| 1. |
- Chia, Ling Yeong, et al.
(författare)
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Adrenoceptor regulation of the mechanistic target of rapamycin in muscle and adipose tissue
- 2019
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:14, s. 2433-2448
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Forskningsöversikt (refereegranskat)abstract
- A vital role of adrenoceptors in metabolism and energy balance has been well documented in the heart, skeletal muscle, and adipose tissue. It has been only recently demonstrated, however, that activation of the mechanistic target of rapamycin (mTOR) makes a significant contribution to various metabolic and physiological responses to adrenoceptor agonists. mTOR exists as two distinct complexes named mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) and has been shown to play a critical role in protein synthesis, cell proliferation, hypertrophy, mitochondrial function, and glucose uptake. This review will describe the physiological significance of mTORC1 and 2 as a novel paradigm of adrenoceptor signalling in the heart, skeletal muscle, and adipose tissue. Understanding the detailed signalling cascades of adrenoceptors and how they regulate physiological responses is important for identifying new therapeutic targets and identifying novel therapeutic interventions. Linked Articles This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc
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| 2. |
- Dehvari, Nodi, et al.
(författare)
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The metabolic effects of mirabegron are mediated primarily by beta(3)-adrenoceptors
- 2020
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Ingår i: Pharmacology Research & Perspectives. - : Wiley. - 2052-1707. ; 8:5
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Tidskriftsartikel (refereegranskat)abstract
- The beta(3)-adrenoceptor agonist mirabegron is approved for use for overactive bladder and has been purported to be useful in the treatment of obesity-related metabolic diseases in humans, including those involving disturbances of glucose homeostasis. We investigated the effect of mirabegron on glucose homeostasis with in vitro and in vivo models, focusing on its selectivity at beta-adrenoceptors, ability to cause browning of white adipocytes, and the role of UCP1 in glucose homeostasis. In mouse brown, white, and brite adipocytes, mirabegron-mediated effects were examined on cyclic AMP, UCP1 mRNA, [H-3]-2-deoxyglucose uptake, cellular glycolysis, and O(2)consumption. Mirabegron increased cyclic AMP levels, UCP1 mRNA content, glucose uptake, and cellular glycolysis in brown adipocytes, and these effects were either absent or reduced in white adipocytes. In brite adipocytes, mirabegron increased cyclic AMP levels and UCP1 mRNA content resulting in increased UCP1-mediated oxygen consumption, glucose uptake, and cellular glycolysis. The metabolic effects of mirabegron in both brown and brite adipocytes were primarily due to actions at beta(3)-adrenoceptors as they were largely absent in adipocytes derived from beta(3)-adrenoceptor knockout mice. In vivo, mirabegron increased whole body oxygen consumption, glucose uptake into brown and inguinal white adipose tissue, and improved glucose tolerance, all effects that required the presence of the beta(3)-adrenoceptor. Furthermore, in UCP1 knockout mice, the effects of mirabegron on glucose tolerance were attenuated. Thus, mirabegron had effects on cellular metabolism in adipocytes that improved glucose handling in vivo, and were primarily due to actions at the beta(3)-adrenoceptor.
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| 3. |
- Dehvari, Nodi, et al.
(författare)
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β2‐Adrenoceptors increase translocation of GLUT4 via GPCR kinase sites in the receptor C‐terminal tail
- 2012
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 165:5, s. 1442-1456
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSEbeta-Adrenoceptor stimulation induces glucose uptake in several insulin-sensitive tissues by poorly understood mechanisms.EXPERIMENTAL APPROACHWe used a model system in CHO-K1 cells expressing the human beta(2)-adrenoceptor and glucose transporter 4 (GLUT4) to investigate the signalling mechanisms involved.KEY RESULTSIn CHO-K1 cells, there was no response to b-adrenoceptor agonists. The introduction of b2-adrenoceptors and GLUT4 into these cells caused increased glucose uptake in response to beta-adrenoceptor agonists. GLUT4 translocation occurred in response to insulin and beta(2)-adrenoceptor stimulation, although the key insulin signalling intermediate PKB was not phosphorylated in response to beta(2)-adrenoceptor stimulation. Truncation of the C-terminus of the beta(2)-adrenoceptor at position 349 to remove known phosphorylation sites for GPCR kinases (GRKs) or at position 344 to remove an additional PKA site together with the GRK phosphorylation sites did not significantly affect cAMP accumulation but decreased beta(2)-adrenoceptor-stimulated glucose uptake. Furthermore, inhibition of GRK by transfection of the bARKct construct inhibited beta(2)-adrenoceptor-mediated glucose uptake and GLUT4 translocation, and overexpression of a kinase-dead GRK2 mutant (GRK2 K220R) also inhibited GLUT4 translocation. Introducing beta(2)-adrenoceptors lacking phosphorylation sites for GRK or PKA demonstrated that the GRK sites, but not the PKA sites, were necessary for GLUT4 translocation.CONCLUSIONS AND IMPLICATIONSGlucose uptake in response to activation of beta(2)-adrenoceptors involves translocation of GLUT4 in this model system. The mechanism is dependent on the C-terminus of the beta(2)-adrenoceptor, requires GRK phosphorylation sites, and involves a signalling pathway distinct from that stimulated by insulin.
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| 4. |
- Evans, Bronwyn A., et al.
(författare)
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Adrenoceptors in white, brown, and brite adipocytes
- 2019
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Ingår i: British Journal of Pharmacology. - : Wiley. - 0007-1188 .- 1476-5381. ; 176:14, s. 2416-2432
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Forskningsöversikt (refereegranskat)abstract
- Adrenoceptors play an important role in adipose tissue biology and physiology that includes regulating the synthesis and storage of triglycerides (lipogenesis), the breakdown of stored triglycerides (lipolysis), thermogenesis (heat production), glucose metabolism, and the secretion of adipocyte-derived hormones that can control whole-body energy homeostasis. These processes are regulated by the sympathetic nervous system through actions at different adrenoceptor subtypes expressed in adipose tissue depots. In this review, we have highlighted the role of adrenoceptor subtypes in white, brown, and brite adipocytes in both rodents and humans and have included detailed analysis of adrenoceptor expression in human adipose tissue and clonally derived adipocytes. We discuss important considerations when investigating adrenoceptor function in adipose tissue or adipocytes.
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| 5. |
- Ham, Seungmin, et al.
(författare)
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Role of G protein-coupled receptor kinases (GRKs) in β2-adrenoceptor-mediated glucose uptake
- 2024
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Ingår i: Pharmacology Research & Perspectives. - 2052-1707. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Truncation of the C-terminal tail of the beta(2)-AR, transfection of beta ARKct or over-expression of a kinase-dead GRK mutant reduces isoprenaline-stimulated glucose uptake, indicating that GRK is important for this response. We explored whether phosphorylation of the beta(2)-AR by GRK2 has a role in glucose uptake or if this response is related to the role of GRK2 as a scaffolding protein. CHO-GLUT4myc cells expressing wild-type and mutant beta(2)-ARs were generated and receptor affinity for [H-3]-CGP12177A and density of binding sites determined together with the affinity of isoprenaline and BRL37344. Following receptor activation by beta(2)-AR agonists, cAMP accumulation, GLUT4 translocation, [H-3]-2-deoxyglucose uptake, and beta(2)-AR internalization were measured. Bioluminescence resonance energy transfer was used to investigate interactions between beta(2)-AR and beta-arrestin2 or between beta(2)-AR and GRK2. Glucose uptake after siRNA knockdown or GRK inhibitors was measured in response to beta(2)-AR agonists. BRL37344 was a poor partial agonist for cAMP generation but displayed similar potency and efficacy to isoprenaline for glucose uptake and GLUT4 translocation. These responses to beta(2)-AR agonists occurred in CHO-GLUT4myc cells expressing beta(2)-ARs lacking GRK or GRK/PKA phosphorylation sites as well as in cells expressing the wild-type beta(2)-AR. However, beta(2)-ARs lacking phosphorylation sites failed to recruit beta-arrestin2 and did not internalize. GRK2 knock-down or GRK2 inhibitors decreased isoprenaline-stimulated glucose uptake in rat L6 skeletal muscle cells. Thus, GRK phosphorylation of the beta(2)-AR is not associated with isoprenaline- or BRL37344-stimulated glucose uptake. However, GRKs acting as scaffold proteins are important for glucose uptake as GRK2 knock-down or GRK2 inhibition reduces isoprenaline-stimulated glucose uptake.
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| 6. |
- Merlin, Jon, et al.
(författare)
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Could burning fat start with a brite spark? Pharmacological and nutritional ways to promote thermogenesis
- 2016
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Ingår i: Molecular Nutrition & Food Research. - : Wiley. - 1613-4125 .- 1613-4133. ; 60:1, s. 18-42
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Forskningsöversikt (refereegranskat)abstract
- There are two types of adipose tissue with distinct functions-white adipose tissue stores chemical energy as triglycerides, whereas brown adipose tissue consumes energy and releases heat (thermogenesis) in response to sympathetic nerve activity. In humans, treatments that promote greater brown adipose tissue deposition and/or activity would be highly beneficial in regimes aimed at reducing obesity. Adult humans have restricted populations of prototypical brown adipocytes in the neck and chest areas, but recent advances have established that adipocytes with similar properties, termed brite adipocytes, can be recruited in subcutaneous depots thought to be primarily white adipose tissue. These brite adipocytes express the protein machinery required for thermogenesis, but to assess brite adipocytes as viable therapeutic targets we need to understand how to promote conversion of white adipocytes to brite adipocytes and ways to increase optimal energy consumption and thermogenesis in these brite adipocytes. This can be accomplished by pharmacological and nutritional therapies to differing degrees, as reviewed in detail here.
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| 7. |
- Merlin, Jon, et al.
(författare)
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Rosiglitazone and a beta(3)-Adrenoceptor Agonist Are Both Required for Functional Browning of White Adipocytes in Culture
- 2018
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Ingår i: Frontiers in Endocrinology. - : Frontiers Media SA. - 1664-2392. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- The recruitment of brite (or beige) adipocytes has been advocated as a means to combat obesity, due to their ability to phenotypically resemble brown adipocytes (BA). Lineage studies indicate that brite adipocytes are formed by differentiation of precursor cells or by direct conversion of existing white adipocytes, depending on the adipose depot examined. We have systematically compared the gene expression profile and a functional output (oxygen consumption) in mouse adipocytes cultured from two contrasting depots, namely interscapular brown adipose tissue, and inguinal white adipose tissue (iWAT), following treatment with a known browning agent, the peroxisome proliferator-activated receptor (PPAR gamma) activator rosiglitazone. Prototypical BA readily express uncoupling protein (UCP)1, and upstream regulators including the beta(3)-adrenoceptor and transcription factors involved in energy homeostasis. Adipocytes from inguinal WAT display maximal UCP1 expression and mitochondrial uncoupling only when treated with a combination of the PPAR. activator rosiglitazone and a beta(3)-adrenoceptor agonist. In conclusion, brite adipocytes are fully activated only when a browning agent (rosiglitazone) and a thermogenic agent (beta(3)-adrenoceptor agonist) are added in combination. The presence of rosiglitazone throughout the 7-day culture period partially masks the effects of beta(3)-adrenoceptor signaling in inguinal white adipocyte cultures, whereas including rosiglitazone only for the first 3 days promotes robust beta(3)-adrenoceptor expression and provides an improved window for detection of beta(3)-adrenoceptor responses.
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| 8. |
- Merlin, Jon, et al.
(författare)
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The M3-muscarinic acetylcholine receptor stimulates glucose uptake in L6 skeletal muscle cells by a CaMKK-AMPK-dependent mechanism
- 2010
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 22:7, s. 1104-13
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Tidskriftsartikel (refereegranskat)abstract
- The role of muscarinic acetylcholine receptors (mAChRs) in regulating glucose uptake in L6 skeletal muscle cells was investigated. [(3)H]-2-Deoxyglucose uptake was increased in differentiated L6 cells by insulin, acetylcholine, oxotremorine-M and carbachol. mAChR-mediated glucose uptake was inhibited by the AMPK inhibitor Compound C. Whole cell radioligand binding using [(3)H]-N-methyl scopolamine chloride identified mAChRs in differentiated but not undifferentiated L6 cells and M(3) mAChR mRNA was detected only in differentiated cells. M(3) mAChRs are Gq-coupled, and cholinergic stimulation by the mAChR agonists acetylcholine, oxotremorine-M and carbachol increased Ca(2+) in differentiated but not undifferentiated L6 cells. This was due to muscarinic but not nicotinic activation as responses were antagonised by the muscarinic antagonist atropine but not the nicotinic antagonist tubocurarine. Western blotting showed that both carbachol and the AMPK activator AICAR increased phosphorylation of the AMPKalpha subunit at Thr172, with responses to carbachol blocked by Compound C and the CaMKK inhibitor STO609 but not by the PI3K inhibitor wortmannin. AICAR-stimulated AMPK phosphorylation was not sensitive to STO-609, confirming that this compound inhibits CaMKK but not the classical AMPK kinase LKB1. The TAK1 inhibitor (5Z)-7-oxozeaenol and the G(i) inhibitor pertussis toxin both failed to block AMPK phosphorylation in response to carbachol. Using CHO-K1 cells stably expressing each of the mAChR subtypes (M(1)-M(4)), it was determined that only the M(1) and M(3) mAChRs phosphorylate AMPK, confirming a G(q)-dependent mechanism. This study demonstrates that activation of M(3) mAChRs in L6 skeletal muscle cells stimulates glucose uptake via a CaMKK-AMPK-dependent mechanism, independent of the insulin-stimulated pathway.
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| 9. |
- Merlin, Jon, et al.
(författare)
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The PPAR gamma agonist rosiglitazone promotes the induction of brite adipocytes, increasing beta-adrenoceptor-mediated mitochondrial function and glucose uptake
- 2018
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Ingår i: Cellular Signalling. - : Elsevier BV. - 0898-6568 .- 1873-3913. ; 42, s. 54-66
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Tidskriftsartikel (refereegranskat)abstract
- Recruitment and activation of brite (or beige) adipocytes has been advocated as a potential avenue for manipulating whole-body energy expenditure. Despite numerous studies illustrating the differences in gene and protein markers between brown, brite and white adipocytes, there is very little information on the adrenergic regulation and function of these brite adipocytes. We have compared the functional (cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, extracellular acidification rates, calcium influx) profiles of mouse adipocytes cultured from three contrasting depots, namely interscapular brown adipose tissue, and inguinal or epididymal white adipose tissues, following chronic treatment with the peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist rosiglitazone. Prototypical brown adipocytes readily express beta(3)-adrenoceptors, and beta(3)-adrenoceptor stimulation increases cyclic AMP accumulation, oxygen consumption rates, mitochondrial function, glucose uptake, and extracellular acidification rates. Treatment of brown adipocytes with rosiglitazone increases uncoupling protein 1 (UCP1) levels, and increases beta(3)-adrenoceptor mitochondrial function but does not affect glucose uptake responses. In contrast, inguinal white adipocytes only express UCP1 and beta(3)-adrenoceptors following rosiglitazone treatment, which results in an increase in all beta(3)-adrenoceptor-mediated functions. The effect of rosiglitazone in epididymal white adipocytes, was much lower compared to inguinal white adipocytes. Rosiglitazone also increased alpha(1)-adrenoceptor mediated increases in calcium influx and glucose uptake (but not mitochondrial function) in inguinal and epididymal white adipocytes. In conclusion, the PPAR gamma agonist rosiglitazone promotes the induction and function of brite adipocytes cultured from inguinal and epididymal white adipose depots.
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| 10. |
- Mukaida, Saori, et al.
(författare)
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Adrenoceptors promote glucose uptake into adipocytes and muscle by an insulin-independent signaling pathway involving mechanistic target of rapamycin complex 2
- 2017
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Ingår i: Pharmacological Research. - : Elsevier BV. - 1043-6618 .- 1096-1186. ; 116, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- Uptake of glucose into skeletal muscle and adipose tissue plays a vital role in metabolism and energy balance. Insulin released from beta-islet cells of the pancreas promotes glucose uptake in these target tissues by stimulating translocation of CLUT4 transporters to the cell surface. This process is complex, involving signaling proteins including the mechanistic (or mammalian) target of rapamycin (mTOR) and Akt that intersect with multiple pathways controlling cell survival, growth and proliferation. mTOR exists in two forms, mTOR complex 1 (mTORC1), and mTOR complex 2 (mTORC2). mTORC1 has been intensively studied, acting as a key regulator of protein and lipid synthesis that integrates cellular nutrient availability and energy balance. Studies on mTORC2 have focused largely on its capacity to activate Akt by phosphorylation at Ser473, however recent findings demonstrate a novel role for mTORC2 in cellular glucose uptake. For example, agonists acting at beta(2)-adrenoceptors (ARs) in skeletal muscle or beta(3)-ARs in brown adipose tissue increase glucose uptake in vitro and in vivo via mechanisms dependent on mTORC2 but not Akt. In this review, we will focus on the signaling pathways downstream of beta-ARs that promote glucose uptake in skeletal muscle and brown adipocytes, and will highlight how the insulin and adrenergic pathways converge and interact in these cells. The identification of insulin-independent mechanisms that promote glucose uptake should facilitate novel treatment strategies for metabolic disease.
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