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Role of ?-adrenoceptors in glucose uptake in astrocytes using ?-adrenoceptor knockout mice.

ABSTRACT: BACKGROUND AND PURPOSE: ?(1) -, ?(2) - and ?(3) -adrenoceptors determined by functional, binding and reverse transcription polymerase chain reaction (RT-PCR) studies are present in chick astrocytes and activation of ?(2) - or ?(3) -adrenoceptors increase glucose uptake. The aims of the present study are to identify which ?-adrenoceptor subtypes are present in mouse astrocytes, the signal transduction mechanisms involved and whether ?-adrenoceptor stimulation regulates glucose uptake. EXPERIMENTAL APPROACH: Astrocytes were prepared from four mouse strains: FVB/N, DBA/1 crossed with C57BL/6J, ?(3) -adrenoceptor knockout and ?(1) ?(2) -adrenoceptor knockout mice. RT-PCR and radioligand binding studies were used to determine ?-adrenoceptor expression. Glucose uptake and cAMP were assayed to elucidate the signalling pathways involved. KEY RESULTS: mRNAs for all three ?-adrenoceptors were identified in astrocytes from wild-type mice. Radioligand binding studies identified that ?(1) - and ?(3) -adrenoceptors were predominant. cAMP studies showed that ?(1) - and ?(2) -adrenoceptors coupled to G(s) whereas ?(3) -adrenoceptors coupled to both G(s) and G(i) . However, activation of any of the three ?-adrenoceptors increased glucose uptake in mouse astrocytes. Interestingly, there was no functional compensation for receptor subtype loss in knockout animals. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that although ?(1) -adrenoceptors are the predominant ?-adrenoceptor in mouse astrocytes and are primarily responsible for cAMP production in response to ?-adrenoceptor stimulation, ?(3) -adrenoceptors are also present in mouse astrocytes and activation of ?(2) - and ?(3) -adrenoceptors increases glucose uptake in mouse astrocytes.

SUBMITTER: Catus SL

PROVIDER: S-EPMC3081115 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Role of β-adrenoceptors in glucose uptake in astrocytes using β-adrenoceptor knockout mice.

Catus Stephanie L SL Gibbs Marie E ME Sato Masaaki M Summers Roger J RJ Hutchinson Dana S DS

British journal of pharmacology 20110401 8

<h4>Background and purpose</h4>β(1) -, β(2) - and β(3) -adrenoceptors determined by functional, binding and reverse transcription polymerase chain reaction (RT-PCR) studies are present in chick astrocytes and activation of β(2) - or β(3) -adrenoceptors increase glucose uptake. The aims of the present study are to identify which β-adrenoceptor subtypes are present in mouse astrocytes, the signal transduction mechanisms involved and whether β-adrenoceptor stimulation regulates glucose uptake.<h4>E ...[more]

PMID: 21138422

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Project description:Aims/hypothesisChronic stimulation of β2-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 β2-adrenoceptors. In the current study we further explored the potential therapeutic relevance of β2-adrenoceptor stimulation to improve glucose homeostasis and the mechanisms responsible for the effect.MethodsC57Bl/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.ResultsConsistent 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/interpretationClenbuterol 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 β2-adrenergic agonists might be an attractive potential treatment for type 2 diabetes. This remains to be confirmed in humans. Graphical abstract.

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Role of ?-adrenoceptors in glucose uptake in astrocytes using ?-adrenoceptor knockout mice.

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Role of β-adrenoceptors in glucose uptake in astrocytes using β-adrenoceptor knockout mice.

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