File Download
Supplementary
-
Citations:
- Appears in Collections:
postgraduate thesis: Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance
Title | Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance |
---|---|
Authors | |
Issue Date | 2018 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Pan, Y. [潘勇]. (2018). Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Adipose tissue macrophages (ATMs) are central to local and systemic inflammation. Upon obesity, ATMs are more prone to polarize to the pro-inflammatory M1 subtype, whereas the anti-inflammatory M2 profile is suppressed. These two events collectively lead to adipose tissue inflammation. However, the underlying mechanisms explaining macrophage polarization are not fully explored. Furthermore, a clinical study has detected altered expression of microRNA (miR)-34a in obese subcutaneous adipose tissue, but whether adipose-originated miR-34a modulates obesity-associated adipose tissue remodeling and whole body metabolism remains elusive.
Therefore, this study aims to investigate: 1) whether adipose miR-34a mediates adipose tissue inflammatory response and systemic insulin insensitivity via affecting macrophage polarization; 2) the potential mechanisms linking adipose miR-34a and macrophage polarization; 3) how adipocytes and macrophages crosstalk with each other under obese condition.
Our results show that high fat diet (HFD) and inflammatory cues cause a strong elevation of miR-34a in adipose tissues. Adipose tissue-specific depletion of miR-34a protects mice from high fat diet-induced glucose intolerance, insulin insensitivity and other metabolic abnormalities. Macrophage depletion experiment demonstrated that the metabolic benefits in adipose-restricted miR-34a knockout mice are mainly attributed to its modulation on adipose macrophages. Indeed, miR-34a deficiency in adipose tissue leads to reduced number of crown-like structures, and increased macrophage polarization toward the anti-inflammatory M2 subtypes.
Luciferase assay determined that miR-34a directly targets 3’-UTR of Kruppel-like factor 4 (Klf4). Lentivirus-mediated knocking-down of Klf4 in miR-34a knockout mice leads to exacerbated macrophage infiltration, pro-inflammatory phenotypes of macrophages in vivo, while overexpression of Klf4 improves diet-induced adipose inflammation. More importantly, adipocyte miR-34a modulates macrophage polarization in a paracrine manner via transportation of exosome. Furthermore, a strong and positive association is revealed between visceral adipose tissue miR-34a and inflammation in overweight/obese human individuals.
Generally, our findings demonstrate adipose miR-34a polarizes macrophages to M1 profile and induces insulin resistance. Furthermore, the miR-34a/KLF4 axis, exhibiting as the crosstalk between adipocytes and macrophages, constitutes a critical branch in the regulation of ATM and systemic metabolic homeostasis.
|
Degree | Doctor of Philosophy |
Subject | Adipose tissues MicroRNA Insulin resistance Metabolic syndrome Obesity - Complications |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/267328 |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Pan, Yong | - |
dc.contributor.author | 潘勇 | - |
dc.date.accessioned | 2019-02-18T08:45:42Z | - |
dc.date.available | 2019-02-18T08:45:42Z | - |
dc.date.issued | 2018 | - |
dc.identifier.citation | Pan, Y. [潘勇]. (2018). Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/267328 | - |
dc.description.abstract | Adipose tissue macrophages (ATMs) are central to local and systemic inflammation. Upon obesity, ATMs are more prone to polarize to the pro-inflammatory M1 subtype, whereas the anti-inflammatory M2 profile is suppressed. These two events collectively lead to adipose tissue inflammation. However, the underlying mechanisms explaining macrophage polarization are not fully explored. Furthermore, a clinical study has detected altered expression of microRNA (miR)-34a in obese subcutaneous adipose tissue, but whether adipose-originated miR-34a modulates obesity-associated adipose tissue remodeling and whole body metabolism remains elusive. Therefore, this study aims to investigate: 1) whether adipose miR-34a mediates adipose tissue inflammatory response and systemic insulin insensitivity via affecting macrophage polarization; 2) the potential mechanisms linking adipose miR-34a and macrophage polarization; 3) how adipocytes and macrophages crosstalk with each other under obese condition. Our results show that high fat diet (HFD) and inflammatory cues cause a strong elevation of miR-34a in adipose tissues. Adipose tissue-specific depletion of miR-34a protects mice from high fat diet-induced glucose intolerance, insulin insensitivity and other metabolic abnormalities. Macrophage depletion experiment demonstrated that the metabolic benefits in adipose-restricted miR-34a knockout mice are mainly attributed to its modulation on adipose macrophages. Indeed, miR-34a deficiency in adipose tissue leads to reduced number of crown-like structures, and increased macrophage polarization toward the anti-inflammatory M2 subtypes. Luciferase assay determined that miR-34a directly targets 3’-UTR of Kruppel-like factor 4 (Klf4). Lentivirus-mediated knocking-down of Klf4 in miR-34a knockout mice leads to exacerbated macrophage infiltration, pro-inflammatory phenotypes of macrophages in vivo, while overexpression of Klf4 improves diet-induced adipose inflammation. More importantly, adipocyte miR-34a modulates macrophage polarization in a paracrine manner via transportation of exosome. Furthermore, a strong and positive association is revealed between visceral adipose tissue miR-34a and inflammation in overweight/obese human individuals. Generally, our findings demonstrate adipose miR-34a polarizes macrophages to M1 profile and induces insulin resistance. Furthermore, the miR-34a/KLF4 axis, exhibiting as the crosstalk between adipocytes and macrophages, constitutes a critical branch in the regulation of ATM and systemic metabolic homeostasis. | - |
dc.language | eng | - |
dc.publisher | The University of Hong Kong (Pokfulam, Hong Kong) | - |
dc.relation.ispartof | HKU Theses Online (HKUTO) | - |
dc.rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works. | - |
dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
dc.subject.lcsh | Adipose tissues | - |
dc.subject.lcsh | MicroRNA | - |
dc.subject.lcsh | Insulin resistance | - |
dc.subject.lcsh | Metabolic syndrome | - |
dc.subject.lcsh | Obesity - Complications | - |
dc.title | Adipose miR-34a in obesity-induced metabolic inflammation and insulin resistance | - |
dc.type | PG_Thesis | - |
dc.description.thesisname | Doctor of Philosophy | - |
dc.description.thesislevel | Doctoral | - |
dc.description.thesisdiscipline | Medicine | - |
dc.description.nature | published_or_final_version | - |
dc.identifier.doi | 10.5353/th_991044019483703414 | - |
dc.date.hkucongregation | 2018 | - |
dc.identifier.mmsid | 991044019483703414 | - |