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Treatment with a β-2-adrenoceptor agonist stimulates glucose uptake in skeletal muscle and improves glucose homeostasis, insulin resistance and hepatic steatosis in mice with diet-induced obesity
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Atrogi AB, Sweden.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute. Atrogi AB, Sweden.
Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
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Number of Authors: 152020 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, no 8, p. 1603-1615Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis Chronic stimulation of beta(2)-adrenoceptors, opposite to acute treatment, was reported to reduce blood glucose levels, as well as to improve glucose and insulin tolerance in rodent models of diabetes by essentially unknown mechanisms. We recently described a novel pathway that mediates glucose uptake in skeletal muscle cells via stimulation of beta(2)-adrenoceptors. In the current study we further explored the potential therapeutic relevance of beta(2)-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect.

Methods C57Bl/6N mice with diet-induced obesity were treated both acutely and for up to 42 days with a wide range of clenbuterol dosages and treatment durations. Glucose homeostasis was assessed by glucose tolerance test. We also measured in vivo glucose uptake in skeletal muscle, insulin sensitivity by insulin tolerance test, plasma insulin levels, hepatic lipids and glycogen.

Results Consistent with previous findings, acute clenbuterol administration increased blood glucose and insulin levels. However, already after 4 days of treatment, beneficial effects of clenbuterol were manifested in glucose homeostasis (32% improvement of glucose tolerance after 4 days of treatment,p < 0.01) and these effects persisted up to 42 days of treatment. These favourable metabolic effects could be achieved with doses as low as 0.025 mg kg(-1) day(-1)(40 times lower than previously studied). Mechanistically, these effects were not due to increased insulin levels, but clenbuterol enhanced glucose uptake in skeletal muscle in vivo both acutely in lean mice (by 64%,p < 0.001) as well as during chronic treatment in diet-induced obese mice (by 74%,p < 0.001). Notably, prolonged treatment with low-dose clenbuterol improved whole-body insulin sensitivity (glucose disposal rate after insulin injection increased up to 1.38 +/- 0.31%/min in comparison with 0.15 +/- 0.36%/min in control mice,p < 0.05) and drastically reduced hepatic steatosis (by 40%,p < 0.01) and glycogen (by 23%,p < 0.05).

Conclusions/interpretation Clenbuterol improved glucose tolerance after 4 days of treatment and these effects were maintained for up to 42 days. Effects were achieved with doses in a clinically relevant microgram range. Mechanistically, prolonged treatment with a low dose of clenbuterol improved glucose homeostasis in insulin resistant mice, most likely by stimulating glucose uptake in skeletal muscle and improving whole-body insulin sensitivity as well as by reducing hepatic lipids and glycogen. We conclude that selective beta(2)-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans.

Place, publisher, year, edition, pages
2020. Vol. 63, no 8, p. 1603-1615
Keywords [en]
beta(2)-Adrenergic signalling, Clenbuterol, Hepatic steatosis, Insulin resistance, Skeletal muscle, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
URN: urn:nbn:se:su:diva-184358DOI: 10.1007/s00125-020-05171-yISI: 000546959500015PubMedID: 32472192OAI: oai:DiVA.org:su-184358DiVA, id: diva2:1473461
Available from: 2020-10-06 Created: 2020-10-06 Last updated: 2022-02-25Bibliographically approved
In thesis
1. Myosin 1c taking adrenergic metabolism for a spin: More than a motor protein
Open this publication in new window or tab >>Myosin 1c taking adrenergic metabolism for a spin: More than a motor protein
2021 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Metabolic diseases like type II diabetes (T2D) and obesity largely stems from an unbalanced energy homeostasis with the fails of the insulin pathway to the point in which the glucose homeostasis is severely disturbed leading to hyperglycemia. We have investigated if the β-adrenergic signaling pathways, in both brown adipose tissue (BAT) and skeletal muscle, could be used as a strategy to alleviate metabolic disease.

As an important protein regulating energy metabolism, Akt has been an interesting target for study also in BAT, but its role in glucose uptake downstream the β-adrenergic receptors (β-ARs) have had conflicting outcomes. We have therefore made efforts to separate Akt and insulin from the β-adrenergic pathway and shown that Akt is not involved in β-adrenergic glucose uptake or thermogenesis in the brown adipocyte and norepinephrine (NE)-driven glucose clearance in vivo (Paper I). We have also shown that a β2-adrenergic agonist, clenbuterol, at low dose, can be used to induce glucose uptake to skeletal muscle, glucose clearance and increase insulin sensitivity in diet-induced obese mice, independently of insulin (Paper II). Administrating an agonist that binds to either the β-ARs on BAT or on skeletal muscle, at low dose to minimize cardiovascular adverse effects, would initiate processes independent of Akt and insulin, and could therefore be administered to patients with T2D to target idle assets.

Further, we have identified Myosin 1c (Myo1c) as a major regulator of basal protein kinase A (PKA) activity and basal glucose uptakein the brown adipocyte (Paper III) and also as a cofactor in chromatin remodeling for uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor gamma coactivator 1α (Pgc1α) transcription in the thermogenic adipocyte (Paper IV). These novel functions of Myo1c will open up the possibilities for future explorations concerning motor proteins in thermogenic adipocytes.

This thesis has expanded current understanding about the independence of Akt and insulin in β-adrenergic metabolism as well as identifying Myo1c as a key component of the β-adrenergic pathway in the thermogenic adipocyte. The work presented herein will hopefully contribute to further exploration into adrenergic signaling in BAT and skeletal muscle.

Place, publisher, year, edition, pages
Stockholm: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, 2021. p. 75
Keywords
Glucose uptake, Glucose transporter, Brown adipose tissue, White adipose tissue, Skeletal muscle, Myosin1c, Nuclear myosin I, Physiology
National Category
Physiology
Research subject
Molecular Bioscience
Identifiers
urn:nbn:se:su:diva-199057 (URN)978-91-7911-714-6 (ISBN)978-91-7911-715-3 (ISBN)
Public defence
2022-01-21, Vivi Täckholmsalen (Q-salen), NPQ-huset, Svante Arrhenius väg 20, and online via Zoom, public link is available at the department website, Stockholm, 14:00 (English)
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Available from: 2021-12-21 Created: 2021-11-28 Last updated: 2022-02-25Bibliographically approved

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Kalinovich, AnastasiaDehvari, NodiÅslund, AliceHalleskog, CarinaOlsen, JessicaRinde, MiaSandström, AnnaBengtsson, Tore

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