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AMP-activated protein kinase in adipose tissue

Kopietz, Franziska LU orcid (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
The AMP-activated protein kinase (AMPK) is a ubiquitously expressed kinase, which is activated in response to depletion of cellular
energy levels. Once active, it functions to alter cellular metabolism in a way that leads to restoration of energy levels. Therefore,
AMPK is described as the key regulator of cellular energy homeostasis. Over the past years, AMPK activation has gained increasing
attention as a promising strategy for the treatment of type 2 diabetes (T2D). However, this view is mainly based on findings obtained
in muscle and liver tissue. Although muscle and liver are important players in the regulation of whole-body glucose homeostasis and
are therefore valid targets in the treatment of T2D, there is also... (More)
The AMP-activated protein kinase (AMPK) is a ubiquitously expressed kinase, which is activated in response to depletion of cellular
energy levels. Once active, it functions to alter cellular metabolism in a way that leads to restoration of energy levels. Therefore,
AMPK is described as the key regulator of cellular energy homeostasis. Over the past years, AMPK activation has gained increasing
attention as a promising strategy for the treatment of type 2 diabetes (T2D). However, this view is mainly based on findings obtained
in muscle and liver tissue. Although muscle and liver are important players in the regulation of whole-body glucose homeostasis and
are therefore valid targets in the treatment of T2D, there is also evidence that dysregulation of adipose tissue function during obesity
is a key factor in the development of insulin resistance and T2D. Despite that, AMPK is only studied to a limited extent in adipose
tissue. Therefore, the aim of this thesis was to contribute to an increased understanding not only of the effect of AMPK activation
on adipocyte metabolism, but also the regulation and expression of AMPK in adipocytes.
The first part of this work (Paper I + II) focuses on potential effects of AMPK activation on adipocyte metabolism. By employing
AMPK activators of a new generation, A-769662 and 991, as well as a mutant mouse model, we provide evidence that AMPK
activation neither affects lipolysis nor glucose uptake in human adipocytes. Thereby, our results suggest that the previously observed
effects are likely to be AMPK-independent and challenge the up to now prevalent view of an anti-lipolytic and glucose uptakeinhibiting
effect of AMPK activation in adipocytes.
The second part (Paper III) constitutes a quantitative analysis of the expression and contribution to overall AMPK kinase activity of
the two regulatory AMPKβ-subunit isoforms. Moreover, we have performed a correlation analysis to investigate potential alterations
in AMPK activity and expression in relation to BMI. Our results suggest that AMPKb1 is the main isoform expressed in human
adipocytes. However, it seems like AMPK activity/and expression does not correlate with human obesity/BMI.
In the last part of the work presented here (Paper IV), we have assessed potential mechanisms underlying the inhibitory effect of
insulin on AMPK activity. While we refute the previously suggested involvement of AMPK Ser485 phosphorylation, we revealed an
overall decrease in cellular energy levels in response to adipocyte insulin stimulation which might mediate the observed inhibition of
AMPK activity. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Thue Treebak, Jonas, University of Copenhagen
organization
publishing date
type
Thesis
publication status
published
subject
keywords
AMPK, adipose tissue, adipocytes, diabetes, insulin, glucose uptake, lipolysis, FA synthesis, ADaM site activators
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2021:35
pages
81 pages
publisher
Lund University, Faculty of Medicine
defense location
Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/69101149695
defense date
2021-05-12 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-041-6
language
English
LU publication?
yes
id
3599db91-9865-40b4-aa2d-54a634d520a8
date added to LUP
2021-04-14 14:54:01
date last changed
2022-01-12 11:25:03
@phdthesis{3599db91-9865-40b4-aa2d-54a634d520a8,
  abstract     = {{The AMP-activated protein kinase (AMPK) is a ubiquitously expressed kinase, which is activated in response to depletion of cellular<br/>energy levels. Once active, it functions to alter cellular metabolism in a way that leads to restoration of energy levels. Therefore,<br/>AMPK is described as the key regulator of cellular energy homeostasis. Over the past years, AMPK activation has gained increasing<br/>attention as a promising strategy for the treatment of type 2 diabetes (T2D). However, this view is mainly based on findings obtained<br/>in muscle and liver tissue. Although muscle and liver are important players in the regulation of whole-body glucose homeostasis and<br/>are therefore valid targets in the treatment of T2D, there is also evidence that dysregulation of adipose tissue function during obesity<br/>is a key factor in the development of insulin resistance and T2D. Despite that, AMPK is only studied to a limited extent in adipose<br/>tissue. Therefore, the aim of this thesis was to contribute to an increased understanding not only of the effect of AMPK activation<br/>on adipocyte metabolism, but also the regulation and expression of AMPK in adipocytes.<br/>The first part of this work (Paper I + II) focuses on potential effects of AMPK activation on adipocyte metabolism. By employing<br/>AMPK activators of a new generation, A-769662 and 991, as well as a mutant mouse model, we provide evidence that AMPK<br/>activation neither affects lipolysis nor glucose uptake in human adipocytes. Thereby, our results suggest that the previously observed<br/>effects are likely to be AMPK-independent and challenge the up to now prevalent view of an anti-lipolytic and glucose uptakeinhibiting<br/>effect of AMPK activation in adipocytes.<br/>The second part (Paper III) constitutes a quantitative analysis of the expression and contribution to overall AMPK kinase activity of<br/>the two regulatory AMPKβ-subunit isoforms. Moreover, we have performed a correlation analysis to investigate potential alterations<br/>in AMPK activity and expression in relation to BMI. Our results suggest that AMPKb1 is the main isoform expressed in human<br/>adipocytes. However, it seems like AMPK activity/and expression does not correlate with human obesity/BMI.<br/>In the last part of the work presented here (Paper IV), we have assessed potential mechanisms underlying the inhibitory effect of<br/>insulin on AMPK activity. While we refute the previously suggested involvement of AMPK Ser485 phosphorylation, we revealed an<br/>overall decrease in cellular energy levels in response to adipocyte insulin stimulation which might mediate the observed inhibition of<br/>AMPK activity.}},
  author       = {{Kopietz, Franziska}},
  isbn         = {{978-91-8021-041-6}},
  issn         = {{1652-8220}},
  keywords     = {{AMPK; adipose tissue; adipocytes; diabetes; insulin; glucose uptake; lipolysis; FA synthesis; ADaM site activators}},
  language     = {{eng}},
  number       = {{2021:35}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{AMP-activated protein kinase in adipose tissue}},
  url          = {{https://lup.lub.lu.se/search/files/96678348/PhDThesis_FranziskaKopietz.pdf}},
  year         = {{2021}},
}