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3. The [beta]3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans

Author

Finlin, Brian S., Memetimin, Hasiyet, Zhu, Beibei, Confides, Amy L., Vekaria, Hemendra J., Khouli, Riham H. El, Johnson, Zachary R., Westgate, Philip M., Chen, Jianzhong, Morris, Andrew J., Sullivan, Patrick G., Dupont-Versteegden, Esther E., and Kern, Philip A.

Subjects
Obesity, Homeostasis, Mirabegron, Glucose, Skeletal muscle, Diabetes therapy, Glycosylated hemoglobin, Adipose tissue, Insulin, Gene expression, Biochemistry, Criminal investigation, CAT scans, Genetic research, Genes, Macrophages, Hemoglobins, Triglycerides, Health care industry
Abstract

BACKGROUND. Beige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains [beta]3-adrenergic receptors ([beta]3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the [beta]3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis. METHODS. Before and after [beta]3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle. RESULTS. The clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and [beta] cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in [beta] cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPAR[gamma] coactivator 1 [alpha] (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001). CONCLUSION. Mirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulinresistant humans. Since [beta] cells and skeletal muscle do not express [beta]3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves [beta] cell function. TRIAL REGISTRATION. Clinicaltrials.gov NCT02919176. FUNDING. NIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998., Introduction The [beta]3-adrenergic receptor ([beta]3-AR) has long been a therapeutic target to combat obesity and metabolic disease. Since the [beta]3-AR is present in adipose tissue, but not in most other [...]

Published
2020
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8. Aldose reductase promotes diet‐induced obesity via induction of senescence in subcutaneous adipose tissue

Author

Thiagarajan, Devi, primary, Quadri, Nosirudeen, additional, Jawahar, Shabnam, additional, Zirpoli, Hylde, additional, del Pozo, Carmen Hurtado, additional, López‐Díez, Raquel, additional, Hasan, Syed Nurul, additional, Yepuri, Gautham, additional, Gugger, Paul F., additional, Finlin, Brian S., additional, Kern, Philip A., additional, Gabbay, Kenneth, additional, Schmidt, Ann Marie, additional, and Ramasamy, Ravichandran, additional

Published
2022
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11. Pioglitazone does not synergize with mirabegron to increase beige fat or further improve glucose metabolism

Author

Finlin, Brian S., primary, Memetimin, Hasiyet, additional, Zhu, Beibei, additional, Confides, Amy L., additional, Vekaria, Hemendra J., additional, El Khouli, Riham H., additional, Johnson, Zachary R., additional, Westgate, Philip M., additional, Chen, Jianzhong, additional, Morris, Andrew J., additional, Sullivan, Patrick G., additional, Dupont-Versteegden, Esther E., additional, and Kern, Philip A., additional

Published
2021
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12. L-type calcium channel [alpha]-subunit and protein kinase inhibitors modulate Rem-mediated regulation of current

Author

Crump, Shawn M., Correll, Robert N., Schroder, Elizabeth A., Lester, William C., Finlin, Brian S., Andres, Douglas A., and Satin, Jonathan

Subjects
Calcium channels -- Physiological aspects, Pancreatic beta cells -- Research, Protein kinases -- Research, Biological sciences
Abstract

Cardiac voltage-gated L-type Ca channels ([Ca.sub.v]) are multiprotein complexes, including accessory subunits such as [Ca.sub.v][beta]2 that increase current expression. Recently, members of the Rad and Gem/Kir-related family of small GTPases have been shown to decrease current, although the mechanism remains poorly defined. In this study, we evaluated the contribution of the L-type Ca channel [alpha]-subunit ([Ca.sub.v]1.2) to [Ca.sub.v][beta]2-Rem inhibition of Ca channel current. Specifically, we addressed whether protein kinase A (PKA) modulation of the Ca channel modifies [Ca.sub.v][beta]2-Rem inhibition of Ca channel current. We first tested the effect of Rem on [Ca.sub.v]1.2 in human embryonic kidney 293 (HEK-293) cells using the whole cell patch-clamp configuration. Rem coexpression with [Ca.sub.v]1.2 reduces Ba current expression under basal conditions, and [Ca.sub.v][beta]2a coexpression enhances Rem block of [Ca.sub.v]1.2 current. Surprisingly, PKA inhibition by 133 nM H-89 or 50 [micro]M Rp-cAMP-S partially relieved the Rem-mediated inhibition of current activity both with and without [Ca.sub.v][beta]2a. To test whether the H-89 action was a consequence of the phosphorylation status of [Ca.sub.v]1.2, we examined Rem regulation of the PKA-insensitive [Ca.sub.v]1.2 serine 1928 (S1928) to alanine mutation ([Ca.sub.v]1.2-S1928A). [Ca.sub.v]1.2-S1928A current was not inhibited by Rem and when coexpression with [Ca.sub.v][beta]2a was not completely blocked by Rem coexpression, suggesting that the phosphorylation of S1928 contributes to Rem-mediated Ca channel modulation. As a model for native Ca channel complexes, we tested the ability of Rem overexpression in HIT-T15 cells and embryonic ventricular myocytes to interfere with native current. We find that native current is also sensitive to Rem block and that H-89 pretreatment relieves the ability of Rem to regulate Ca current. We conclude that Rem is capable of regulating L-type current, that release of Rem block is modulated by cellular kinase pathways, and that the [Ca.sub.v] 1.2 COOH terminus contributes to Rem-dependent channel inhibition. cardiac myocyte; monomeric GTPase; Rad and Gem/Kir-related family; insulin-secreting cell; calcium imaging; heart development

Published
2006

15. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans

Author

Finlin, Brian S., primary, Memetimin, Hasiyet, additional, Zhu, Beibei, additional, Confides, Amy L., additional, Vekaria, Hemendra J., additional, El Khouli, Riham H., additional, Johnson, Zachary R., additional, Westgate, Philip M., additional, Chen, Jianzhong, additional, Morris, Andrew J., additional, Sullivan, Patrick G., additional, Dupont-Versteegden, Esther E., additional, and Kern, Philip A., additional

Published
2020
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21. Human adipose beiging in response to cold and mirabegron

Author

Finlin, Brian S., primary, Memetimin, Hasiyet, additional, Confides, Amy L., additional, Kasza, Ildiko, additional, Zhu, Beibei, additional, Vekaria, Hemendra J., additional, Harfmann, Brianna, additional, Jones, Kelly A., additional, Johnson, Zachary R., additional, Westgate, Philip M., additional, Alexander, Caroline M., additional, Sullivan, Patrick G., additional, Dupont-Versteegden, Esther E., additional, and Kern, Philip A., additional

Published
2018
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28. Insulin-resistant subjects have normal angiogenic response to aerobic exercise training in skeletal muscle, but not in adipose tissue

Author

Walton, R. Grace, primary, Finlin, Brian S., additional, Mula, Jyothi, additional, Long, Douglas E., additional, Zhu, Beibei, additional, Fry, Christopher S., additional, Westgate, Philip M., additional, Lee, Jonah D., additional, Bennett, Tamara, additional, Kern, Philip A., additional, and Peterson, Charlotte A., additional

Published
2015
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29. Increasing Adipocyte Lipoprotein Lipase Improves Glucose Metabolism in High Fat Diet-induced Obesity

Author

Walton, R. Grace, primary, Zhu, Beibei, additional, Unal, Resat, additional, Spencer, Michael, additional, Sunkara, Manjula, additional, Morris, Andrew J., additional, Charnigo, Richard, additional, Katz, Wendy S., additional, Daugherty, Alan, additional, Howatt, Deborah A., additional, Kern, Philip A., additional, and Finlin, Brian S., additional

Published
2015
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36. Regulation of Small Ubiquitin-Like Modifier-1, Nuclear Receptor Coreceptor, Histone Deacetylase 3, and Peroxisome Proliferator-Activated Receptor-γ in Human Adipose Tissue

Author

Finlin, Brian S., primary, Bodles-Brakhop, Angela M., additional, Yao-Borengasser, Aiwei, additional, Zhu, Beibei, additional, Starnes, Catherine P., additional, McGehee, Robert E., additional, Peterson, Charlotte A., additional, Kern, Philip A., additional, and Rasouli, Neda, additional

Published
2012
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43. RERG Is a Novel ras-related, Estrogen-regulated and Growth-inhibitory Gene in Breast Cancer

Author

Finlin, Brian S., primary, Gau, Chia-Ling, additional, Murphy, Gretchen A., additional, Shao, Haipeng, additional, Kimel, Tracy, additional, Seitz, Robert S., additional, Chiu, Yen-Feng, additional, Botstein, David, additional, Brown, Patrick O., additional, Der, Channing J., additional, Tamanoi, Fuyuhiko, additional, Andres, Douglas A., additional, and Perou, Charles M., additional

Published
2001
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44. The Metabolic Labeling and Analysis of Isoprenylated Proteins.

Author

Walker, John M., Andres, Douglas A., Crick, Dean C., Finlin, Brian S., and Waechter, Charles J.

Abstract

The posttranslational modification of proteins by the covalent attachment of farnesyl and geranylgeranyl groups to cysteine residues at or near the carboxyl-(C)-terminus via a thioether bond is now well established in mammalian cells (1-6). Most isoprenylated proteins are thought to serve as regulators of cell signaling and membrane trafficking. Farnesylation and geranylgeranylation of the cysteinyl residues has been shown to promote both protein-protein and protein-membrane interactions (6-8). Isoprenylation, and in some cases the subsequent palmitoylation, provide a mechanism for the membrane association of polypeptides that lack a transmembrane domain, and appear to be prerequisite for their in vivo activity (6,9,10). [ABSTRACT FROM AUTHOR]

Published
2002
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49. Rapid Identification of Cysteine-Linked Isoprenyl Groups by Metabolic Labeling with [3H]Farnesol and [3H]Geranylgeraniol.

Author

Walker, John M., Gelb, Michael H., Andres, Douglas A., Crick, Dean C., Finlin, Brian S., and Waechter, Charles J.

Abstract

The posttranslational modification of proteins by the covalent attachment of farnesyl and geranylgeranyl groups to cysteine residues at or near the C-terminus via a thioether bond is now well established in mammalian cells (1-6). Most isoprenylated proteins are thought to serve as regulators of cell signaling and membrane trafficking. Farnesylation and geranylgeranylation of the cysteinyl residues have been shown to promote both protein-protein and protein-membrane interactions (6-8). Isoprenylation, and, in some cases, the subsequent palmitoylation, provide a mechanism for the membrane association of polypeptides, which lack a transmembrane domain, and appear to be prerequisite for their in vivo activity (6,9,10). [ABSTRACT FROM AUTHOR]

Published
1999
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50. Analysis of the Complex between Ca2+ Channel β-Subunit and the Rem GTPase.

Author

Finlin, Brian S., Correll, Robert N., Chunyan Pang, Crump, Shawn M., Satin, Jonathan, and Andres, Douglas A.

Subjects
*CALCIUM channels, *ION channels, *GUANOSINE triphosphatase, *PHOSPHATASES, *CELL membranes, *BIOLOGICAL membranes
Abstract

Voltage-gated calcium channels are multiprotein complexes that regulate calcium influx and are important contributors to cardiac excitability and contractility. The auxiliary β-subunit (Cavβ) binds a conserved domain (the a-interaction domain (AID)) of the pore-forming Cavα1 subunit to modulate channel gating properties and promote cell surface trafficking. Recently, members of the RGK family of small GTPases (Rem, Rem2, Rad, Gem/Kir) have been identified as novel contributors to the regulation of L-type calcium channel activity. Here, we describe the Rem-association domain within Cavβ2a. The Rem interaction module is located in a ~130-residue region within the highly conserved guanylate kinase domain that also directs AID binding. Importantly, Cavβ mutants were identified that lost the ability to bind AID but retained their association with Rem, indicating that the AID and Rem association sites of Cavβ2a are structurally distinct. In vitro binding studies indicate that the affinity of Rem for Cavβ2a interaction is lower than that of AID for Cavβ2a. Furthermore, in vitro binding studies indicate that Rem association does not inhibit the interaction of Cavβ2a with AID. Instead, Cavβ can simultaneously associate with both Rem and Cavα1-AID. Previous studies had suggested that RGK proteins may regulate Ca2+ channel activity by blocking the association of Cavβ subunits with Cavα1 to inhibit plasma membrane trafficking. However, surface biotinylation studies in HIT-T15 cells indicate that Rem can acutely modulate channel function without decreasing the density of L-type channels at the plasma membrane. Together these data suggest that Rem-dependent Ca2+ channel modulation involves formation of a RemCavfrAID regulatory complex without the need to disrupt Cavα1·Cavβ association or alter Cavα1 expression at the plasma membrane. [ABSTRACT FROM AUTHOR]

Published
2006
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