Thurl E Harris
- PhD, Baylor University
- Assistant Professor, Pharmacology
- Phone: 434-924-1584
- Email: email@example.com
Molecular mechanisms controlling insulin signaling and fat synthesis.
As Paleolithic hunter gatherers, the human diet was relatively low in fats and simple carbohydrates. Technological advances, beginning with the agricultural revolution 12,000 years ago and culminating with the mechanization of food production in the last century, have provided a significant portion of the world’s population with access to inexpensive, energy-dense food. In the modern age the ready availability of carbohydrates and fats, combined with a large reduction in physical labor, has lead to a predictable rise in obesity. Two thirds of the U.S. population is defined as overweight or obese. As an underlying risk factor for type II diabetes and cardiovascular disease, understanding how obesity promotes the development of these diseases is of extreme importance for worldwide health.
Food intake triggers the release of insulin, an anabolic hormone that promotes nutrient storage and protein synthesis. Mechanisms underlying the storage of carbohydrates and fats as triacylglycerol (TAG) in adipose tissue and the dysregulation of insulin signaling that occurs during obesity are the primary focus of the laboratory.
Triacylglycerol Storage in Adipocytes and Inflammation –An important research interest in the laboratory are the enzymatic pathways by which adipocytes store fatty acids as TAG, and the functional consequences of excess TAG storage. Lipin 1 has dual functions; 1) it is a phosphatidic acid phosphatase (PAP), catalyzing a crucial step in the synthesis of TAG, and 2) is a transcriptional co-activator and co-repressor. How lipin 1 activity is regulated in adipocytes by insulin is a key component of our studies. Complementary research in the laboratory investigates the link between lipin 1 and inflammation. As adipocytes accumulate increasing amount of TAG during obesity (hypertrophy) they activate inflammatory pathways that lead to adipocyte dysfunction, macrophage infiltration of adipose tissue, and eventually contribute to peripheral insulin resistance. We are actively pursuing both the involvement of lipin 1 in the mechanisms that initiate inflammation in adipocytes, as well as changes in lipid metabolites that occur during the development of adipocyte hypertrophy. The mTOR Signaling Pathway - A key player in the insulin signaling cascade is the mammalian target of rapamycin (mTOR), a highly conserved Ser-Thr phosphatidylinositol 3-kinase-related protein kinase that integrates cellular energy status and growth factors to regulate cellular growth, survival, and metabolism. mTOR forms two distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) each of which catalyzes the phosphorylation of different substrates in response to insulin. The rapamycin sensitive mTOR complex (mTORC1) contains mTOR, raptor, PRAS40 and LST8, while the rapamycin insensitive mTOR complex (mTORC2) contains mTOR, rictor, LST8 and Sin1. Under conditions of caloric excess, such as that seen during diet-induced obesity, both arms of the mTOR pathway can be affected. We study the molecular mechanisms of how insulin signaling activates the two different mTOR complexes, the targets of mTORC1 and 2, and the functional consequences of obesity on mTOR activity.
- Eaton J, Takkellapati S, Lawrence R, McQueeney K, Boroda S, Mullins G, Sherwood S, Finck B, Villén J, Harris T. Lipin 2 binds phosphatidic acid by the electrostatic hydrogen bond switch mechanism independent of phosphorylation. The Journal of biological chemistry. 2014;289(26): 18055-66. PMID: 24811178 | PMCID: PMC4140300
- Zhang C, Cooper D, Grevengoed T, Li L, Klett E, Eaton J, Harris T, Coleman R. Glycerol-3-phosphate acyltransferase-4-deficient mice are protected from diet-induced insulin resistance by the enhanced association of mTOR and rictor. American journal of physiology. Endocrinology and metabolism. 2014;307(3): E305-15. PMID: 24939733 | PMCID: PMC4121579
- Creutz C, Eaton J, Harris T. Assembly of high molecular weight complexes of lipin on a supported lipid bilayer observed by atomic force microscopy. Biochemistry. 2013;52(30): 5092-102. PMID: 23862673 | PMCID: PMC4041088
- Dominguez C, Floyd D, Xiao A, Mullins G, Kefas B, Xin W, Yacur M, Abounader R, Lee J, Wilson G, Harris T, Purow B. Diacylglycerol kinase α is a critical signaling node and novel therapeutic target in glioblastoma and other cancers. Cancer discovery. 2013;3(7): 782-97. PMID: 23558954 | PMCID: PMC3710531
- Eaton J, Mullins G, Brindley D, Harris T. Phosphorylation of lipin 1 and charge on the phosphatidic acid head group control its phosphatidic acid phosphatase activity and membrane association. The Journal of biological chemistry. 2013;288(14): 9933-45. PMID: 23426360 | PMCID: PMC3617293
- Kok B, Dyck J, Harris T, Brindley D. Differential regulation of the expressions of the PGC-1α splice variants, lipins, and PPARα in heart compared to liver. Journal of lipid research. 2013;54(6): 1662-77. PMID: 23505321 | PMCID: PMC3646467
- Derecka M, Gornicka A, Koralov S, Szczepanek K, Morgan M, Raje V, Sisler J, Zhang Q, Otero D, Cichy J, Rajewsky K, Shimoda K, Poli V, Strobl B, Pellegrini S, Harris T, Seale P, Russell A, McAinch A, O'Brien P, Keller S, Croniger C, Kordula T, Larner A. Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity. Cell metabolism. 2012;16(6): 814-24. PMID: 23217260 | PMCID: PMC3522427
- Mitra M, Chen Z, Ren H, Harris T, Chambers K, Hall A, Nadra K, Klein S, Chrast R, Su X, Morris A, Finck B. Mice with an adipocyte-specific lipin 1 separation-of-function allele reveal unexpected roles for phosphatidic acid in metabolic regulation. Proceedings of the National Academy of Sciences of the United States of America. 2012;110(2): 642-7. PMID: 23267081 | PMCID: PMC3545773
- Wu D, Chapman J, Wang L, Harris T, Shabanowitz J, Hunt D, Fu Z. Intestinal cell kinase (ICK) promotes activation of mTOR complex 1 (mTORC1) through phosphorylation of Raptor Thr-908. The Journal of biological chemistry. 2012;287(15): 12510-9. PMID: 22356909 | PMCID: PMC3321000
- Zhang C, Wendel A, Keogh M, Harris T, Chen J, Coleman R. Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Proceedings of the National Academy of Sciences of the United States of America. 2012;109(5): 1667-72. PMID: 22307628 | PMCID: PMC3277174
- Glidden E, Gray L, Vemuru S, Li D, Harris T, Mayo M. Multiple site acetylation of Rictor stimulates mammalian target of rapamycin complex 2 (mTORC2)-dependent phosphorylation of Akt protein. The Journal of biological chemistry. 2011;287(1): 581-8. PMID: 22084251 | PMCID: PMC3249112
- González I, Martin P, Burdsal C, Sloan J, Mager S, Harris T, Sutherland A. Leucine and arginine regulate trophoblast motility through mTOR-dependent and independent pathways in the preimplantation mouse embryo. Developmental biology. 2011;361(2): 286-300. PMID: 22056783 | PMCID: PMC3246567
- Harris T, Finck B. Dual function lipin proteins and glycerolipid metabolism. Trends in endocrinology and metabolism: TEM. 2011;22(6): 226-33. PMID: 21470873 | PMCID: PMC3118913
- Nascimento N, Kemp B, Howell N, Gildea J, Santos C, Harris T, Carey R. Role of SRC family kinase in extracellular renal cyclic guanosine 3',5'-monophosphate- and pressure-induced natriuresis. Hypertension. 2011;58(1): 107-13. PMID: 21482955 | PMCID: PMC3117057
- Peterson T, Sengupta S, Harris T, Carmack A, Kang S, Balderas E, Guertin D, Madden K, Carpenter A, Finck B, Sabatini D. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell. 2011;146(3): 408-20. PMID: 21816276 | PMCID: PMC3336367
- Blancquaert S, Wang L, Paternot S, Coulonval K, Dumont J, Harris T, Roger P. cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4. Molecular endocrinology (Baltimore, Md.). 2010;24(7): 1453-68. PMID: 20484410 | PMCID: PMC2903905
- Kim H, Kumar A, Wang L, Liu G, Keller S, Lawrence J, Finck B, Harris T. Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors. Molecular and cellular biology. 2010;30(12): 3126-39. PMID: 20385772 | PMCID: PMC2876672
- Kumar A, Lawrence J, Jung D, Ko H, Keller S, Kim J, Magnuson M, Harris T. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes. 2010;59(6): 1397-406. PMID: 20332342 | PMCID: PMC2874700
- Liu G, Qu J, Carmack A, Kim H, Chen C, Ren H, Morris A, Finck B, Harris T. Lipin proteins form homo- and hetero-oligomers. The Biochemical journal. 2010;432(1): 65-76. PMID: 20735359 | PMCID: PMC3117669