Alan Attie

Research Description:
Genetics of diabetes. Our laboratory uses mouse genetics to identify genes and pathways involved in obesity-induced type 2 diabetes. We have reproduced the obesity/diabetes dichotomy in mice by studying two strains that when made obese, differ in diabetes susceptibility. Using this model system, we have mapped several diabetes gene loci. We recently identified two genes underlying these loci. One of the genes affects insulin action and the other affects insulin secretion.

Gene causal networks and diabetes. Using microarray technology, we have identified genes whose expression changes before, during, and after the onset of diabetes. Many of these patterns are highly correlated, indicating coordinate regulation of networks of gene expression. These networks have control points, e.g. signaling molecules or transcription factors. We are identifying these points and testing their function in biological systems.

Molecular biology of ß-cell proliferation. We have identified several factors involved in stimulating ß-cell proliferation. We wish to discover the receptors and the signaling pathways involved in this critically important process.

The genetics of gene expression. Traditional genetics correlates genotype with phenotype in a complex outbred population or in an experimental cross. This identifies areas of the genome controlling the phenotype of interest. We expand our definition of phenotype to include mRNA abundance on the large scale available through microarray technology. By mapping mRNA abundance, we map gene loci controlling the expression of many thousands of mRNA transcripts. These loci are termed expression quantitative trait loci (eQTL). With this approach, we are uncovering gene regulatory networks that are dysregulated in obesity and diabetes.

Micro-RNA regulation of insulin secretion. We have identified two miRNAs that stimulate insulin secretion. We are working to identify the targets of these miRNAs the mechanisms underlying their effect on insulin secretion.

Genetics of hepatic steatosis. Hepatic steatosis (fatty liver) is the pathological accumulation of excess lipid (usually triglyceride) in hepatocytes. We have mapped a locus that affects this trait and identified two novel candidate genes.

Representative Publications:
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Kreznar JH, Keller MP, Traeger LL, Rabaglia ME, Schueler KL, Stapleton DS, Zhao W, Vivas EI, Yandell BS, Broman AT, Hagenbuch B, Attie AD, Rey FE. Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes. Cell Rep 2017; 18:1739-1750

Attie AD, Churchill GA, Nadeau JH. How mice are indispensable for understanding obesity and diabetes genetics. Current Opinion in Endocrinology Diabetes and Obesity 2017; 24:83-91

Tian J, Keller MP, Broman AT, Kendziorski C, Yandell BS, Attie AD, Broman KW. The Dissection of Expression Quantitative Trait Locus Hotspots. Genetics 2016; 202:1563-1574

Paul PK, Rabaglia ME, Wang CY, Stapleton DS, Leng N, Kendziorski C, Lewis PW, Keller MP, Attie AD. Histone chaperone ASF1B promotes human beta-cell proliferation via recruitment of histone H3.3. Cell Cycle 2016; 15:3191-3202

Krautkramer KA, Kreznar JH, Romano KA, Vivas EI, Barrett-Wilt GA, Rabaglia ME, Keller MP, Attie AD, Rey FE, Denu JM. Diet-Microbiota Interactions Mediate Global Epigenetic Programming in Multiple Host Tissues. Mol Cell 2016;

Keller MP, Paul PK, Rabaglia ME, Stapleton DS, Schueler KL, Broman AT, Ye SI, Leng N, Brandon CJ, Neto EC, Plaisier CL, Simonett SP, Kebede MA, Sheynkman GM, Klein MA, Baliga NS, Smith LM, Broman KW, Yandell BS, Kendziorski C, Attie AD. The Transcription Factor Nfatc2 Regulates beta-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets. PLoS Genet 2016; 12:e1006466

Tian J, Keller MP, Oler AT, Rabaglia ME, Scheuler KL, Stapleton DS, Broman AT, Zhao W, Kendziorski C, Yandell BS, Hagenbuch B, Broman KW, Attie AD. Identification of Slco1a6 as a candidate gene that broadly affects gene expression in mouse pancreatic islets. Genetics 2015; in press

Soni MS, Rabaglia ME, Bhatnagar S, Shang J, Ilkayeva O, Mynatt R, Zhou YP, Schadt EE, Thornberry NA, Muoio DM, Keller MP, Attie AD. Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion. Diabetes 2014; 63:3805-3814

Kebede MA, Oler AT, Gregg T, Balloon AJ, Johnson A, Mitok K, Rabaglia M, Schueler K, Stapleton D, Thorstenson C, Wrighton L, Floyd BJ, Richards O, Raines S, Eliceiri K, Seidah NG, Rhodes C, Keller MP, Coon JL, Audhya A, Attie AD. SORCS1 is necessary for normal insulin secretory granule biogenesis in metabolically stressed beta cells. J Clin Invest 2014; 124:4240-4256

Kebede MA, Attie AD. Insights into obesity and diabetes at the intersection of mouse and human genetics. Trends Endocrinol Metab 2014; 25:493-501

Bhatnagar S, Soni MS, Wrighton LS, Hebert AS, Zhou AS, Paul PK, Gregg T, Rabaglia ME, Keller MP, Coon JJ, Attie AD. Phosphorylation and Degradation of Tomosyn-2 De-represses Insulin Secretion. J Biol Chem 2014; 289:25276-25286

O’Halloran TV, Kebede M, Philips SJ, Attie AD. Zinc, insulin, and the liver: a menage a trois. J Clin Invest 2013; 123:4136-4139

Neto EC, Broman AT, Keller MP, Attie AD, Zhang B, Zhu J, Yandell BS. Modeling causality for pairs of phenotypes in system genetics. Genetics 2013; 193:1003-1013

Kimple ME, Keller MP, Rabaglia MR, Pasker RL, Truchan NA, Neuman JC, Brar HK, Attie AD. The prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes 2013;

Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin. Trends Endocrinol Metab 2013; 24:391-397

Wang CY, Stapleton DS, Schueler KL, Rabaglia ME, Oler AT, Keller MP, Kendziorski CM, Broman KW, Yandell BS, Schadt EE, Attie AD. Tsc2, a positional candidate gene underlying a quantitative trait locus for hepatic steatosis. J Lipid Res 2012; 53:1493-1501

Neto EC, Keller MP, Broman AF, Attie AD, Jansen RC, Broman KW, Yandell BS. Quantile-based permutation thresholds for quantitative trait loci hotspots. Genetics 2012; 191:1355-1365

Grimsrud PA, Carson JJ, Hebert AS, Hubler SL, Niemi NM, Bailey DJ, Jochem A, Stapleton DS, Keller MP, Westphall MS, Yandell BS, Attie AD, Coon JJ, Pagliarini DJ. A quantitative map of the liver mitochondrial phosphoproteome reveals posttranslational control of ketogenesis. Cell Metab 2012; 16:672-683

Raines SM, Richards OC, Schneider LR, Schueler KL, Rabaglia ME, Oler AT, Stapleton DS, Genove G, Dawson JA, Betsholtz C, Attie AD. Loss of PDGF-B activity increases hepatic vascular permeability and enhances insulin sensitivity. Am J Physiol Endocrinol Metab 2011; 301:E517-526

Bhatnagar S, Oler AT, Rabaglia ME, Stapleton DS, Schueler KL, Truchan NA, Worzella SL, Stoehr JP, Clee SM, Yandell BS, Keller MP, Thurmond DC, Attie AD. Positional cloning of a type 2 diabetes quantitative trait locus; tomosyn-2, a negative regulator of insulin secretion. PLoS Genet 2011; 7:e1002323

Richards OC, Raines SM, Attie AD. The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action. Endocr Rev 2010; 31:343-363

Newgard CB, Attie AD. Getting biological about the genetics of diabetes. Nature medicine 2010; 16:388-391

Lane RF, Raines SM, Steele JW, Ehrlich ME, Lah JA, Small SA, Tanzi RE, Attie AD, Gandy S. Diabetes-associated SorCS1 regulates Alzheimer’s amyloid-beta metabolism: evidence for involvement of SorL1 and the retromer complex. J Neurosci 2010; 30:13110-13115

Keller MP, Attie AD. Physiological insights gained from gene expression analysis in obesity and diabetes. Annu Rev Nutr 2010; 30:341-364

Hudkins KL, Pichaiwong W, Wietecha T, Kowalewska J, Banas MC, Spencer MW, Muhlfeld A, Koelling M, Pippin JW, Shankland SJ, Askari B, Rabaglia ME, Keller MP, Attie AD, Alpers CE. BTBR Ob/Ob mutant mice model progressive diabetic nephropathy. J Am Soc Nephrol 2010; 21:1533-1542

Davis DB, Lavine JA, Suhonen JI, Krautkramer KA, Rabaglia ME, Sperger JM, Fernandez LA, Yandell BS, Keller MP, Wang IM, Schadt EE, Attie AD. FoxM1 is up-regulated by obesity and stimulates beta-cell proliferation. Mol Endocrinol 2010; 24:1822-1834

Babak T, Garrett-Engele P, Armour CD, Raymond CK, Keller MP, Chen R, Rohl CA, Johnson JM, Attie AD, Fraser HB, Schadt EE. Genetic validation of whole-transcriptome sequencing for mapping expression affected by cis-regulatory variation. BMC Genomics 2010; 11:473

Attie AD, Keller MP. Gene co-expression modules and type 2 diabetes. Results Probl Cell Differ 2010; 52:47-56