| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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| 4. |
- 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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| 5. |
- 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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| 6. |
- 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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| 7. |
- 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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| 8. |
- Mukaida, Saori, et al.
(författare)
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BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via beta(2)-adrenoceptors without causing classical receptor desensitization
- 2019
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Ingår i: American Journal of Physiology. Regulatory Integrative and Comparative Physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 316:5, s. R666-R677
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Tidskriftsartikel (refereegranskat)abstract
- The type 2 diabetes epidemic makes it important to find insulinin-dependent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual beta(2)-/beta(3)-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, beta(2)-adrenoceptor desensitization, beta-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of beta(2)-adrenoceptors, with a similar potency and efficacy to that of the nonselective beta-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit beta-arrestin1/2 to the beta(2)-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a beta(2)-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.
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| 9. |
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