Nicholas Gekakis, Sc.D.

Research Associate Professor

Education

Sc.D., Nutritional Biochemistry, 1993, Harvard School of Public Health, Nutrition Department, Boston, MA. Transcriptional Regulation of the Phosphofructokinase Family of Genes.

B.S., Biochemistry, 1986, State University of New York at Buffalo, Department of Biochemistry, Buffalo, NY

Research Experience

Research Associate Professor, November 2013 – Present, San Diego State University. Obesity, non-alcoholic fatty liver disease (NAFLD), lipid metabolism in the liver.

Assistant Professor, September 2006 – January 2013, The Scripps Research Institute. Genetics of Metabolic Disease.

Project Leader, August 1999 – August 2006, Genomics Institute of the Novartis Research Foundation (GNF). Metabolic Disease Research.

Postdoctoral Fellow, September 1993 – July 1999, Harvard Medical School, Department of Neurobiology. Molecular Mechanisms Underlying the Generation of Circadian Rhythms.

Research Interests

My interest is in the causes of metabolic diseases such as obesity and non-alcoholic fatty liver disease (NAFLD). Two main projects are under way: lipid metabolism in the liver and genetics of obesity.

Liver is the central metabolic organ. In addition to its role in maintaining plasma glucose, the liver also processes, synthesizes, and secretes lipids, namely triglyceride (TG) and cholesterol. Under pathological conditions (e.g. obesity), the liver also stores excess lipid giving rise to NAFLD. Lipid processing in the liver and NAFLD play important roles in cardiovascular disease and diabetes. Through forward genetic screening in the mouse, my lab has discovered several novel genes or alleles that affect these processes.

• Mia2 is a completely novel gene that is involved in the production of lipoproteins in liver and intestine. Mice with a point mutation in Mia2 have very low plasma lipids due to reduced secretion by the liver. My goal is to understand precisely what role Mia2 plays in lipoprotein secretion and see if this pathway can be exploited to treat dyslipidemia, a risk factor for heart disease.


• Sec61a1 encodes the channel responsible for protein import into the endoplasmic reticulum (ER) and mutation of Sec61a1 leads to ER stress and the heat shock response (HSR), pathological conditions in which the cells capacity to fold and process proteins, both in the secretory compartment and the cytosol, is overwhelmed. This combination of ER stress and HSR lead to increased uptake of fatty acids by the liver and NAFLD. I would like to know how HSR contributes to NAFLD and whether it is involved in NAFLD associated with obesity.


• Dgat2 encodes diacylglycerol acyltransferase, which catalyzes the final step in TG synthesis and a point mutation in Dgat2 causes hypolipidemia in mice due to decreased TG synthesis in liver. Since the mutation does not directly affect Dgat2 activity, I’d like to know how it affects TG synthesis, possibly abnormal subcellular localization.

Obesity is a worldwide epidemic, which contributes to cardiovascular disease, diabetes, certain cancers, and other chronic diseases. Twin studies have estimated that 30 – 70% of obesity is heritable and genome-wide association studies have begun to identify the genes that affect obesity. Variation in the ADCY3 gene, which encodes adenylate cyclase 3, a component of cAMP signaling, has been associated with obesity in humans. In mice, loss of Adcy3 function leads to obesity. We have recently identified a mouse with a gain-of-function mutation in Adcy3, which is resistant to diet-induce obesity (DIO). Mechanistically, I’d like to know the tissue in which the mutant allele acts to prevent DIO. This work will also be translated to human biology by screening for small-molecule activators of ADCY3 and by searching for ADCY3 alleles in human populations that confer a lean phenotype.

Selected Publications

1. Wheeler, MC and Gekakis, N. Hsp90 modulates PPARγ activity in a mouse model of non-alcoholic fatty liver disease (In preparation: Hepatology)


2. Pitman, JL, Wheeler, MC, Lloyd, DJ, Glynne, RJ, Walker, JR, and Gekakis, N. A gain-of-function mutation in adenylate cyclase 3 protects mice from diet-induced obesity. (Submitted: PLoS One).


3. Wheeler, MC and Gekakis, N. Defective ER Associated Degradation of a Model Luminal Substrate in Yeast Carrying a Mutation in the 4th ER Luminal Loop of Sec61p. Biochem Biophys Res Comm. 2012 Nov 2; 427(4): 768-73. PMCID: PMC3490007.


4. Pitman, JL, Bonnet, DJ, Curtiss, L, and Gekakis, N. Reduced cholesterol and triglyceride in mice with a mutation in Mia2, a liver protein that localizes to ER exit sites. J Lipid Res. 2011 Oct 52(10): 1775-86. PMCID: PMC3173003.


5. Lloyd, DJ, Wheeler, MC, and Gekakis, N. A Point Mutation in Sec61α1 Leads to Diabetes and Hepatosteatosis in Mice. Diabetes 2010 Feb 59(2) 460-70. PMCID: PMC2809972.


6. Huang, SA, Hancock, MK, Pitman, JL, Orth, AP, and Gekakis, N. Negative Regulators of Insulin Signaling Revealed in a Genome-wide Functional Screen. PLoS One. 2009 Sep 3; 4(9): e6871. PMCID: PMC2731165.


7. Wilkes, JJ, Lloyd, DJ, and Gekakis, N. A loss-of-function mutation in myostatin reduces TNFα production and protects liver against obesity-induced insulin resistance. Diabetes 2009 May; 58(5) 1133-43. PMCID: PMC2671051.


8. Wen-Ning Zhao, Nikolay Malinin, Fu-Chia Yang, David Staknis, Nicholas Gekakis, Bert Maier, Silke Reischl, Achim Kramer, Charles J. Weitz. CIPC, a mammalian circadian clock protein without invertebrate homologs. Nat Cell Biol. 2007 Mar; 9(3): 268-75.


9. Guochun Li, Raquel Vega, Keats Nelms, Nicholas Gekakis, Christopher Goodnow, Peter McNamara, Hua Wu, Nancy A. Hong and Richard Glynne. A role for the Alström syndrome protein, Alms1, in ciliogenesis and regulation of cellular quiescence in kidney proximal tubules. PLoS Genet. 2007 Jan 5; 3(1): e8. PMCID: PMC1761047.


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


11. Lloyd DL, Hall FW, Tarantino LM, and Gekakakis N. Diabetes insipidus in mice with a mutation in aquaporin-2. PLoS Genet. 2005 1(2): e20. PMCID: PMC1189073.


12. Donaldson KM, Yin H, Gekakis N, Supek F, Joazeiro CA. Ubiquitin Signals Protein Trafficking via Interaction with a Novel Ubiquitin Binding Domain in the Membrane Fusion Regulator, Vps9p. Curr Biol. 2003 Feb 4; 13(3): 258-62.


13. Sangoram AM, Saez L, Antoch MP, Gekakis N, Staknis D, Whiteley A, Fruechte EM, Vitaterna MH, Shimomura K, King DP, Young MW, Weitz CJ, Takahashi JS. Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron. 1998 Nov; 21(5): 1101-13.


14. Darlington TK, Wager-Smith K, Ceriani MF, Staknis D, Gekakis N, Steeves TD, Weitz CJ, Takahashi JS, Kay SA. Closing the circadian loop: CLOCK-induced transcription of its own inhibitors per and tim. Science. 1998 Jun 5; 280(5369): 1599-603.


15. Gekakis N, Staknis D, Nguyen HB, Davis FC, Wilsbacher LD, King DP, Takahashi JS, Weitz CJ. Role of the CLOCK protein in the mammalian circadian mechanism. Science. 1998 Jun 5; 280(5369): 1564-9.


16. Gekakis N, Saez L, Delahaye-Brown AM, Myers MP, Sehgal A, Young MW, Weitz CJ. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science. 1995 Nov 3; 270(5237): 811-5.


17. Gekakis N, Sul HS. Control of the murine phosphofructokinase-A gene during muscle differentiation. Biochemistry. 1994 Feb 22; 33(7): 1771-7.


18. Gekakis N, Johnson RC, Jerkins A, Mains RE, Sul HS.. Structure, distribution, and functional expression of the phosphofructokinase C isozyme. J Biol Chem. 1994 Feb 4; 269(5): 3348-55.


19. Gekakis N, Gehnrich SC, Sul HS. Phosphofructokinase isozyme expression during myoblast differentiation. J Biol Chem. 1989 Mar 5; 264(7): 3658-61.


20. Gehnrich SC, Gekakis N, Sul HS. Liver (B-type) phosphofructokinase mRNA. Cloning, structure, and expression. J Biol Chem. 1988 Aug 25; 263(24): 11755-9.