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Research Focus

Through forward genetic screening in the mouse, we have identified several novel genes associated with metabolic disorders, including obesity, diabetes, and dyslipidemia. Our work now focuses on understanding the mechanism by which mutations in these genes cause disease.

A mutation in Sec61alpha, a component of the ER protein import channel, causes diabetes in the mouse. Sec61alpha, along with Sec61beta and gamma, is part of the trimeric Sec61 translocon, which in mammals is responsible for all protein import into the ER. The mutation that causes diabetes (Y344H) leads to ER stress in the insulin-secreting beta cells of the pancreas. ER stress is the condition in which the ER's capacity to fold and process proteins is exceeded by demand, leading to an accumulation of unfolded proteins in the ER. The cell responds to ER stress in three important ways: (i) attenuated translation of new proteins, (ii) increased production of ER components in order to increase the capacity of the ER to fold and process proteins, and (iii) increased proteasomal degradation of unfolded proteins from the ER. If these responses are insufficient to restore homeostasis to ER protein processing, apoptosis ensues. Such is the case in Sec61a mutant mice, beta-cell apoptosis, which leads to insulin insufficiency and diabetes. In order to understand how a Sec61alpha mutation leads ER stress, we have constructed a yeast strain harboring the homologous Sec61p mutation. Preliminary data show that SEC61 mutant yeast have a defect in the degradation of unfolded proteins in the ER.

Other work in the lab focuses on the other novel disease-causing genes we have discovered. A mutation in Pc1, a protease that processes hormones and neuropeptides, leads to obesity. We are now investigating which cell types mediate this pathogenesis and what is the key substrate whose defective processing leads to obesity. In another mutant mouse line, a gain of function in cAMP signaling leads to resistance to diet-induced obesity. Our work now is asking whether this mutation acts on brown adipose tissue to increase energy dissipation, on the hypothalamus to affect energy intake and expenditure, or some combination thereof.

Education

D.Sc., Nutritional Biochemistry, Harvard University, 1993
B.S., Biochemistry, State University of New York at Buffalo, 1986

Selected References

Pitman JL, Bonnet DJ, Curtiss LK, and Gekakis N. (2011).  Reduced cholesterol and triglycerides in mice with a mutation in Mia2, a liver protein that localizes to endoplasmic reticulum exit sites.  J Lipid Res. Aug 1, 2011, ePub ahead of print.

Lloyd DJ, Wheeler MC, Gekakis N. (2010).  A point mutation in Sec61α1 leads to diabetes and hepatosteatosis in mice.  Diabetes. 2010 Feb;59(2):460-70.

Huang SM, Hancock MK, Pitman JL, Orth AP, Gekakis N. (2009).  Negative regulators of insulin signaling revealed in a genome-wide functional screen.  PLoS One. Sep 3;4(9):e6871.

Wilkes JJ, Lloyd DJ, Gekakis N (2009).  Loss-of-function mutation in myostatin reduces tumor necrosis factor α production and protects liver against obesity-induced insulin resistance.  Diabetes. 2009 May;58(5):1133-43.

Lloyd DJ, Bohan S, Gekakis N. (2006).  Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice.  Hum Mol Genet. 2006 Jun 1;15(11):1884-93.

Lloyd DJ, Hall FW, Tarantino LM, Gekakis N. (2005).  Diabetes insipidus in mice with a mutation in aquaporin-2.  PLoS Genet. 2005 Aug;1(2):e20.