Hormones of stress and control of adipocyte biological "colour"
Lu, Buyu (2011) Hormones of stress and control of adipocyte biological "colour". PhD thesis, University of Warwick.Full text not available from this repository.
Official URL: http://webcat.warwick.ac.uk/record=b2568763~S1
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.
|Item Type:||Thesis or Dissertation (PhD)|
|Subjects:||Q Science > QP Physiology|
|Library of Congress Subject Headings (LCSH):||Stress (Physiology), Adipose tissues, Peptides, Metabolism|
|Official Date:||September 2011|
|Institution:||University of Warwick|
|Theses Department:||Warwick Medical School|
|Supervisor(s)/Advisor:||Grammatopoulos, Dimitris ; Feelisch, Martin|
|Extent:||xv, 212 leaves : ill., charts|
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