Cell biology of fuel utilization in adipocytes and skeletal muscle

The modern Western diet coupled with a sedentary lifestyle has led to an epidemic of obesity, a consequence of which is a dramatic rise in the incidence of type II diabetes mellitus, a malfunction in insulin-regulated metabolism. At the cellular level, type II diabetes is characterized by failure of insulin to act in liver, muscle and fat and we study insulin action in the latter two tissues. Insulin resistance in muscle (and fat) derives from the failure of insulin to activate the tissue-specific glucose transporter GLUT4. The activation mechanism for this process involves vesicle trafficking and protein targeting with regard to GLUT4 and the insulin receptor. We are characterizing the formation and protein content of GLUT4-containing vesicles (2, 5) in order to identify the organelles through which they pass on their way to and from the cell surface and we are probing the signaling from the insulin receptor to the GLUT4-containing vesicles (5) as well as the regulation of Glut4 expression (4).

A morphological feature of fat and muscle cells is their numerous cell surface (plasma membrane) micro-domains called caveolae (for little caves or invaginations). Caveolae are involved in lipid trafficking in adipocytes and other cells (1, 3, 6, 7), and we have discovered that their composition and regulation is much more complex than previously thought (7). Thus the broad goal is to study adipocyte and muscle cell biology in order to understand the interplay between glucose and fat metabolism as well as the interplay between adipocytes and muscle required for overall metabolic homeostasis. Understanding these pathways will help us to figure out how they are compromised in pathophysiological states such as diabetes.

References:

1. Meshulam T, Simard JR, Wharton J, Hamilton JA, Pilch PF. (2006) Role of caveolin-1 and cholesterol in transmembrane fatty acid movement. Biochemistry 45:2882-93.
   
   
2. Liu L, Jedrychowski MP, Gygi SP, Pilch PF. (2006) Role of Insulin-dependent Cortical Fodrin/Spectrin Remodeling in GLUT4 Translocation in Rat Adipocytes. Mol Biol Cell. 17: 4249-4256.
   
   
3. Pilch PF, Souto RP, Liu L, Jedrychowski MP, Berg EA, Costello CE, Gygi SP. (2007) Cellular spelunking: exploring adipocyte caveolae. J Lipid Res. 48, 2103-2111.
   
   
4. Chao LC, Zhang Z, Pei L, Saito T, Tontonoz P, Pilch PF. (2007) Nur77 coordinately regulates expression of genes linked to glucose metabolism in skeletal muscle. Mol Endocrinol. 21, 2152-2163.
   
   
5. Saito, T., Jones, C.C., Huang, S., Czech, M.P. and Pilch, P.F. (2007) The interaction of AKT with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 282:32280-32287
   
   
6. Liu L and Pilch P.F. ( 2008) A critical role of cavin (PTRF) in caveolae formation and organization. J Biol Chem.  283, 4314-4322.
   
   
7. Liu, L., Brown, D., McKee, M. LeBrasseur, N. K.,Yang, D.. Albrecht, K.H., Ravid, K. and Pilch, P.F. (2008) Deletion of Cavin/PTRF Causes Global Loss of Caveolae, Dyslipidemia, and Glucose Intolerance, Cell Metabolism, 8, 310-317.