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Title: Hormones of stress and control of adipocyte biological "colour"
Author: Lu, Buyu
ISNI:       0000 0004 2724 0450
Awarding Body: University of Warwick
Current Institution: University of Warwick
Date of Award: 2011
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The family of “stress” peptides that includes CRH and UCNs are emerging as important regulators of the homeostatic mechanisms regulating energy balance and metabolism. These peptides exert well documented central anorectic and thermogenic actions in controlling food uptake and optimise energy losses. Furthermore, CRH acting through specific G-protein coupled receptors, CRH-R1 and R2 can target multiple peripheral tissues such as skeletal muscle and adipose tissue to influence important metabolic pathways. Two types of adipose tissue exist in mammals: WAT and BAT. Since WAT is the largest energy reserve in mammals and BAT can utilize energy through adaptive thermogenesis, one of the goals in this study was to identify the presence of CRH system components in adipose tissue. Real time RT-PCR and immunofluorescence demonstrated that CRH-Rs as well as CRH, UCN-I, and UCN-II are expressed in both WAT and BAT, raising the possibility that CRH and UCNs are important regulators of energy storage and adaptive thermogenesis. Also the functional roles of CRH-Rs in adipose tissue were investigated. Using an experimental paradigm the T37i fibroblast that can differentiate into brown adipocyte, it was demonstrated that CRH at low (nanomolar) but not high (submicromolar) concentrations stimulated a signaling pathway involving the AC/cAMP/PKA/AMPK signaling cascade that regulates downstream phosphorylation of HSL. This was associated with a significant translocation of HSL toward lipid droplets and association with perilipin, as demonstrated with immunofluorescence. Studies applying quantitative RT-PCR also suggested that CRH-R1 appears to regulate genes important for adaptive thermogenesis, whereas CRH-R2 likely regulates brown adipocyte formation. Further analysis using an experimental paradigm the 3T3L1 fibroblast that can differentiate into white adipocyte showed that exposure of 3T3L1 cells to UCN-II (a specific CRH-R2 agonist) or NBI-27914 (a CRH-R1 specific antagonist) were able to induce morphological and biochemical characteristics suggesting adipocyte differentiation to a “beige” phenotype in white preadipocytes/adipocytes. Thus, CRH-R1 and R2 could be of potential importance in maintenance of energy homeostasis. Moreover, in vivo analysis showed that CRH system seems to demonstrate a certain degree of plasticity in response to stress perturbation. For instance, HFD significantly repressed the expression of CRH-Rs and their agonists, whereas food deprivation dramatically increased their expression. The analysis of quantitative RTPCR demonstrated that this activation of CRH system might be associated with induction of ‘beige’ cells in white fat depots. Since CRH-R1 KO mice displayed a lean phenotype and resistance to HFD-induced fat accumulation and these phenotypes can be reversed by supplementation of corticosterone, role of CRH-R2 in adipose tissue of these KO mice was investigated. Data showed that CRH-R2 activation likely induced BAT activity and transdifferentiation from WAT to BAT in CRH-R1 KO mice. Corticosterone reversed these changes in KO mice via potential suppression of CRH-R2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QP Physiology