Presenter Abstracts – C.2: Obesity & Metabolic Disorders
Session Chairs
Dr. Edie Goldsmith, University of South Carolina School of Medicine (SC INBRE)
Dr. Jackie Stephens, LSU Pennington Biomedical Research Center (LA COBRE)
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Dr. T.K.S. Kumar (Suresh Kumar Thallapuranum), University of Arkansas
Design of novel, stable metabolic fibroblast growth factor
Suresh Thallapuranam1, Phuc Phan1, Shivakumar Sonniala1, Jingyi Chem1, and Kyle Quinn2
1Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR, 2Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR
Background. Human fibroblast growth factors (FGFs) are heparin binding cytokines that exhibit endocrine and paracrine activities. FGFs mediate key physiological properties such as cell proliferation, cell differentiation, tumor growth, wound healing, and metabolic activities. Despite their critical cellular roles, their inherent instability has largely limited their biomedical applications. In this study, using a site-directed mutagenesis approach, we designed a novel human fibroblast growth factor (hFGF) that is hyper-stable and signals significant metabolic activity.
Hypothesis. Elimination of heparin binding affinity increases the structural stability of the human acidic fibroblast growth factor (hFGF1) and concomitantly enhances both its cell proliferation and metabolic activities.
Results. Isothermal titration calorimetry data on the hFGF1 variant, consisting of mutations in the putative heparin binding pocket, showed that the protein loses affinity to bind to the glycosaminoglycan. Differential scanning calorimetry results show that designed hFGF1 variant was more than 20 Centigrade more stable than wild type hFGF1. Limited trypsin digestion and thrombin cleavage assays show that the designed hFGF1 is completely resistant to proteases. Far UV CD and intrinsic fluorescence data suggest that no major conformational changes occur due to the mutations introduced in the hFGF1. Interestingly, the hyper-stable hFGF1 variant promotes enhanced proliferation of adipocytes and also increases the oxidation of fatty acids.
Conclusions. The designed novel hyper-stable hFGF1 exhibits potent proliferation of adipocytes and also enhances the oxidation of saturated fatty acids.
Dr. Travis Salisbury, Marshall University School of Medicine
Inhibition of Leucine-Stimulated Induction of mTOR1 to Suppress Breast Cancer in Obesity
Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV
Introduction/Background. Obesity is a national epidemic in the United States. Hyperactivity of the mTOR complex 1 (mTORC1) pathway is important for the pathogenesis of breast cancer in obesity. The amino acid leucine, which is increased in plasma during obesity, may support cancer progression by promoting mTORC1 hyperactivity. The primary pathway for the uptake of leucine by breast cancer cells is through L-Type Amino Acid Transporter 1 (LAT1).
Hypothesis/Goal of Study. We hypothesize that peritumor (PT) breast adipose-derived secretome (PT-ADS) induces signaling in breast cancer cells that increase the expression of LAT1, which in turn supports mTORC1 signaling.
Methods and Results. PT-ADS from women was applied to human estrogen receptor-positive breast cancer cells. LAT1 activity was determined by uptake of 3H-Leucine by breast cancer cells. LAT1 antagonists 2-Amino-2-norbornanecarboxylic acid (BCH) and JPH203 (KYT-0353) were used to inhibit LAT1 activity. Cell migration and cell invasion were determined by xCELLigence CIM-Plate assays. ELISA assays were used to measure cytokine levels in PT-ADS. In breast cancer cells, PT-ADS from women with BMIs > 30 induced significantly higher activity of LAT1, which was correlated with increased mTORC1 activity and cancer cell invasiveness, than PT-ADS from women with BMIs < 30.
Discussion/Conclusions. Based on these findings, we hypothesize that the increase in LAT1 activity in breast cancer cells in response to PT-ADS is mediated by an increase in the affinity of leucine for LAT1, and this change in LAT1 affinity for leucine is mediated by an increase in the phosphorylation of LAT1.
Grant/Funding Support. INBRE grant (P20GM103434), COBRE (1P20GM121299), THE EDWARDS FOUNDATION at the Edwards Comprehensive Cancer Center
Dr. Glenn Weaver, University of South Carolina
Preventing Childhood Obesity: The Case for Structure
Department of Exercise Science, University of South Carolina, Columbia, SC
Introduction/Background. Children’s (5-12 years) BMI gain accelerates during the summer making it a critical window for the prevention and treatment of childhood obesity. The structured days hypothesis posits that ‘structured days’ (i.e., days with pre-planned, segmented, and adult-supervised compulsory environments) protect children from engagement in obesogenic behaviors.
Hypothesis/Goal of Study. The goal of this presentation is to synthesize the state of the science related to the structured days hypothesis and discuss current and future work in the area of accelerated summer BMI gain.
Methods and Results. A number of observational and preliminary experimental studies will be highlighted that demonstrate the relationship with and potential impact of structure on children’s BMI gain and related behaviors.
Discussion/Conclusions. Preventive interventions for childhood obesity may be more successful if they are designed to target times that are less structured. Outcomes beyond BMI gain and related behaviors should be explored (e.g., social, emotional, behavioral, etc).
Grant/Funding Support. NIH Grants P20GM130420, R21HD095164, R21HD090647; Arnold Childhood Obesity Initiative.
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