File Download
Supplementary
-
Citations:
- Appears in Collections:
postgraduate thesis: Adipocyte fatty acid binding protein as a novel player of adaptive thermogenesis : mechanisms and physiological implications
Title | Adipocyte fatty acid binding protein as a novel player of adaptive thermogenesis : mechanisms and physiological implications |
---|---|
Authors | |
Issue Date | 2016 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Shu, L. [束玲玲]. (2016). Adipocyte fatty acid binding protein as a novel player of adaptive thermogenesis : mechanisms and physiological implications. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Adipocyte fatty acid binding protein (A-FABP) is an abundant adipokine which serves as a fatty acid chaperone to regulate trafficking, fluxes and signaling of free fatty acids (FFAs), and plays a critical role in linking lipid metabolism with inflammation, critically implicated in obesity-related cardio-metabolic complications. Recently, A-FABP has been shown to regulate adaptive thermogenesis, however its physiological role and precise underlying mechanism in adaptive thermogenesis have not been fully explored.
Therefore, this study aims to investigate: 1) the physiological role of A-FABP in diet- and cold-induced adaptive thermogenesis; 2) the precise underlying mechanism of A-FABP regulate adaptive thermogenesis; 3) the implication of the beneficial effects of A-FABP in energy metabolism.
Here we showed that A-FABP levels were elevated in both white and brown adipose tissues and in bloodstream in response to various thermogenic stimuli. A-FABP knockout (KO) mice exhibited a high fat diet (HFD)-induced morbidly obese phenotype, which was associated with a marked impairment in cold stress-and HFD-induced whole body energy expenditure due to the defective adaptive thermogenesis in BAT, whereas chronic infusion of recombinant A-FABP (rA-FABP) significantly reversed these impairments in A-FABP KO mice.
Mechanistically, circulating A-FABP facilitates the transportation of FFAs released from WAT to BAT for β-oxidation. Furthermore, the elevated A-FABP in BAT mediates the expression of type-II iodothyronine deiodinase (D2) via suppression of the nuclear receptor liver X receptor α (LXRα), thereby promoting the intracellular conversion of thyroid hormones from its inactive form T4 to bioactive T3. Replenishment of rA-FABP enhanced the abrogated capacity of thermogenic responses to T4 in A-FABP KO mice. In conclusion, our study demonstrated A-FABP acts as a physiological stimulator via its actions on facilitation of the release and transport of the energy substrate FFAs from WAT to BAT for β oxidation, and on the conversion of T4 to T3 by modulation of the LXRα-Dio2 signaling axis.
This study, together with previous studies highlight the complex functions of A-FABP in obesity and its associated cardio-metabolic complications due to its
differential effects on multiple target tissues at different stages of obesity. Therefore, global pharmacological inhibition of A-FABP may not be an optimal therapeutic strategy for treating obesity-related metabolic disorders due to the potential impairment of adaptive thermogenesis. Further investigations including dissection of the structural and molecular basis underlying the differential effects of A-FABP in various tissues are needed in order to investigate more effective and specific therapeutic strategies for obesity and its related medical complications aim at targeting A-FABP. |
Degree | Doctor of Philosophy |
Subject | Fatty acid-binding proteins Body temperature |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/250728 |
HKU Library Item ID | b5846362 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Shu, Lingling | - |
dc.contributor.author | 束玲玲 | - |
dc.date.accessioned | 2018-01-26T01:59:23Z | - |
dc.date.available | 2018-01-26T01:59:23Z | - |
dc.date.issued | 2016 | - |
dc.identifier.citation | Shu, L. [束玲玲]. (2016). Adipocyte fatty acid binding protein as a novel player of adaptive thermogenesis : mechanisms and physiological implications. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/250728 | - |
dc.description.abstract | Adipocyte fatty acid binding protein (A-FABP) is an abundant adipokine which serves as a fatty acid chaperone to regulate trafficking, fluxes and signaling of free fatty acids (FFAs), and plays a critical role in linking lipid metabolism with inflammation, critically implicated in obesity-related cardio-metabolic complications. Recently, A-FABP has been shown to regulate adaptive thermogenesis, however its physiological role and precise underlying mechanism in adaptive thermogenesis have not been fully explored. Therefore, this study aims to investigate: 1) the physiological role of A-FABP in diet- and cold-induced adaptive thermogenesis; 2) the precise underlying mechanism of A-FABP regulate adaptive thermogenesis; 3) the implication of the beneficial effects of A-FABP in energy metabolism. Here we showed that A-FABP levels were elevated in both white and brown adipose tissues and in bloodstream in response to various thermogenic stimuli. A-FABP knockout (KO) mice exhibited a high fat diet (HFD)-induced morbidly obese phenotype, which was associated with a marked impairment in cold stress-and HFD-induced whole body energy expenditure due to the defective adaptive thermogenesis in BAT, whereas chronic infusion of recombinant A-FABP (rA-FABP) significantly reversed these impairments in A-FABP KO mice. Mechanistically, circulating A-FABP facilitates the transportation of FFAs released from WAT to BAT for β-oxidation. Furthermore, the elevated A-FABP in BAT mediates the expression of type-II iodothyronine deiodinase (D2) via suppression of the nuclear receptor liver X receptor α (LXRα), thereby promoting the intracellular conversion of thyroid hormones from its inactive form T4 to bioactive T3. Replenishment of rA-FABP enhanced the abrogated capacity of thermogenic responses to T4 in A-FABP KO mice. In conclusion, our study demonstrated A-FABP acts as a physiological stimulator via its actions on facilitation of the release and transport of the energy substrate FFAs from WAT to BAT for β oxidation, and on the conversion of T4 to T3 by modulation of the LXRα-Dio2 signaling axis. This study, together with previous studies highlight the complex functions of A-FABP in obesity and its associated cardio-metabolic complications due to its differential effects on multiple target tissues at different stages of obesity. Therefore, global pharmacological inhibition of A-FABP may not be an optimal therapeutic strategy for treating obesity-related metabolic disorders due to the potential impairment of adaptive thermogenesis. Further investigations including dissection of the structural and molecular basis underlying the differential effects of A-FABP in various tissues are needed in order to investigate more effective and specific therapeutic strategies for obesity and its related medical complications aim at targeting A-FABP. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.subject.lcsh | Fatty acid-binding proteins | - |
dc.subject.lcsh | Body temperature | - |
dc.title | Adipocyte fatty acid binding protein as a novel player of adaptive thermogenesis : mechanisms and physiological implications | - |
dc.type | PG_Thesis | - |
dc.identifier.hkul | b5846362 | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.mmsid | 991044001140303414 | - |