Susanna R. Keller, MD
Graduate School: University of Zurich, Switzerland
Primary Appointment: Associate Professor, Medicine, Endocrinology and Metabolism
Insulin signaling; insulin-regulated membrane trafficking and associated changes in cellular function and whole body physiology.
Email Address: email@example.com
The research in my laboratory focuses on insulin signaling and the regulation of the trafficking of membrane proteins, specifically the glucose transporter GLUT4 and the insulin-regulated aminopeptidase IRAP, predominantly in adipocytes and skeletal muscles. Furthermore, we are interested in how insulin, through its action on the trafficking of GLUT4 and IRAP, affects cell function and whole body physiology.
The proper control of the subcellular distribution of GLUT4 in muscle and fat cells is key to the maintenance of glucose homeostasis. Under fasting conditions GLUT4 localizes mostly to intracellular vesicles (GLUT4 vesicles) and only a low amount of GLUT4 is at the cell surface. This limits glucose uptake into muscle and fat cells thereby allowing the circulating glucose to be used as fuel by the brain. After food intake, when glucose levels rise, insulin is released into the circulation and stimulates, within minutes, the movement to, docking and fusion of GLUT4 vesicles with the plasma membrane. The resulting increase of GLUT4 at the cell surface leads to increased glucose uptake into muscle and fat cells, thereby normalizing circulating glucose levels after a meal. The molecular mechanism by which GLUT4 is retained within fat and muscle cells in vivo in primary adipocytes and muscles under fasting conditions, and by which insulin releases GLUT4 to the cell surface, has not been established. However, studies in cultured fat and muscle cells attributed roles in GLUT4 retention and release to the Rab GTPase activating proteins (Rab GAPs) AS160 and Tbc1d1.
With our current research we are investigating the roles of AS160 and Tbc1d1 in the regulation of the subcellular distribution of GLUT4 and thus glucose uptake in primary adipocytes and skeletal muscles and whole body glucose homeostasis using knockout mice. Our research has direct implications for major diseases, including obesity, the metabolic syndrome, and diabetes. In each of these, glucose homeostasis is impaired concomitant with dysregulation of the trafficking of GLUT4.
My past research has focused on the regulation of the trafficking of IRAP and its physiological role. IRAP is regulated like GLUT4; it is efficiently sequestered within the same intracellular compartments as GLUT4 under basal conditions and relocates to the cell surface of muscle and fat cells in response to insulin. With regard to IRAP's physiological function, we have discovered that IRAP is responsible for the cleavage of circulating vasopressin and that insulin can accelerate extracellular vasopressin cleavage by relocating IRAP to the cell surface. The physiological significance of this finding will be further elucidated in future research.
Derecka M, Gornicka A, Koralov SB, 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 TE, Seale P, Russell AP, McAinch AJ, O'Brien PE, Keller SR, Croniger CM, Kordula T, Larner AC. Tyk2 and Stat3 regulate brown adipose tissue differentiation and obesity. Cell Metab. 2012 Dec 5;16(6):814-24. doi: 10.1016/j.cmet.2012.11.005. PubMed PMID: 23217260; PubMed Central PMCID: PMC3522427.
Lansey MN, Walker NN, Hargett SR, Stevens JR, Keller SR. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis. Am J Physiol Endocrinol Metab. 2012 Nov 15;303(10):E1273-86. doi: 10.1152/ajpendo.00316.2012. Epub 2012 Sep 25. PubMed PMID: 23011063; PubMed Central PMCID: PMC3517634.
Galkina EV, Butcher M, Keller SR, Goff M, Bruce A, Pei H, Sarembock IJ, Sanders JM, Nagelin MH, Srinivasan S, Kulkarni RN, Hedrick CC, Lattanzio FA, Dobrian AD, Nadler JL, Ley K. Accelerated atherosclerosis in Apoe-/- mice heterozygous for the insulin receptor and the insulin receptor substrate-1. Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):247-56. doi: 10.1161/ATVBAHA.111.240358. Epub 2011 Dec 22. PubMed PMID: 22199371.
Cutchins A, Harmon DB, Kirby JL, Doran AC, Oldham SN, Skaflen M, Klibanov AL, Meller N, Keller SR, Garmey J, McNamara CA. Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion. Arterioscler Thromb Vasc Biol. 2012 Feb;32(2):317-24. doi: 10.1161/ATVBAHA.111.234856. Epub 2011 Nov 10. PubMed PMID: 22075252; PubMed Central PMCID: PMC3262109.
Padia SH, Kemp BA, Howell NL, Keller SR, Gildea JJ, Carey RM. Mechanisms of dopamine D(1) and angiotensin type 2 receptor interaction in natriuresis. Hypertension. 2012 Feb;59(2):437-45. doi: 10.1161/HYPERTENSIONAHA.111.184788. Epub 2011 Dec 27. PubMed PMID: 22203736; PubMed Central PMCID: PMC3279722.
Hinault C, Kawamori D, Liew CW, Maier B, Hu J, Keller SR, Mirmira RG, Scrable H, Kulkarni RN. Δ40 Isoform of p53 controls β-cell proliferation and glucose homeostasis in mice. Diabetes. 2011 Apr;60(4):1210-22. doi: 10.2337/db09-1379. Epub 2011 Feb 25. PubMed PMID: 21357466; PubMed Central PMCID: PMC3064094.
Kemp BA, Howell NL, Gray JT, Keller SR, Nass RM, Padia SH. Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats. Hypertension. 2011 Mar;57(3):633-9. doi: 10.1161/HYPERTENSIONAHA.110.166413. Epub 2011 Jan 10. PubMed PMID: 21220707; PubMed Central PMCID: PMC3041845.
Chakrabarti SK, Wen Y, Dobrian AD, Cole BK, Ma Q, Pei H, Williams MD, Bevard MH, Vandenhoff GE, Keller SR, Gu J, Nadler JL. Evidence for activation of inflammatory lipoxygenase pathways in visceral adipose tissue of obese Zucker rats. Am J Physiol Endocrinol Metab. 2011 Jan;300(1):E175-87. doi:10.1152/ajpendo.00203.2010. Epub 2010 Oct 26. PubMed PMID: 20978234; PubMed Central PMCID: PMC3023204.
Roland AV, Nunemaker CS, Keller SR, Moenter SM. Prenatal androgen exposure programs metabolic dysfunction in female mice. J Endocrinol. 2010 Nov;207(2):213-23. doi: 10.1677/JOE-10-0217. Epub 2010 Aug 16. PubMed PMID:20713501.
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