Protein kinases in hormonal regulation of adipocyte metabolism.
(2014) In Lund University Faculty of Medicine Doctoral Dissertation Series 2014:90.- Abstract
- Abstract
Along with liver and muscle tissue, adipose tissue helps maintain normal levels of
glucose and lipids in the blood and has a very important role when it comes to storing
lipids that can provide whole-body energy. After a meal is ingested, adipocytes take
up glucose from the circulation and use it as a substrate for synthesis of new fatty
acids (FAs) in a process known as de novo fatty acid synthesis, as well as for synthesis
of glycerol. Adipocytes also take up fatty acids from the circulation and incorporate
both newly synthesized and imported FAs into triacylglycerides (TAGs), in a process
known as lipogenesis. TAGs are stored in large lipid droplets... (More) - Abstract
Along with liver and muscle tissue, adipose tissue helps maintain normal levels of
glucose and lipids in the blood and has a very important role when it comes to storing
lipids that can provide whole-body energy. After a meal is ingested, adipocytes take
up glucose from the circulation and use it as a substrate for synthesis of new fatty
acids (FAs) in a process known as de novo fatty acid synthesis, as well as for synthesis
of glycerol. Adipocytes also take up fatty acids from the circulation and incorporate
both newly synthesized and imported FAs into triacylglycerides (TAGs), in a process
known as lipogenesis. TAGs are stored in large lipid droplets in the cytosol, and
during fasting, or in response to physical exercise, they are hydrolysed in a process
known as lipolysis, in which FAs are released into the bloodstream for use as energy
substrates in other tissues. These cycles of lipogenesis and lipolysis are controlled by
the concerted actions of insulin, a hormone that is secreted by the pancreas and
catecholamines, hormones that are secreted by the adrenal glands, or derive from the
nervous system. Both glucose- and fatty acid uptake, as well as lipid storage and
mobilization, are regulated by cellular signaling, and kinases are central enzymatic
players in hormone-induced cellular signaling. A dysfunctional adipose tissue can
contribute to insulin resistance in many obese individuals. Therefore it is important
to elucidate the cellular mechanisms that govern metabolic processes in adipocytes.
Insulin is the hormone that promotes glucose uptake and lipogenesis in adipocytes,
and when it induces glucose uptake, insulin exerts it actions through protein kinase B
(PKB). Although PKB is known to mediate many effects of insulin, its role in
lipogenesis in adipocytes is less clear. We show that PKB is important for the effects
of insulin on lipogenesis (de novo and total). We also reveal that PKB can regulate
Amp-activated protein kinase (AMPK) in adipocytes by a mechanism previously only
seen in heart muscle cells. AMPK is a sensor of cellular energy status and known to
inhibit lipogenesis. We speculate that insulin possibly mediates its lipogenic effects via
a decrease in AMPK activity accomplished by PKB-phosphorylation of S485 on
AMPK.
Furthermore, we find that salt-inducible kinase 3 (SIK3), a kinase that belongs to the
AMPK-related family of kinases, and displays structural similarities to AMPK, can be
regulated by catecholamines in adipocytes. Catecholamines are hormones that bind to
β-adrenergic receptors and act by increasing cellular levels of cAMP, which in turn
activates protein kinase A (PKA). We find that in response to such β-adrenergic
stimuli, SIK3 is phosphorylated on multiple serine and threonine residues. This 10
regulation coincides with an increase in binding of SIK3 to 14-3-3 molecules. 14-3-3
proteins are cellular scaffolding proteins that can result in cellular re-localization of
their binding partners or in their binding to other proteins or lipids. We find that
when SIK3 is phosphorylated in response to β-adrenergic stimuli, the kinase does not
re-localize, but is partially de-activated. We speculate that SIK3 could potentially have
a role in adipocyte metabolism, as it is regulated by catecholamines in this tissue.
Finally, we address the current understanding of the role for AMPK in modulation of
the effects of insulin and catecholamines on glucose uptake and lipid metabolism. To
this date, it has been suggested that AMPK reduces insulin-induced glucose uptake
and lipogenesis, as well as inhibits catecholamine-induced lipolysis in adipocytes.
These findings are mainly based on studies performed with AMPK activating agents
that act on AMPK in an indirect manner. We have used the allosteric activator
A769662, that binds directly to AMPK, and find that AMPK does not appear to
modulate hormonally induced glucose uptake, lipolysis or total lipogenesis. However,
when we specifically measured the synthesis of new FAs, using acetate as a lipogenic
substrate (as opposed to using glucose as a substrate, a molecule which can participate
in both FA and glycerol synthesis), we observe that AMPK does indeed reduce
insulin-induced de novo fatty acid synthesis.
Collectively, we add novel findings to the available knowledge on key kinases and
cellular signaling in adipocyte metabolism. Our findings contribute to the
understanding of insulin- and catecholamine-mediated control of lipid storage in
adipose tissue, a biological function that, when dysfunctional, is strongly linked to
insulin resistance and type 2 diabetes (T2D). (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4646812
- author
- Berggreen, Christine LU
- supervisor
-
- Olga Göransson LU
- Eva Degerman LU
- opponent
-
- Professor Wojtaszewski, Jørgen, Köpenhamn Univ.
- organization
- publishing date
- 2014
- type
- Thesis
- publication status
- published
- subject
- keywords
- Adipocyte, PKB, AMPK, SIK3, insulin, catecholamines, lipolysis, lipogenesis, glucose uptake, de novo fatty acid synthesis, A769662, Akti, cAMP
- in
- Lund University Faculty of Medicine Doctoral Dissertation Series
- volume
- 2014:90
- pages
- 80 pages
- publisher
- Protein Phosphorylation, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17, Lund.
- defense date
- 2014-09-05 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-7619-019-7
- language
- English
- LU publication?
- yes
- id
- c5addb21-c78d-4976-ae55-dbb5ac0eeee3 (old id 4646812)
- date added to LUP
- 2016-04-01 14:05:20
- date last changed
- 2023-04-18 20:22:27
@phdthesis{c5addb21-c78d-4976-ae55-dbb5ac0eeee3, abstract = {{Abstract<br/><br> Along with liver and muscle tissue, adipose tissue helps maintain normal levels of <br/><br> glucose and lipids in the blood and has a very important role when it comes to storing <br/><br> lipids that can provide whole-body energy. After a meal is ingested, adipocytes take <br/><br> up glucose from the circulation and use it as a substrate for synthesis of new fatty <br/><br> acids (FAs) in a process known as de novo fatty acid synthesis, as well as for synthesis <br/><br> of glycerol. Adipocytes also take up fatty acids from the circulation and incorporate <br/><br> both newly synthesized and imported FAs into triacylglycerides (TAGs), in a process <br/><br> known as lipogenesis. TAGs are stored in large lipid droplets in the cytosol, and <br/><br> during fasting, or in response to physical exercise, they are hydrolysed in a process <br/><br> known as lipolysis, in which FAs are released into the bloodstream for use as energy <br/><br> substrates in other tissues. These cycles of lipogenesis and lipolysis are controlled by <br/><br> the concerted actions of insulin, a hormone that is secreted by the pancreas and <br/><br> catecholamines, hormones that are secreted by the adrenal glands, or derive from the<br/><br> nervous system. Both glucose- and fatty acid uptake, as well as lipid storage and <br/><br> mobilization, are regulated by cellular signaling, and kinases are central enzymatic <br/><br> players in hormone-induced cellular signaling. A dysfunctional adipose tissue can <br/><br> contribute to insulin resistance in many obese individuals. Therefore it is important <br/><br> to elucidate the cellular mechanisms that govern metabolic processes in adipocytes. <br/><br> Insulin is the hormone that promotes glucose uptake and lipogenesis in adipocytes,<br/><br> and when it induces glucose uptake, insulin exerts it actions through protein kinase B <br/><br> (PKB). Although PKB is known to mediate many effects of insulin, its role in <br/><br> lipogenesis in adipocytes is less clear. We show that PKB is important for the effects <br/><br> of insulin on lipogenesis (de novo and total). We also reveal that PKB can regulate <br/><br> Amp-activated protein kinase (AMPK) in adipocytes by a mechanism previously only <br/><br> seen in heart muscle cells. AMPK is a sensor of cellular energy status and known to <br/><br> inhibit lipogenesis. We speculate that insulin possibly mediates its lipogenic effects via <br/><br> a decrease in AMPK activity accomplished by PKB-phosphorylation of S485 on <br/><br> AMPK. <br/><br> Furthermore, we find that salt-inducible kinase 3 (SIK3), a kinase that belongs to the <br/><br> AMPK-related family of kinases, and displays structural similarities to AMPK, can be <br/><br> regulated by catecholamines in adipocytes. Catecholamines are hormones that bind to <br/><br> β-adrenergic receptors and act by increasing cellular levels of cAMP, which in turn <br/><br> activates protein kinase A (PKA). We find that in response to such β-adrenergic <br/><br> stimuli, SIK3 is phosphorylated on multiple serine and threonine residues. This 10<br/><br> regulation coincides with an increase in binding of SIK3 to 14-3-3 molecules. 14-3-3 <br/><br> proteins are cellular scaffolding proteins that can result in cellular re-localization of <br/><br> their binding partners or in their binding to other proteins or lipids. We find that <br/><br> when SIK3 is phosphorylated in response to β-adrenergic stimuli, the kinase does not <br/><br> re-localize, but is partially de-activated. We speculate that SIK3 could potentially have <br/><br> a role in adipocyte metabolism, as it is regulated by catecholamines in this tissue. <br/><br> Finally, we address the current understanding of the role for AMPK in modulation of <br/><br> the effects of insulin and catecholamines on glucose uptake and lipid metabolism. To <br/><br> this date, it has been suggested that AMPK reduces insulin-induced glucose uptake <br/><br> and lipogenesis, as well as inhibits catecholamine-induced lipolysis in adipocytes. <br/><br> These findings are mainly based on studies performed with AMPK activating agents <br/><br> that act on AMPK in an indirect manner. We have used the allosteric activator <br/><br> A769662, that binds directly to AMPK, and find that AMPK does not appear to <br/><br> modulate hormonally induced glucose uptake, lipolysis or total lipogenesis. However, <br/><br> when we specifically measured the synthesis of new FAs, using acetate as a lipogenic <br/><br> substrate (as opposed to using glucose as a substrate, a molecule which can participate <br/><br> in both FA and glycerol synthesis), we observe that AMPK does indeed reduce <br/><br> insulin-induced de novo fatty acid synthesis.<br/><br> Collectively, we add novel findings to the available knowledge on key kinases and <br/><br> cellular signaling in adipocyte metabolism. Our findings contribute to the <br/><br> understanding of insulin- and catecholamine-mediated control of lipid storage in <br/><br> adipose tissue, a biological function that, when dysfunctional, is strongly linked to <br/><br> insulin resistance and type 2 diabetes (T2D).}}, author = {{Berggreen, Christine}}, isbn = {{978-91-7619-019-7}}, issn = {{1652-8220}}, keywords = {{Adipocyte; PKB; AMPK; SIK3; insulin; catecholamines; lipolysis; lipogenesis; glucose uptake; de novo fatty acid synthesis; A769662; Akti; cAMP}}, language = {{eng}}, publisher = {{Protein Phosphorylation, Faculty of Medicine}}, school = {{Lund University}}, series = {{Lund University Faculty of Medicine Doctoral Dissertation Series}}, title = {{Protein kinases in hormonal regulation of adipocyte metabolism.}}, url = {{https://lup.lub.lu.se/search/files/3771942/4646815.pdf}}, volume = {{2014:90}}, year = {{2014}}, }