic mouse model, we are looking at the role of p85 in regulating chemotactic signals that lead to macrophage activation and/or recruitment to adipose tissue.
1-2 Most Significant Publications
1. CE McCurdy*, J Bishop*, SM Williams, JE. Friedman and KL Grove. Maternal high fat diet triggers lipotoxicity in the fetal livers of nonhuman primates. Journal of Clinical Investigation. 119:323-35, 2009.
2. CE McCurdy, RT Davidson, GD Cartee. Calorie Restriction Increases the Ratio of Phosphatidylinositol 3-Kinase Catalytic to Regulatory Subunits in Rat Skeletal Muscle. Am J Physiol Endocrinol Metab. 288: E996-E1001, 2005.
Primary Focus Area (if part of the obesity initiative)
· Mechansims of Obesity-Induced Insulin Resistance
Secondary Focus Areas (if part of the obesity initiative)
· Maternal Obesity-Induced Fetal Programming of Skeletal Muscle Metabolism and Insulin sensitivity
Benefit of CNRU
The major benefit of the CNRU for me has been the enhanced interaction and collaboration with other CNRU investigators. Additionally, the CNRU core laboratories have allowed me to expand the scope of my research questions. These laboratories provide services in a cost-effective manner than I could not develop in my own laboratory.
CNRU Cores Used
Metabolic and Energy Balance Core
CNRU CollaborationsJacob Friedman,Robert Eckel, Paul MacLean, Peggy Neville