Susanna R. Keller

Primary Appointment

  • Associate Professor, Medicine- Endocrinology and Metabolism

Contact

Research Interest(s)

Insulin signaling, insulin-regulated membrane trafficking and associated changes in cellular function and whole body physiology

Research Description

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.

Selected Publications

  • Kemp B, Howell N, Gildea J, Keller S, Padia S, Carey R. AT₂ receptor activation induces natriuresis and lowers blood pressure. Circulation research. 2014;115(3): 388-99. PMID: 24903104 | PMCID: PMC4116673
  • Taddeo E, Laker R, Breen D, Akhtar Y, Kenwood B, Liao J, Zhang M, Fazakerley D, Tomsig J, Harris T, Keller S, Chow J, Lynch K, Chokki M, Molkentin J, Turner N, James D, Yan Z, Hoehn K. Opening of the mitochondrial permeability transition pore links mitochondrial dysfunction to insulin resistance in skeletal muscle. Molecular metabolism. 2014;3(2): 124-34. PMID: 24634818 | PMCID: PMC3953683
  • Kemp B, Howell N, Gildea J, Keller S, Padia S. Intrarenal ghrelin receptors regulate ENaC-dependent sodium reabsorption by a cAMP-dependent pathway. Kidney international. 2013;84(3): 501-8. PMID: 23698230
  • Lansey M, Walker N, Hargett S, Stevens J, Keller S. Deletion of Rab GAP AS160 modifies glucose uptake and GLUT4 translocation in primary skeletal muscles and adipocytes and impairs glucose homeostasis. American journal of physiology. Endocrinology and metabolism. 2012;303(10): E1273-86. PMID: 23011063 | PMCID: PMC3517634
  • Cutchins A, Harmon D, Kirby J, Doran A, Oldham S, Skaflen M, Klibanov A, Meller N, Keller S, Garmey J, McNamara C. Inhibitor of differentiation-3 mediates high fat diet-induced visceral fat expansion. Arteriosclerosis, thrombosis, and vascular biology. 2011;32(2): 317-24. PMID: 22075252 | PMCID: PMC3262109
  • Jordens I, Molle D, Xiong W, Keller S, McGraw T. Insulin-regulated aminopeptidase is a key regulator of GLUT4 trafficking by controlling the sorting of GLUT4 from endosomes to specialized insulin-regulated vesicles. Molecular biology of the cell. 2010;21(12): 2034-44. PMID: 20410133 | PMCID: PMC2883947
  • 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
  • Chavez J, Roach W, Keller S, Lane W, Lienhard G. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. The Journal of biological chemistry. 2008;283(14): 9187-95. PMID: 18258599 | PMCID: PMC2431020
  • Wallis M, Lankford M, Keller S. Vasopressin is a physiological substrate for the insulin-regulated aminopeptidase IRAP. American journal of physiology. Endocrinology and metabolism. 2007;293(4): E1092-102. PMID: 17684103
  • The insulin-regulated aminopeptidase: a companion and regulator of GLUT4. Frontiers in bioscience : a journal and virtual library. 2003;8 s410-20. PMID: 12700100
  • Keller S, Davis A, Clairmont K. Mice deficient in the insulin-regulated membrane aminopeptidase show substantial decreases in glucose transporter GLUT4 levels but maintain normal glucose homeostasis. The Journal of biological chemistry. 2002;277(20): 17677-86. PMID: 11884418
  • Fantin V, Wang Q, Lienhard G, Keller S. Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. American journal of physiology. Endocrinology and metabolism. 2000;278(1): E127-33. PMID: 10644546
  • Liu S, Wang Q, Lienhard G, Keller S. Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. The Journal of biological chemistry. 1999;274(25): 18093-9. PMID: 10364263
  • Keller S, Scott H, Mastick C, Aebersold R, Lienhard G. Cloning and characterization of a novel insulin-regulated membrane aminopeptidase from Glut4 vesicles. The Journal of biological chemistry. 1995;270(40): 23612-8. PMID: 7559527
  • Keller S, Lienhard G. Insulin signalling: the role of insulin receptor substrate 1. Trends in cell biology. 1994;4(4): 115-9. PMID: 14731733