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β-Adrenergic Signalling Through mTOR
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Adrenergic signalling is part of the sympathetic nervous system and is activated upon stimulation by the catecholamines epinephrine and norepinephrine. This regulates heart rate, energy mobilization, digestion and helps to divert blood flow to important organs. Insulin is released to regulate metabolism of carbohydrates, fats and proteins, mainly by taking up glucose from the blood. The insulin and the catecholamine hormone systems are normally working as opposing metabolic regulators and are therefore thought to antagonize each other.

One of the major regulators involved in insulin signalling is the mechanistic target of rapamycin (mTOR). There are two different complexes of mTOR; mTORC1 and mTORC2, and they are essential in the control of cell growth, metabolism and energy homeostasis. Since mTOR is one of the major signalling nodes for anabolic actions of insulin it was thought that catecholamines might oppose this action by inhibiting the complexes. However, lately there are studies demonstrating that this may not be the case. mTOR is for instance part of the adrenergic signalling pathway resulting in hypertrophy of cardiac and skeletal muscle cells and inhibition of smooth muscle relaxation and helps to regulate browning in white adipose tissue and thermogenesis in brown adipose tissue (BAT).

In this thesis I show that β-adrenergic signalling leading to glucose uptake occurs independently of insulin in skeletal muscle and BAT, and does not activate either Akt or mTORC1, but that the master regulator of this pathway is mTORC2. Further, my co-workers and I demonstrates that β-adrenergic stimulation in skeletal muscle and BAT utilizes different glucose transporters. In skeletal muscle, GLUT4 is translocated to the plasma membrane upon stimulation. However, in BAT, β-adrenergic stimulation results in glucose uptake through translocation of GLUT1. Importantly, in both skeletal muscle and BAT, the role of mTORC2 in β-adrenergic stimulated glucose uptake is to regulate GLUT-translocation.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University , 2017.
Keywords [en]
Glucose uptake, Brown adipose tissue, White adipose tissue, Skeletal muscle, Mechanistic target of rapamycin, Glucose transporter, Physiology
National Category
Physiology
Research subject
Physiology
Identifiers
URN: urn:nbn:se:su:diva-142169ISBN: 978-91-7649-850-7 (print)ISBN: 978-91-7649-851-4 (electronic)OAI: oai:DiVA.org:su-142169DiVA, id: diva2:1091625
Public defence
2017-06-14, sal E306, Arrheniuslaboratorierna, Svante Arrhenius väg 20 C, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 4: Manuscript.

Available from: 2017-05-22 Created: 2017-04-27 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle
Open this publication in new window or tab >>Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle
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2014 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 63, no 12, p. 4115-4129Article in journal (Refereed) Published
Abstract [en]

There is an increasing worldwide epidemic of type 2 diabetes that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high-fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate cAMP-dependent protein kinase, which phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle after activation of the sympathetic nervous system is likely to be of high physiological relevance because mTORC2 activation was observed at the cellular, tissue, and whole-animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.

National Category
Physiology Endocrinology and Diabetes
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143131 (URN)10.2337/db13-1860 (DOI)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved
2. Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation
Open this publication in new window or tab >>Glucose uptake in brown fat cells is dependent on mTOR complex 2-promoted GLUT1 translocation
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2014 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 207, no 3, article id 365Article in journal (Refereed) Published
Abstract [en]

Brown adipose tissue is the primary site for thermogenesis and can consume, in addition to free fatty acids, a very high amount of glucose from the blood, which can both acutely and chronically affect glucose homeostasis. Here, we show that mechanistic target of rapamycin (mTOR) complex 2 has a novel role in β3-adrenoceptor-stimulated glucose uptake in brown adipose tissue. We show that β3-adrenoceptors stimulate glucose uptake in brown adipose tissue via a signaling pathway that is comprised of two different parts: one part dependent on cAMP-mediated increases in GLUT1 transcription and de novo synthesis of GLUT1 and another part dependent on mTOR complex 2-stimulated translocation of newly synthesized GLUT1 to the plasma membrane, leading to increased glucose uptake. Both parts are essential for β3-adrenoceptor-stimulated glucose uptake. Importantly, the effect of β3-adrenoceptor on mTOR complex 2 is independent of the classical insulin-phosphoinositide 3-kinase-Akt pathway, highlighting a novel mechanism of mTOR complex 2 activation.

National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143136 (URN)10.1083/jcb.201403080 (DOI)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved
3. β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway
Open this publication in new window or tab >>β3-Adrenergically induced glucose uptake in brown adipose tissue is independent of UCP1 presence or activity: Mediation through the mTOR pathway
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2017 (English)In: Molecular Metabolism, ISSN 2109-5671, E-ISSN 1762-3162, Vol. 6, no 6, p. 611-619Article in journal (Refereed) Published
Abstract [en]

Objective

Today, the presence and activity of brown adipose tissue (BAT) in adult humans is generally equated with the induced accumulation of [2-18F]2-fluoro-2-deoxy-d-glucose([18F]FDG) in adipose tissues, as investigated by positron emission tomography (PET) scanning. In reality, PET-FDG is currently the only method available for in vivoquantification of BAT activity in adult humans. The underlying assumption is that the glucose uptake reflects the thermogenic activity of the tissue.

Methods

To examine this basic assumption, we here followed [18F]FDG uptake by PET and by tissue [3H]-2-deoxy-d-glucose uptake in wildtype and UCP1(−/−) mice, i.e. in mice that do or do not possess the unique thermogenic and calorie-consuming ability of BAT.

Results

Unexpectedly, we found that β3-adrenergically induced (by CL-316,243) glucose uptake was UCP1-independent. Thus, whereas PET-FDG scans adequately reflect glucose uptake, this acute glucose uptake is not secondary to thermogenesis but is governed by an independent cellular signalling, here demonstrated to be mediated via the previously described KU-0063794-sensitive mTOR pathway.

Conclusions

Thus, PET-FDG scans do not exclusively reveal active BAT deposits but rather any tissue possessing an adrenergically-mediated glucose uptake pathway. In contrast, we found that the marked glucose uptake-ameliorating effect of prolonged β3-adrenergictreatment was UCP1 dependent. Thus, therapeutically, UCP1 activity is required for any anti-diabetic effect of BAT activation.

Keywords
Brown adipose tissue, Uncoupling protein 1, Glucose uptake, Adrenergic signaling, Positron emission tomography
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143137 (URN)10.1016/j.molmet.2017.02.006 (DOI)000405453000015 ()
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved
4. Akt is not required for β3-adrenergically induced glucose uptake in brown adipose tissue
Open this publication in new window or tab >>Akt is not required for β3-adrenergically induced glucose uptake in brown adipose tissue
(English)Manuscript (preprint) (Other academic)
National Category
Physiology
Research subject
Physiology
Identifiers
urn:nbn:se:su:diva-143138 (URN)
Available from: 2017-05-15 Created: 2017-05-15 Last updated: 2018-01-13Bibliographically approved

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