Date of Award

5-2012

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Comparative and Experimental Medicine

Major Professor

Madhu Dhar

Committee Members

John Biggerstaff, Guoxun Chen, Carla Sommardahl

Abstract

Atp10c/ATP10C is a putative aminophospholipid translocase or “flippase” that encodes for a type 4 P-type ATPase. Based on previous research, we hypothesize that Atp10c/ATP10C due to its flippase nature plays a role in diet-induced obesity and type 2 diabetes as Atp10c heterozygous mice display this phenotype. For purposes of this dissertation, Atp10c/ATP10C was characterized both generally and biologically to gleam information about its molecular weight, cellular location and possible biological roles and/or functions. Multiple experiments, both in vitro and in vivo, were performed in order to accomplish these characterizations and are discussed at length. Essential results from this dissertation work include the validation of ATP10C’s expected molecular weight (~165 kD), the localization of ATP10C to the plasma membrane, its possible co-localization with GLUT4, and the high expression of Atp10c in key tissues (skeletal muscle and adipose tissue) of two mice models, one a model of diet-induced obesity mice and another a genetic model (ob/ob). To identify molecular and cellular targets of ATP10C, Atp10c expression was altered in vitro in C2C12 and L6-G4myc skeletal muscle myotubes. Functional outcomes of GLUT4 translocation and glucose uptake assays were performed resulting in the significant alteration of normal GLUT4 regulation and a significant decrease in glucose uptake. Additionally, when the expression of Atp10c was altered both experimentally and genetically, significant up-regulation of native and activated mitogen-activated protein kinases, p38, and ERK1/2 were observed. These results demonstrate that Atp10c-silencing does affect these main mitogen-activated protein kinase proteins and in turn, glucose metabolism via both insulin-independent and insulin-dependent manners. Taken together, all these results presented in this dissertation indicate that Atp10c/ATP10C has an important role in the regulation of glucose metabolism, at least in part via the mitogen-activated protein kinase pathway, and as such, plays a significant role in the development of insulin resistance and type 2 diabetes.

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