The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists

Arch, Jonathan R. S.

doi:10.1007/s00210-008-0271-1

Cited by 99Regulation of Appetite and ObesityPharmacology and Obesity TreatmentReceptor Mechanisms and Signaling

The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists

Arch, Jonathan R. S.·2008·Naunyn-Schmiedeberg's Archives of Pharmacology

DOI 10.1007/s00210-008-0271-1

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Abstract

Although beta3-adrenoceptor (beta3AR) agonists have not become drugs for the treatment of obesity or diabetes, they offer perspectives on obesity drug discovery, the physiology of energy expenditure and receptor pharmacology. beta3AR agonists, some of which also stimulate other betaARs in humans, selectively stimulate fat oxidation in rodents and humans. This appears to be why they improve insulin sensitivity and reduce body fat whilst preserving lean body mass. Regulatory authorities ask that novel anti-obesity drugs improve insulin sensitivity and reduce mainly body fat. Drugs that act on different targets to stimulate fat oxidation may also offer these benefits. Stimulation of energy expenditure may be easy to detect only when the sympathetic nervous system is activated. Leptin resembles beta3AR agonists in that it increases fat oxidation, energy expenditure and insulin sensitivity. This is partly because it raises sympathetic activity, but it may also promote fat oxidation by directly stimulating muscle leptin receptors. The beta1AR and beta2AR can, like the beta3AR, display atypical pharmacologies. Moreover, the beta3AR can display variable pharmacologies of its own, depending on the radioligand used in binding studies or the functional response measured. Studies on the beta3AR demonstrate both the difficulties of predicting the in vivo effects of agonist drugs from in vitro data and that there may be opportunities for identifying drugs that act at a single receptor but have different profiles in vivo.

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A second generation of β3 agonists with better binding properties had poor oral bioavailability or unfavorable pharmacokinetics.
“A second generation of β3 agonists with better binding properties had poor oral bioavailability or unfavorable pharmacokinetics 141.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [141]
The effect of L-796568 seemed to be lost after 28 days of treatment.
“One β3 agonist, L-796568, increased lipolysis and energy expenditure in overweight men acutely 142, but its effect seemed to be lost after 28 days of treatment 79,141.”
From Cellular bioenergetics as a target for obesity therapy (2010) · cites this paper as [141]

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A within-trial cost-effectiveness analysis of primary care referral to a commercial provider for weight loss treatment, relative to standard care—an international randomised controlled trial
Fuller, N. R., Colagiuri, S., SCHOFIELD, D. J., Olson, A. D., Shrestha, R. N., Holzapfel, C., Wolfenstetter, S. B., Holle, R., Ahern, A. L., Hauner, H., et al. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.139 · Cited by 2,125 · see citing works
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Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat
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Polymorphic Variants of Adrenoceptors: Pharmacology, Physiology, and Role in Disease
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Nebivolol Improves Diastolic Dysfunction and Myocardial Remodeling Through Reductions in Oxidative Stress in the Zucker Obese Rat
Zhou, X., Ma, L., Habibi, J., Whaley-Connell, A., Hayden, M. R., Tilmon, R. D., Brown, A. N., Kim, J.-A., DeMarco, V. G., & Sowers, J. R. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.145136 · Cited by 116 · see citing works
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G Protein–Coupled Receptors Targeting Insulin Resistance, Obesity, and Type 2 Diabetes Mellitus
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Mechanisms underlying current and future anti-obesity drugs
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β-Adrenergic Receptors and Adipose Tissue Metabolism: Evolution of an Old Story
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Gene expression in human brown adipose tissue
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Hypothalamic Obesity in Craniopharyngioma Patients: Disturbed Energy Homeostasis Related to Extent of Hypothalamic Damage and Its Implication for Obesity Intervention
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Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome
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Current and Future Drug Targets in Weight Management
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Human brown adipose tissue as a target for obesity management; beyond cold‐induced thermogenesis
Loh, R. K. C., Kingwell, B. A., & Carey, A. L. (2017) · Obesity Reviews · doi:10.1111/obr.12584 · Cited by 77 · see citing works
Recruitment of Brown Adipose Tissue as a Therapy for Obesity-Associated Diseases
Boss, O., & Farmer, S. R. (2012) · Frontiers in Endocrinology · doi:10.3389/fendo.2012.00014 · Cited by 70 · see citing works
Growth Differentiation Factor-5 Promotes Brown Adipogenesis in Systemic Energy Expenditure
Hinoi, E., Nakamura, Y., Takada, S., Fujita, H., Iezaki, T., Hashizume, S., Takahashi, S., Odaka, Y., Watanabe, T., & Yoneda, Y. (2013) · Diabetes · doi:10.2337/db13-0808 · Cited by 63 · see citing works
β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis
Mattsson, C. L., Csikasz, R. I., Chernogubova, E., Yamamoto, D. L., Högberg, H. T., Amri, E., Hutchinson, D. S., & Bengtsson, T. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00085.2011 · Cited by 66 · see citing works
Human adipose dynamics and metabolic health
Feng, B., Zhang, T., & Xu, H. (2013) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12009 · Cited by 65 · see citing works
Pharmacological Characterization of a Novel Beta 3 Adrenergic Agonist, Vibegron: Evaluation of Antimuscarinic Receptor Selectivity for Combination Therapy for Overactive Bladder
Salvo, J. D., Nagabukuro, H., Wickham, L. A., Abbadie, C., DeMartino, J. A., Fitzmaurice, A., Gichuru, L., Kulick, A. A., Donnelly, M. J., Jochnowitz, N., et al. (2016) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.116.237313 · Cited by 60 · see citing works
Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action
Jenkins, L., Harries, N., Lappin, J. E., Mackenzie, A. E., Neetoo‐Isseljee, Z., Southern, C., McIver, E. G., Nicklin, S. A., Taylor, D. L., & Milligan, G. (2012) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.112.198945 · Cited by 58 · see citing works
Physiology and relevance of human adaptive thermogenesis response
Celi, F. S., Le, T. N. H., & Ni, B. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.03.003 · Cited by 57 · see citing works
Contributions of adipocyte lipid metabolism to body fat content and implications for the treatment of obesity
Marcelin, G., & Chua, S. C. (2010) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2010.05.008 · Cited by 53 · see citing works
Unlock the Thermogenic Potential of Adipose Tissue: Pharmacological Modulation and Implications for Treatment of Diabetes and Obesity
Peng, X., Gennemark, P., O’Mahony, G., & Bartesaghi, S. (2015) · Frontiers in Endocrinology · doi:10.3389/fendo.2015.00174 · Cited by 49 · see citing works
Antiobesity Effect of MK-5046, a Novel Bombesin Receptor Subtype-3 Agonist
Guan, X.-M., Metzger, J. M., Yang, L., Raustad, K. A., Wang, S.-P., Spann, S. K., Kosinski, J. A., Yu, H., Shearman, L. P., Faidley, T. D., et al. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.110.174763 · Cited by 49 · see citing works
Tissue functions mediated by β3-adrenoceptors—findings and challenges
Michel, M. C., Ochodnický, P., & Summers, R. J. (2010) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-010-0529-2 · Cited by 45 · see citing works
Do we need anti‐obesity drugs?
Hainer, V., & Hainerová, I. A. (2012) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2349 · Cited by 43 · see citing works
Breaking BAT: can browning create a better white?
Warner, A., & Mittag, J. (2015) · Journal of Endocrinology · doi:10.1530/joe-15-0408 · Cited by 43 · see citing works
Targeting adipose tissue
Haas, B., Schlinkert, P., Mayer, P. E., & Eckstein, N. (2012) · Diabetology & Metabolic Syndrome · doi:10.1186/1758-5996-4-43 · Cited by 42 · see citing works
Do gene polymorphisms alone or in combination affect the function of human β3‐adrenoceptors?
Vrydag, W., Alewijnse, A. E., & Michel, M. C. (2008) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00014.x · Cited by 42 · see citing works
Specificity evaluation of antibodies against human β3-adrenoceptors
Černecká, H., Ochodnický, P., Lamers, W. H., & Michel, M. C. (2012) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-012-0767-6 · Cited by 39 · see citing works
Are there functional β3‐adrenoceptors in the human heart?
Michel, M. C., Harding, S. E., & Bond, R. A. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.01005.x · Cited by 38 · see citing works
Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity
Reddy, N. L., Tan, B. K., Barber, T. M., & Randeva, H. S. (2014) · BMC Obesity · doi:10.1186/s40608-014-0013-5 · Cited by 36 · see citing works
Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine
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C-Type Natriuretic Peptide as a New Regulator of Food Intake and Energy Expenditure
Inuzuka, M., Tamura, N., Yamada, N., Katsuura, G., Oyamada, N., Taura, D., Sonoyama, T., Fukunaga, Y., Ohinata, K., Sone, M., et al. (2010) · Endocrinology · doi:10.1210/en.2010-0141 · Cited by 35 · see citing works
Brown adipose tissue transplantation ameliorates diabetic nephropathy through the miR-30b pathway by targeting Runx1
Zhang, Y., Cai, Y., Zhang, H., Zhang, J., Zeng, Y., Fan, C., Zou, S., Wu, C., Fang, S., Li, P., et al. (2021) · Metabolism · doi:10.1016/j.metabol.2021.154916 · Cited by 34 · see citing works
Of mice and men: novel insights regarding constitutive and recruitable brown adipocytes
Townsend, K. L., & Tseng, Y.-H. (2015) · International Journal of Obesity Supplements · doi:10.1038/ijosup.2015.5 · Cited by 31 · see citing works
Human atrial β1L‐adrenoceptor but not β3‐adrenoceptor activation increases force and Ca2+current at physiological temperature
Christ, T., Molenaar, P., Klenowski, P. M., Ravens, U., & Kaumann, A. J. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00996.x · Cited by 30 · see citing works
Npvf: Hypothalamic Biomarker of Ambient Temperature Independent of Nutritional Status
Jarosławska, J., Chabowska-Kita, A., Kaczmarek, M. M., & Kozak, L. P. (2015) · PLoS Genetics · doi:10.1371/journal.pgen.1005287 · Cited by 30 · see citing works
Targeting thermogenesis and related pathways in anti-obesity drug discovery
Clapham, J. C., & Arch, J. R. S. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.04.004 · Cited by 29 · see citing works
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Biochemical adaptations in white adipose tissue following aerobic exercise: from mitochondrial biogenesis to browning
McKie, G. L., & Wright, D. C. (2020) · Biochemical Journal · doi:10.1042/bcj20190466 · Cited by 29 · see citing works
Thermogenic Brown Fat in Humans: Implications in Energy Homeostasis, Obesity and Metabolic Disorders
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Contrasts between the effects of zinc-α2-glycoprotein, a putative β3/2-adrenoceptor agonist and the β3/2-adrenoceptor agonist BRL35135 in C57Bl/6 (ob/ob) mice
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Authors: Arch, J. R. S.
Affiliations: University of Buckingham (GB)
Corresponding author: Arch, Jonathan R. S.
Venue: Naunyn-Schmiedeberg's Archives of Pharmacology
Publisher: Springer Science and Business Media LLC
Published: 2008-07-09
Volume: 378
Issue: 2
Pages: 225-240
ISSN: 0028-1298 (ISSN-L)
1432-1912
DOI: 10.1007/s00210-008-0271-1
OpenAlex: W1984351353
Cited by: 96
References: 200
Citations by year: 2026: 1 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 5 · 2016: 7 · 2015: 11 · 2014: 5 · 2013: 7 · 2012: 13
FWCI: 1.25
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Naunyn-Schmiedeberg s Archives of Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: beta3-adrenergic agonists, leptin, energy expenditure, fat oxidation, insulin sensitivity, beta1-adrenergic receptor, beta2-adrenergic receptor, sympathetic nervous system, leptin receptor, receptor pharmacology, fat loss, lean body mass
MeSH terms: Adrenergic beta-Agonists, Animals, Energy Metabolism, Humans, Obesity, Oxidation-Reduction, Anti-Obesity Agents, Leptin, Receptors, Adrenergic, beta-3, History, 20th Century, Lipid Metabolism, Receptors, Leptin, Adrenergic beta-3 Receptor Agonists

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The discovery of drugs for obesity, the metabolic effects of leptin and variable receptor pharmacology: perspectives from β3-adrenoceptor agonists

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