Identifier

etd-07082009-154838

Degree

Doctor of Philosophy (PhD)

Department

Biological Sciences

Document Type

Dissertation

Abstract

Obesity is characterized by an overabundance of fat cells, or adipocytes, and is currently a global epidemic. Adipocytes store energy, respond to insulin, and participate in diverse endocrine signaling pathways by secreting adipokines. Obesity leads to the dysregulation of adipocyte function, which could lead to numerous metabolic diseases, such as Type II diabetes. Understanding the mechanisms that regulate adipocyte development and involvement in endocrine signaling will lead to a greater understanding of the importance of fat metabolism in full-body health. Many lines of evidence demonstrate the importance of various transcription factors in regulating adipogenic processes, and one of which is the Signal Transducer and Activator of Transcription (STAT) proteins. Work by a variety of laboratories has demonstrated that STAT proteins, particularly STAT5A, are activated and induced during adipogenesis and play an important role in adipose tissue development. Novel studies highlighted in this dissertation demonstrate that pyruvate dehydrogenase kinase (PDK)-4, a known regulator of glycolysis, is highly induced in adipocytes by growth hormone (GH) or prolactin (PRL) in a STAT5 dependent manner. Under these conditions, the induction of PDK4 is accompanied by insulin resistance. Because adipocytes also express other STATs, we observed the effects of other STAT activators on adipocytes both in vitro and in vivo. Adipocytes are responsive to gp130 cytokines, and these cytokines have diverse functions in adipocytes, as well as other tissues. All gp130 cytokines share glycoprotein 130 as a common transducer protein in their functional receptor complex and typically activate STAT3. Several gp130 cytokines differentially affect adipogenesis and insulin-stimulated glucose uptake, as well as crosstalk with other members of the gp130 family to alter one another’s signaling. Novel studies highlighted in these studies demonstrate that adipocytes both in vitro and in vivo are responsive to neuropoietin (NP), which can inhibit adipogenesis and negatively regulate insulin signaling. Importantly, NP does not activate the LIF receptor, although previously reported to do so, and does not crosstalk with other gp130 cytokines. An in-depth analysis of STATs, as well as their activators, will enable us to understand how their role in adipocytes could contribute to the pathogenesis of metabolic disease.

Date

2009

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Jacqueline Stephens

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