Thurl E Harris
- PhD, Baylor College of Medicine
- Assistant Professor, Pharmacology
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 led to a predictable rise in obesity. By the year 2015 it is estimated that 34% of the U.S. population will be characterized as overweight (B.M.I. of 25-30), and another 41% will be obese (B.M.I.>30), giving an astonishing 3 out 4 Americans 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. Our laboratory is interested in the mechanisms underlying the storage of carbohydrates and fats as triacylglycerol (TAG) in adipose tissue, and the dysregulation of insulin signaling that occurs during obesity.
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. 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.
Triacylglycerol Storage in Adipocytes and Inflammation - Another 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 and the functional consequences of this regulation are key components 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.
- 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
- Mullins G, Wang L, Raje V, Sherwood S, Grande R, Boroda S, Eaton J, Blancquaert S, Roger P, Leitinger N, Harris T. Catecholamine-induced lipolysis causes mTOR complex dissociation and inhibits glucose uptake in adipocytes. Proceedings of the National Academy of Sciences of the United States of America. 2014. PMID: 25422441
- 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
- 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
- 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
- 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