Function and activation of signal transducer and activator of transcription 3 (STAT3) in adipose tissue formation and metabolism Public Deposited

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  • March 21, 2019
  • Cernkovich, Erin Rice.
    • Affiliation: Gillings School of Global Public Health, Department of Nutrition
  • Obesity is a significant medical and public heath concern due to its prevalence, associated co-morbidities, and economic impact. Obesity ensues when adipocytes accommodate excess energy through enhanced triacylglycerol (TAG) storage, and when adipocytes increase in number via adipogenesis. Signal Transducer and Activator of Transcription 3 (STAT3), a mitogenic signaling protein, is activated during the proliferative phases of adipogenesis. We hypothesized therefore, that STAT3 plays a necessary role in adipogenesis. This dissertation describes two independent projects that examined the function and activation of STAT3 in adipose tissue formation and adipocyte metabolism. Using an adipocyte cell line, we determined that STAT3 activation during adipogenesis occurred indirectly through the synthesis of an autocrine/paracrine factor. We identified the factor to be midkine, a pleiotrophic growth factor, and determined that the midkine-STAT3 signaling pathway plays a necessary role in adipogenesis. This study supported the hypothesis that STAT3 is necessary for adipogenesis and prompted a subsequent study aimed to determine the physiological role of STAT3 in adipogenesis in animals. In this study we used Cre-loxP DNA recombination to create mice with an adipocyte-specific disruption of the STAT3 gene (ASKO mice). aP2-Cre driven disappearance of STAT3 expression occurred on day 6 of adipogenesis, a time point when preadipocytes have already undergone conversion to adipocytes. Thus, this knockout model examined the role of STAT3 in mature, but not differentiating adipocytes ASKO mice weighed more than their littermate controls and had increased adipose tissue mass associated with adipocyte hypertrophy, but not adipocyte hyperplasia, hyperphagia, or reduced energy expenditure. Leptin-induced lipolysis was impaired in ASKO adipocytes, which may partially explain the adipocyte hypertrophy. Despite reduced adiponectin and increased liver TAG, ASKO mice did not develop impaired glucose tolerance or other obesity-related metabolic perturbations. Overall, this work improved our understanding of preadipocyte proliferation, differentiation, and metabolism by establishing a necessary role for STAT3 and the midkine/STAT3 signaling pathway in these processes. This work will help to direct efforts to identify potential adipose-tissue driven causes of obesity and to discover targets for the treatment of diseases such as obesity, hepatic steatosis, and insulin resistance.
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  • In Copyright
  • Harp, Joyce B.
  • Open access

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