AMP-activated protein kinase in adipose tissue

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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Sammanfattning

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.
Originalspråkengelska
KvalifikationDoktor
Tilldelande institution
  • Institutionen för experimentell medicinsk vetenskap
Handledare
  • Göransson, Olga, handledare
  • Degerman, Eva, Biträdande handledare
Tilldelningsdatum2021 maj 12
UtgivningsortLund
Förlag
Tryckta ISBN978-91-8021-041-6
StatusPublished - 2021

Bibliografisk information

Defence details
Date: 2021-05-12
Time: 09:00
Place: Belfragesalen, BMC D15, Klinikgatan 32 i Lund. Join by Zoom: https://lu-se.zoom.us/j/69101149695
External reviewer(s)
Name: [Thue Treebak, Jonas
Title: Associate Professor
Affiliation: University of Copenhagen

Ämnesklassifikation (UKÄ)

  • Cell- och molekylärbiologi

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