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The effects of interleukin-6 and estrogen on lipolysis and glucose homeostasis

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Title: The effects of interleukin-6 and estrogen on lipolysis and glucose homeostasis
Author: MacDonald, Tara
Department: Department of Human Health and Nutritional Sciences
Program: Human Health and Nutritional Sciences
Advisor: Dyck, DavidWright, David
Abstract: Cytokines and hormones exert significant control over lipolysis and whole-body glucose homeostasis; two of these include interleukin-6 (IL-6) and 17-β-estradiol, or estrogen (E2). IL-6 is released from skeletal muscle during exercise alongside elevated epinephrine (Epi), however, it is unknown whether they synergistically regulate lipolysis in skeletal muscle. Other studies suggest that E2 also regulates metabolism, given that ovariectomized (OVX) rodents and menopausal women demonstrate visceral adipose accretion, derangements in lipolysis and perturbed glucose homeostasis. Exercise has been postulated as a viable alternative to hormone replacement therapy (HRT) during E2 deficiency since it improves insulin signaling and glucose tolerance, but the precise mechanisms of E2 action on lipid and glucose metabolism are unknown. In the first study of this thesis, IL-6 independently stimulated subtle increases in glycerol accumulation, in vitro, in EDL muscle from wildtype (WT) mice, but not soleus. Conversely, soleus had elevated basal glycerol accumulation in IL-6 KO mice; and a significant response to Epi only occurred in WT mice. This highlighted a fiber-type specific role of IL-6 in stimulating lipolysis in fast-twitch skeletal muscle. In the second study, the relative efficacies of E2 and exercise were compared in treating glucose intolerance observed in OVX rats. Our most novel finding showed that 4 weeks of treadmill training was equally effective as daily E2 supplementation in improving whole-body glucose homeostasis. In order to explore the role of E2 in adipose tissue metabolism (study 3), β3 agonist CL 316, 243 was injected in vivo or applied to adipose explants from SHAM, OVX or OVX E2 rats to examine lipolysis. Plasma FFAs were different, and lower in OVX and OVX E2 rats relative to SHAMs, but glycerol, HSL Ser660 and Ser563 phosphorylation were not impaired in vivo, and E2 had no direct effect on lipolysis ex vivo. This suggests that changes in adipose lipolysis consequent to E2 loss are secondary to changes in a circulating factor or adipocyte morphology. Taken together, the findings in this thesis suggest that intact IL-6 signaling and the presence of E2 are required for functional lipolysis and the presence of E2 is critical for maintaining glucose homeostasis.
Date: 2016
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