Year: 2015
Type: dissertation
Abstract: Obesity and the metabolic syndrome represent a serious global public health issue due to their long-term complications including type 2 diabetes, non-alcoholic fatty liver disease, cardiovascular disease and some cancers. As a systemic metabolic disorder, obesity affects many organ systems and has a complex etiology. Mechanisms linking obesity to its complications are poorly understood. The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway mediates the signal transduction of numerous cytokines, growth factors and hormones that regulate energy homeostasis and metabolism and may be important in the development of obesity and the metabolic syndrome. In this work, we developed transgenic mouse models to investigate the in vivo metabolic role of JAK2, an essential player in the JAK-STAT pathway, in the liver and adipose tissue under both physiological and pathophysiological conditions. Specifically, in Chapter IV, we deleted JAK2 in the adipose tissue and found that JAK2 deficiency resulted in increased body weight gain and adiposity due to impaired lipolysis in visceral fat, leading to insulin resistance and impaired glucose tolerance with aging. In Chapter V, we further explored the role of JAK2 in brown adipose tissue and show that JAK2 is required for cold- and diet-induced uncoupling protein 1 (UCP1) expression and thermogenesis. As such, mice lacking JAK2 in their adipocytes were cold sensitive, and were susceptible to high fat diet (HFD)-induced obesity, insulin resistance and glucose intolerance. In Chapter VI, we report that hepatocyte-specific deletion of JAK2 led to the development of spontaneous lipid accumulation in the liver. Surprisingly, despite the profound hepatosteatosis, deletion of JAK2 did not sensitize the liver to accelerated inflammatory injury on a HFD. This was accompanied by complete protection against HFD-induced systemic insulin resistance and glucose intolerance. Taken together, the results presented in this thesis reveal novel roles of the JAK-STAT pathway in metabolism and may facilitate development of preventative and therapeutic strategies for obesity and associated disorders.
Source: TSpace (University of Toronto)
Author: Sally Yu Shi
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2610959190