Editors' ChoicePharmacology

New connections: Getting the good without the bad

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Science Signaling  01 Nov 2016:
Vol. 9, Issue 452, pp. ec253
DOI: 10.1126/scisignal.aal2971

Targeting receptors with synthetic versions of their endogenous ligands or with designed ligands is a therapeutic strategy that carries the risk of dangerous side effects, because many receptors are found in multiple tissues and organs. Finan et al. (see also Saghatelian and Cravatt) found that conjugating glucagon and thyroid hormone (T3) together conferred the metabolic benefits of either hormone administered alone while attenuating each hormone’s side effects. Glucagon and T3 act on the liver and white adipose tissue to limit dyslipidemia, which refers to abnormally high circulating concentrations of cholesterol or triglycerides (or both) and which contributes to the pathogenesis of several metabolic disorders. In mice that had diet- or genetically induced metabolic disorders, the glucagon/T3 conjugate reduced dyslipidemia, prevented hepatic steatosis, or induced weight loss at a dose lower than that which was needed for glucagon or T3 alone to reduce body weight. Like T3, the conjugate enhanced whole body energy expenditure but without triggering the hyperphagia (overfeeding) that T3 alone did. The ability of the glucagon/T3 conjugate to reduce dyslipidemia, induce weight loss, and increase energy expenditure required the presence of glucagon receptor and that of the thyroid hormone receptor β in the liver, the tissue in which the conjugate accumulated to the greatest extent. Unlike glucagon, the glucagon/T3 conjugate enhanced glucose handling and did not increase gluconeogenesis and, unlike T3, the conjugate did not induce cardiovascular side effects, such as cardiac hypertrophy or impaired cardiac function.

Similar to glucagon and T3, currently available estrogen therapies have undesirable side effects. Madak-Erdogan et al. used structural information to design estrogen-like molecules with lower receptor affinity to limit their ability to stimulate cell proliferation in breast or uterine tissue and thus cause cancer in these reproductive tissues. These molecules enhanced the repair of blood vessels after injury and improved metabolism in the liver and white adipose tissue without triggering ductal mammary gland branching (a sign of mammary gland growth) or increasing uterine weight in ovariectomized mice. These studies demonstrate that it is possible to modify endogenous ligands or design synthetic versions that have fewer of the side effects of the original ligand.

B. Finan, C. Clemmensen, Z. Zhu, K. Stemmer, K. Gauthier, L. Müller, M. De Angelis, K. Moreth, F. Neff, D. Perez-Tilve, K. Fischer, D. Lutter, M. A. Sánchez-Garrido, P. Liu, J. Tuckermann, M. Malehmir, M. E. Healy, A. Weber, M. Heikenwalder, M. Jastroch, M. Kleinert, S. Jall, S. Brandt, F. Flamant, K.-W. Schramm, H. Biebermann, Y. Döring, C. Weber, K. M. Habegger, M. Keuper, V. Gelfanov, F. Liu, J. Köhrle, J. Rozman, H. Fuchs, V. Gailus-Durner, M. Hrabě de Angelis, S. M. Hofmann, B. Yang, M. H. Tschöp, R. DiMarchi, T. D. Müller, Chemical hybridization of glucagon and thyroid hormone optimizes therapeutic impact for metabolic disease. Cell 167, 843–857 (2016). [PubMed]

A. Saghatelian, B. Cravatt, Glucagon and thyroid hormone: A championship team. Cell 167, 604–605 (2016). [PubMed]

Z. Madak-Erdogan, S. H. Kim, P. Gong, Y. C. Zhao, H. Zhang, K. L. Chambliss, K. E. Carlson, C. G. Mayne, P. W. Shaul, K. S. Korach, J. A. Katzenellenbogen, B. S. Katzenellenbogen, Design of pathway preferential estrogens that provide beneficial metabolic and vascular effects without stimulating reproductive tissues. Sci. Signal. 9, ra53 (2016). [Abstract]

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