Identifier

etd-03252004-134502

Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Members of the gp130 cytokine family are known for their pleiotropic roles in various cell types. Our work has focused on their actions in adipocytes. CNTF administration has been shown to ameliorate most complications associated with obesity and type 2 diabetes through an unknown mechanism. In this study CNTF is shown to activate JAK/STAT and MAPK signaling, both in vitro and in vivo. In 3T3-L1 adipocytes, chronic CNTF also regulates the expression of SREBP-1, FAS, IRS-1 and GLUT4. Acute CNTF administration enhances the activation of IRS-1 and Akt by insulin. Our data also demonstrate that the expression of CNTF-specific receptor, CNTFRalpha, is decreased during adipocyte differentiation, but that this protein is expressed in several other tissues, and the level of CNTFRalpha glycosylation varies between different tissues. Most importantly, the expression of CNTFRalpha is dramatically increased in the fat pads of obese and diabetic animals. Even though CT-1 is mostly known for its actions in cardiomyocytes, the work presented demonstrates that, in fat cells, CT-1 can potently induce JAK/STAT and MAPK signaling. Neither CT-1 nor CNTF affected adipocyte differentiation, but chronic CT-1 did induce a decrease in FAS and IRS-1 protein expression. Both CNTF and CT-1 also induced a transient increase in SOCS-3 and a transient decrease in PPARgamma mRNA levels, in a MAPK-independent manner. Our studies also demonstrate that several gp130 cytokines, namely CT-1, LIF and OSM, have the ability to block signaling by other gp130 cytokines, but not GH. These cytokines can also dramatically reduce the half-life of LIFR protein in adipocytes, and this change in LIFR stability correlates with the ability of CT-1, LIF and OSM, to block subsequent gp130 cytokine signaling. The loss of LIFR protein can be prevented by the lysosome inhibitors leupeptin and chloroquine, but not by proteasome inhibitors. In summary, these studies demonstrate than gp130 cytokines have a wide spectrum of effects on both cultured and native adipocytes, and that their actions may be important in various aspects of adipocyte physiology.

Date

2004

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jacqueline Stephens

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