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Analysis of two candidate genes in obesity and metabolism : pyruvate dehydrogenase kinase 1 and integrin alpha 6

University of British Columbia

Genetic factors affect an individual’s risk of developing obesity, but in most cases each individual factor has a small effect. Discovery of these genetic factors may provide clues to biological processes affecting obesity and point to new ways the disease can be treated. Model organisms can facilitate genetic discovery in obesity because environmental factors can be better controlled. We study inbred mouse strains to identify novel genes affecting obesity and glucose metabolism. BTBR T⁺ Itpr3tf/J (BTBR) mice are fatter and more glucose intolerant than C57BL/6J (B6) mice. Prior genetic studies of these strains identified an obesity locus on chromosome 2. Using congenic mice it was found that genotype in a ~316 kb region, with only two known genes, Pyruvate dehydrogenase kinase 1 (Pdk1) and Integrin alpha 6 (Itga6), affects obesity. Both genes had mutations affecting their amino acid sequence, reduced expression levels, and have functions that could affect obesity. Knockdown of either Pdk1 or Itga6 could also affect insulin secretion and glucose and lipid metabolism. We hypothesized that genetic variation in or near Pdk1 and/or Itga6 causes reduced expression of Pdk1 and Itga6 and promotes obesity and impaired glucose tolerance. We used Pdk1 and Itga6 knockout mice fed a high fat diet to test this. A challenge to our work was that we found the effect of the genetic locus on body weight is altered by environmental factors. Due to facility renovations over the duration of the studies, our mice were housed in different locations. We tested the hypothesis that the genotypic effect of this locus on body weight is modified by stress. In our studies, we were unable to detect a contribution of either Pdk1 or Itga6 to body weight. However, we found Pdk1 plays a role in lipid metabolism and specifically that reduced Pdk1 promotes lipid accumulation in the heart. Together these data suggest an important and previously unknown role of Pdk1 in metabolism and that Pdk1 may have metabolic effects that need to be considered when using Pdk1 inhibitors as a potential therapeutic.

Text

2020-03-11

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73715

Cell and Developmental Biology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/