We have studied Akt, the direct effector of PI3K and the primary mediator of insulin's metabolic actions. In the course of those studies, we isolated ClipR-59, whose expression is elevated during adipocyte differentiation and decreased during development of obesity, as an Akt interaction protein. ClipR-59 does not involve Akt activation. Instead, it modulates Akt cellular compartmentalization following Akt activation, in particular, Akt membrane association. The regulation of Akt membrane association by ClipR-59 is critical for glucose transport, as evidenced by the finding that forced expression of ClipR-59 promotes, whereas silencing of ClipR-59 impairs, adipocyte glucose transport. Adipocyte glucose uptake is essential for the maintenance of whole-body glucose homeostasis. Due to the prevalence of obesity, type II diabetes has become epidemic and a major public health burden. Given that ClipR-59 interacts with Akt and regulates glucose transport, further studies of ClipR-59 are warranted studies. Our current studies indicated that a) expression of ClipR-59 in adipose tissue in mice results in reduced fat mass and increased glucose tolerance, an indication that ClipR-59 might play a role in maintaining whole-body glucose homeostasis;b) palmitoylation of ClipR-59, likely mediated by protein palmitoyltransferase DHHC17, is critical for ClipR-59 to modulate Akt cellular membrane association, implying that regulation of ClipR-59 palmitoylation by DHHC17 constitutes an important mechanism by which ClipR-59 modulates Akt signaling;and c) ClipR-59 is complexed with AS160, a Rab-GAP protein that connects insulin signaling and Glut4 vesicles. Because ClipR-59 also interacts directly with Akt, ClipR-59 may function as a scaffold protein to connect Akt signaling to AS160. To further study the function and regulation of ClipR-59, we proposed the experiments to address following specific questions: 1. Determine the impact of forced expression of ClipR-59 in adipose tissue on whole-body glucose homeostasis and on the development and progression of obesity, insulin resistance, and diabetes;2. Determine the role of protein palmitoyltransferase DHHC17 in Akt signaling and adipocyte glucose transport by modulating ClipR-59 palmitoylation;and 3. Determine the functional importance of the interaction between ClipR-59 and AS160 in adipocyte glucose transport. Overall, the studies proposed here will demonstrate that how specified Akt insulin signaling by ClipR-59 modulates whole body glucose homeostasis and adipocyte function thereby, providing insight knowledge into the importance of specified Akt signaling in insulin action.

Public Health Relevance

Adipocytes plays an essential role in maintaining energy homeostasis via glucose uptake and adipokine production. The studies proposed are to investigate how specified insulin signaling through interaction between Akt and ClipR-59 modulates glucose transport and adipocyte function. Thus, this research will provide invaluable knowledge to understand the development of fat insulin resistance and identify novel drug target for treatment of type II diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084319-04
Application #
8460580
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2010-07-01
Project End
2015-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
4
Fiscal Year
2013
Total Cost
$315,194
Indirect Cost
$116,959
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Ren, Wenying; Sun, Yingmin; Cheema, Sarwat et al. (2013) Interaction of constitutive photomorphogenesis 1 protein with protein-tyrosine phosphatase 1B suppresses protein-tyrosine phosphatase 1B activity and enhances insulin signaling. J Biol Chem 288:10902-13
Ren, Wenying; Sun, Yingmin; Du, Keyong (2013) DHHC17 palmitoylates ClipR-59 and modulates ClipR-59 association with the plasma membrane. Mol Cell Biol 33:4255-65
Ren, Wenying; Jhala, Ulupi S; Du, Keyong (2013) Proteomic analysis of protein palmitoylation in adipocytes. Adipocyte 2:17-28