- PhD, University of New Hampshire
Multifactorial Regulation of Metabolic Disease
Complex metabolic syndromes such as obesity are caused by interactions between an individual’s genetic predisposition and the nutritional and physical environment. Although studies have shown that nutritional status during development can ‘permanently’ alter an individual’s susceptibility to developing obesity and related metabolic disorders in later life, very little is known about the biological mechanisms and genes that cause these ‘epigenetic’ changes in predisposition for the development of diseases such as obesity and diabetes.
To identify potential ‘epigenetic’ contributions to obesity, we have characterized an inbred mouse strain that gives rise to large variations in bodyweight among individuals when fed a high fat diet and reared in a controlled environment. Analyses of gene expression in adipose tissue of these mice identified a number of genes that were associated with variations in the development of obesity among individuals. These included imprinted genes, developmental genes; and, genes related to molecular signaling cascades, angiogenesis, vascularization and cytoskeletal organization. Because individual mice within our inbred mouse population are essentially ‘genetically identical’, we hypothesize that epigenetic mechanisms must underlie the regulation of some of the genes, or gene pathways associated with the development of obesity in this model. Our goal is to identify the epigenetic mechanism(s) that regulate the development of obesity and related metabolic disease in mice.
Our studies will unravel novel biological mechanisms associated with variations of adiposity in the absence of genetic variation and identify pathways that can be evaluated as therapeutic targets for the treatment of human obesity and related diseases.
Guerra, C., R.A. Koza, H.H. Yamashita, K.W. King, and L.P. Kozak. Emergence of brown adipocytes in white fat is under genetic control. Effects on body weight and adiposity. J. Clin. Invest. 102: 412-420, 1998. PMCID: PMC508900
Koza, R.A., S.M. Hohmann, C.Guerra, M. Rossmeisl, L.P. Kozak. Synergistic Gene Interactions Control the Induction of the Mitochondrial Uncoupling Protein (Ucp1) Gene in White Fat Tissue. J. Biol. Chem. 275: 34486-34492, 2000. PMID: 10931824
Koza, R.A., K. Flurkey, D.M. Graunke, C. Braun, H. Pan, P.C. Reifsnyder, L.P. Kozak and E.H. Leiter. Contributions of dysregulated energy metabolism to type 2 diabetes development in NZO/H1Lt mice with polygenic obesity. Metabolism 53: 799-808, 2004. PMID: 15164332
Koza R.A., L. Nikonova, J. Hogan, J.S. Rim, T. Mendoza, C. Faulk, J. Skaf and L.P. Kozak. Changes in Gene Expression Foreshadow Diet-Induced Obesity in Genetically Identical Mice. PLoS Genet 2(5): e81, 2006. PMCID: PMC1464831
Nikonova, L., R.A. Koza, T. Mendoza, P.M. Chao, J.P. Curley and L.P. Kozak. Mesoderm-specific transcript is associated with fat mass expansion in response to a positive energy balance. FASEB J 22 (11): 3925-37, 2008. PMCID: PMC2574032
Koza R.A., P. Rogers and L. P. Kozak. Inter-individual variation of dietary fat-induced mesoderm specific transcript in adipose tissue within inbred mice is not caused by altered promoter methylation. Epigenetics 4 (7): 512-518, 2009. PMCID: PMC3951159
Kozak, L.P., S. Newman, P-M. Chao, T. Mendoza and R.A Koza. The Early Nutritional Environment of the Mouse Determines the Capacity for Adipose Tissue Expansion by Modulating Genes of Caveolae Structure. PLoS One 5(6): e11015, 2010. PMCID: PMC2888576
Doucette, CR, Horowitz MC, Berry R, MacDougald OA, Anunciado-Koza R, Koza RA,Rosen CJ. A High Fat Diet Increases Bone Marrow Adipose Tissue (MAT) But Does Not Alter Trabecular or Cortical Bone Mass in C57BL/6J Mice. J Cell Physiol. 2015 Feb 7. doi: 10.1002/jcp.24954. [Epub ahead of print] PubMed PMID: 25663195.
Anunciado-Koza RP, Higgins DC, Koza RA. Adipose tissue Mest and Sfrp5 are concomitant with variations of adiposity among inbred mouse strains fed a non-obesogenic diet. Biochimie. 2015 May 21. pii: S0300-9084(15)00141-8. doi: 10.1016/j.biochi.2015.05.007. [Epub ahead of print] PMID: 26005096