AMP-activated protein kinase in adipose tissue

• The AMP-activated protein kinase (AMPK) is a ubiquitously expressed kinase, which is activated in response to depletion of cellularenergy 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 increasingattention as a promising strategy for the treatment of type 2 diabetes (T2D). However, this view is mainly based on findings obtainedin muscle and liver tissue. Although muscle and liver are important players in the regulation of whole-body glucose homeostasis andare therefore valid targets in the treatment of T2D, there is also evidence that dysregulation of adipose tissue function during obesityis a key factor in the development of insulin resistance and T2D. Despite that, AMPK is only studied to a limited extent in adiposetissue. Therefore, the aim of this thesis was to contribute to an increased understanding not only of the effect of AMPK activationon 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 employingAMPK activators of a new generation, A-769662 and 991, as well as a mutant mouse model, we provide evidence that AMPKactivation neither affects lipolysis nor glucose uptake in human adipocytes. Thereby, our results suggest that the previously observedeffects are likely to be AMPK-independent and challenge the up to now prevalent view of an anti-lipolytic and glucose uptakeinhibitingeffect of AMPK activation in adipocytes.The second part (Paper III) constitutes a quantitative analysis of the expression and contribution to overall AMPK kinase activity ofthe two regulatory AMPKβ-subunit isoforms. Moreover, we have performed a correlation analysis to investigate potential alterationsin AMPK activity and expression in relation to BMI. Our results suggest that AMPKb1 is the main isoform expressed in humanadipocytes. 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 ofinsulin on AMPK activity. While we refute the previously suggested involvement of AMPK Ser485 phosphorylation, we revealed anoverall decrease in cellular energy levels in response to adipocyte insulin stimulation which might mediate the observed inhibition ofAMPK activity.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

AMPK

adipose tissue

adipocytes

diabetes

insulin

glucose uptake

lipolysis

FA synthesis

ADaM site activators

Publikations- och innehållstyp

dok (ämneskategori)

vet (ämneskategori)