Alex Soukas, M.D., PhD

Diabetes and Obesity Genetics in C. elegans and Mice

  1.   Fat regulatory gene discovery in C. elegans. The lab uses the soil roundworm C. elegans in large-scale gene discovery screens to uncover and characterize genetic pathways involved in storage and utilization of body fat stores. We have developed high-throughput screening methodology permitting us to examine thousands of RNA-interference (RNAi) gene inactivations per week for genes which affect fat storage or fat utilization. We have used this platform to screen the entire C. elegans genome for lipid regulatory genes, uncovering 513 heretofore unappreciated genes involved in lipid storage. More than 75% of the genes emerging from this screen have a human ortholog. The genetic pathways emerging from this screen are the focus of intesnse follow up investigation in the lab. We use molecular genetic, cell biological, biochemical, and genetic approaches to further characterize the mechanisms of lipid regulation by genes emerging from this screen. Further, given the power and facility of the screening platform we have set up, we are in an ideal place to characterize gene-gene interactions regulating metabolism.

  2. Conserved metabolic regulation by TOR complex 2. The lab has a major area of focus on metabolic regulation by target of rapamycin complex 2 (TORC2). We identified that TORC2 has a major role in lipid metabolism in C. elegans and mammals alike. Our work also shows that mTORC2 is a major regulator of glucose homeostasis in mice. We have created mouse models to study mTORC2 action in liver. As TORC2 is a protein kinase involved in transduction of signals from insulin, growth factors and nutrient-sensing pathways, we are using biochemical and genetic approaches to uncover novel elements of the TORC2 pathway in order to identify the next generation of therapeutic targets for type 2 diabetes and related disorders such as hepatic steatosis.

  3. Molecular pathways contributing to the response to metformin. Metformin is the most commonly prescribed medicine for type 2 diabetes. Much has been learned about the molecular mode of action of metformin in the past few years, but its actions which lead to favorable effects on blood glucose and a reduction in cancer susceptibility are not fully characterized. We have taken an approach using gene discovery in C. elegans to identify molecular pathways of metformin response and are collaborating with human geneticists to merge our data with human genome-wide association studies for metformin response to find conserved elements. The power of C. elegans allows us to characterize the mechanisms by which metformin response pathways act.

 

References.

1. Soukas, A., Cohen, P., Socci, N.D., and Friedman, J.M. (2000). Leptin-specific patterns of gene expression in white adipose tissue. Genes and Development 14: 963-80. PMCID: PMC316534.

 

2. Soukas, A., Socci, N.D., Saatkamp, B.D., Novelli, S., and Friedman, J.M. (2001). Distinct transcriptional profiles of adipogenesis in vivo and in vitro. Journal of Biological Chemistry 276: 34167-74. PMID: 11445576. http://www.jbc.org/cgi/content/full/276/36/34167

 

3. Soukas, A.A., Kane, E.A., Carr, C.E., Melo, J.A., Ruvkun, G. (2009). Rictor/TORC2 regulates fat metabolism, feeding, growth, and lifespan in Caenorhabditis elegans. Genes and Development, 23: 496-511. PMCID: PMC2648650.

 

4. Soukas, A.A.*, O’Rourke, E.J.*, Carr, C.E., Ruvkun, G. (2009). C. elegans major fats are stored in vesicles distinct from lysosome-related organelles. Cell Metabolism, 10: 430-5. PMCID: PMC2921818

 

5. Yuan, M., Pino, E., Wu, L., Kacergis, M., Soukas, A.A. (2012). Identification of Akt-independent regulation of hepatic lipogenesis by mammalian target of rapamycin (mTOR) complex 2. Journal of Biological Chemistry, 287: 29579-88. PMCID: PMC3436168.

 

6. Pino, E.C., Webster, C.M., Carr, C.A., Soukas, A.A. (2013). Biochemical and high-throughput microscopic assessment of fat mass in Caenorhabditis elegans. Journal of Visualized Experiments, Mar 30(73). PMCID: PMC3944676.

 

7. Webster, C.M., Wu, L., Douglas, D., Soukas, A.A. (2013) A non-canonical role for the C. elegans dosage compensation complex in growth and metabolic regulation downstream of TOR complex 2. Development, 140: 3601-12. PMCID: PMC3742143 [Available on 2014/9/1].

 

8. Soukas, A.A.*, Carr, C.E., Ruvkun, G*. (2013) Genetic regulation of Caenorhabditis elegans lysosome related organelle function. PLoS Genetics, 9(10): e1003908. PMCID: PMC3812091.

 

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