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postgraduate thesis: The MDM2-p53 axis maintains adipose tissue function and metabolic homeostasis during ageing
Title | The MDM2-p53 axis maintains adipose tissue function and metabolic homeostasis during ageing |
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Authors | |
Advisors | |
Issue Date | 2019 |
Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
Citation | Liu, Z. [劉卓浩]. (2019). The MDM2-p53 axis maintains adipose tissue function and metabolic homeostasis during ageing. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. |
Abstract | Adipose tissues undergo remodeling to maintain systemic glucose, energy and lipid metabolism in response to environment changes. However, functions of adipose tissues decline during ageing, leading to a cluster of cardiometabolic diseases. The driving force contributes to adipose tissue dysfunction during ageing remains obscure.
Chronic activation of p53 triggers systemic metabolic disorders and leads to systemic ageing. As the major negative regulator of p53, murine double minute 2 (MDM2) is known to restrict chronic activation via a negative feedback loop. In adipose tissues, activity of p53 is elevated in obesity, which contributes to insulin resistance and glucose intolerance. Two in vitro studies found that MDM2 involves in the regulation of adipogenesis, but its physiological function in adipose tissue is still unknown. In this project, I examined the role of MDM2 in maintaining adipocyte function during ageing using an adipocyte-specific MDM2 knockout mouse model (so-called KO mice hereafter). By using in vivo and in vitro approaches, I provided a series of evidence showing disruption of MDM2-p53 axis leads to severe lipodystrophy and its related metabolic complications.
Key findings:
(1) Downregulation of MDM2 and upregulation of p53 in white and brown adipose tissues were observed in extreme old C57/BL6 mice, which were correlated with adipose tissue dysfunction including fat loss, apoptosis, senescence, cold sensitivity and inflammation.
(2) Adipocyte-specific abrogation of MDM2 led to profound loss of white and brown adipose tissues, which were accompanied with type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia and defective adaptive thermogenesis. Inactivation of p53 by genetic knockout approach completely reversed the lipodystrophy and its associated metabolic complications in KO mice.
(3) Apoptosis was induced in adipocytes and adipose tissues lacking MDM2. Treatment with the caspase inhibitor Z-VAD-FMK (ZVAD) relieved the adipocyte apoptosis, and hence alleviated lipodystrophy and its related metabolic complications in KO mice.
(4) Apart from apoptosis, adipocytes lacking MDM2 displayed senescence-associated phenotypes including increased expression of p21 and pro-inflammatory cytokines. Furthermore, in vitro experiments demonstrated that senescence-associated secretory factors from MDM2 deficiency adipocytes suppressed de novo adipogenesis in progenitors. The simultaneous effect of adipocyte apoptosis and senescence resulted in accelerated fat loss and dysfunction of adipose tissue in the KO mice.
(5) In addition, the KO mice exhibited premature ageing, as evidenced by shorter lifespan, premature multi-organ senescence, exercise intolerance and heart dysfunction. The above physiological deficits were largely rescued by transplantation with young and healthy subcutaneous fat or genetic inactivation of p53.
Conclusion:
The above data indicates that proper function of MDM2-p53 axis in adipocyte is required for proper adipose tissue function and metabolic homeostasis during ageing. Loss of adipocyte MDM2 triggers p53-dependent apoptosis, senescence and impedes adipogenesis in adipocytes, leading to lipodystrophy and its associated systemic metabolic complications.
An abstract of 451 words |
Degree | Doctor of Philosophy |
Subject | Adipose tissues Ligases p53 protein Protein-protein interactions Ubiquitin |
Dept/Program | Medicine |
Persistent Identifier | http://hdl.handle.net/10722/281292 |
DC Field | Value | Language |
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dc.contributor.advisor | Xu, A | - |
dc.contributor.advisor | Cheng, KY | - |
dc.contributor.author | Liu, Zhuohao | - |
dc.contributor.author | 劉卓浩 | - |
dc.date.accessioned | 2020-03-10T08:46:33Z | - |
dc.date.available | 2020-03-10T08:46:33Z | - |
dc.date.issued | 2019 | - |
dc.identifier.citation | Liu, Z. [劉卓浩]. (2019). The MDM2-p53 axis maintains adipose tissue function and metabolic homeostasis during ageing. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. | - |
dc.identifier.uri | http://hdl.handle.net/10722/281292 | - |
dc.description.abstract | Adipose tissues undergo remodeling to maintain systemic glucose, energy and lipid metabolism in response to environment changes. However, functions of adipose tissues decline during ageing, leading to a cluster of cardiometabolic diseases. The driving force contributes to adipose tissue dysfunction during ageing remains obscure. Chronic activation of p53 triggers systemic metabolic disorders and leads to systemic ageing. As the major negative regulator of p53, murine double minute 2 (MDM2) is known to restrict chronic activation via a negative feedback loop. In adipose tissues, activity of p53 is elevated in obesity, which contributes to insulin resistance and glucose intolerance. Two in vitro studies found that MDM2 involves in the regulation of adipogenesis, but its physiological function in adipose tissue is still unknown. In this project, I examined the role of MDM2 in maintaining adipocyte function during ageing using an adipocyte-specific MDM2 knockout mouse model (so-called KO mice hereafter). By using in vivo and in vitro approaches, I provided a series of evidence showing disruption of MDM2-p53 axis leads to severe lipodystrophy and its related metabolic complications. Key findings: (1) Downregulation of MDM2 and upregulation of p53 in white and brown adipose tissues were observed in extreme old C57/BL6 mice, which were correlated with adipose tissue dysfunction including fat loss, apoptosis, senescence, cold sensitivity and inflammation. (2) Adipocyte-specific abrogation of MDM2 led to profound loss of white and brown adipose tissues, which were accompanied with type 2 diabetes, non-alcoholic fatty liver disease (NAFLD), hyperlipidemia and defective adaptive thermogenesis. Inactivation of p53 by genetic knockout approach completely reversed the lipodystrophy and its associated metabolic complications in KO mice. (3) Apoptosis was induced in adipocytes and adipose tissues lacking MDM2. Treatment with the caspase inhibitor Z-VAD-FMK (ZVAD) relieved the adipocyte apoptosis, and hence alleviated lipodystrophy and its related metabolic complications in KO mice. (4) Apart from apoptosis, adipocytes lacking MDM2 displayed senescence-associated phenotypes including increased expression of p21 and pro-inflammatory cytokines. Furthermore, in vitro experiments demonstrated that senescence-associated secretory factors from MDM2 deficiency adipocytes suppressed de novo adipogenesis in progenitors. The simultaneous effect of adipocyte apoptosis and senescence resulted in accelerated fat loss and dysfunction of adipose tissue in the KO mice. (5) In addition, the KO mice exhibited premature ageing, as evidenced by shorter lifespan, premature multi-organ senescence, exercise intolerance and heart dysfunction. The above physiological deficits were largely rescued by transplantation with young and healthy subcutaneous fat or genetic inactivation of p53. Conclusion: The above data indicates that proper function of MDM2-p53 axis in adipocyte is required for proper adipose tissue function and metabolic homeostasis during ageing. Loss of adipocyte MDM2 triggers p53-dependent apoptosis, senescence and impedes adipogenesis in adipocytes, leading to lipodystrophy and its associated systemic metabolic complications. An abstract of 451 words | - |
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 | Ligases | - |
dc.subject.lcsh | p53 protein | - |
dc.subject.lcsh | Protein-protein interactions | - |
dc.subject.lcsh | Ubiquitin | - |
dc.title | The MDM2-p53 axis maintains adipose tissue function and metabolic homeostasis during ageing | - |
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_991044104147503414 | - |
dc.date.hkucongregation | 2019 | - |
dc.identifier.mmsid | 991044104147503414 | - |