Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease

被引：158

作者：

Finan, Brian ^{[1
,2
,3
]}

Clemmensen, Christoffer ^{[1
,2
,3
]}

Zhu, Zhimeng ^{[4
]}

Stemmer, Kerstin ^{[1
,2
,3
]}

Gauthier, Karine ^{[5
]}

Mueller, Luisa ^{[1
]}

De Angelis, Meri ^{[6
]}

Moreth, Kristin ^{[7
]}

Neff, Frauke ^{[7
,23
]}

Perez-Tilve, Diego ^{[8
]}

Fischer, Katrin ^{[1
,2
]}

Lutter, Dominik ^{[1
,2
,3
]}

Sanchez-Garrido, Miguel A. ^{[1
,2
]}

Liu, Peng ^{[9
]}

Tuckermann, Jan ^{[9
]}

Malehmir, Mohsen ^{[10
,11
]}

Healy, Marc E. ^{[10
,11
]}

Weber, Achim ^{[10
,11
]}

Heikenwalder, Mathias ^{[12
,13
]}

Jastroch, Martin ^{[1
,2
]}

Kleinert, Maximilian ^{[1
,2
,24
]}

Jall, Sigrid ^{[1
,2
]}

Brandt, Sara ^{[1
,2
]}

Flamant, Frederic ^{[5
]}

Schramm, Karl-Werner ^{[6
]}

Biebermann, Heike ^{[14
]}

Doering, Yvonne ^{[15
,25
]}

Weber, Christian ^{[15
,26
]}

Habegger, Kirk M. ^{[16
,17
]}

Keuper, Michaela ^{[18
]}

Gelfanov, Vasily ^{[4
]}

Liu, Fa ^{[19
]}

Koehrle, Josef ^{[20
]}

Rozman, Jan ^{[3
,7
]}

Fuchs, Helmut ^{[7
]}

Gailus-Durner, Valerie ^{[7
]}

de Angelis, Martin Hrabe ^{[3
,7
,21
]}

Hofmann, Susanna M. ^{[3
,18
,22
]}

Yang, Bin

Tschoep, Matthias H. ^{[1
,2
,3
]}

DiMarchi, Richard ^{[4
]}

Mueller, Timo D. ^{[1
,2
,3
]}

机构：

[1] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Inst Diabet & Obes, D-85764 Neuherberg, Germany

[2] Tech Univ Munich, Div Metab Dis, Dept Med, D-80333 Munich, Germany

[3] German Ctr Diabet Res DZD, D-85764 Neuherberg, Germany

[4] Indiana Univ, Dept Chem, Bloomington, IN 47405 USA

[5] Univ Lyon, Ecole Normale Super Lyon, CNRS, Inst Genom Fonct Lyon,INRA, F-69364 Lyon, France

[6] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Mol EXpos, D-85764 Neuherberg, Germany

[7] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Expt Genet, German Mouse Clin, D-85764 Neuherberg, Germany

[8] Univ Cincinnati, Coll Med, Metab Dis Inst, Div Endocrinol,Dept Internal Med, Cincinnati, OH 45237 USA

[9] Univ Ulm, Inst Comparat Mol Endocrinol, D-89081 Ulm, Germany

[10] Univ Zurich, Dept Pathol & Mol Pathol, CH-8091 Zurich, Switzerland

[11] Univ Zurich Hosp, CH-8091 Zurich, Switzerland

[12] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany

[13] German Canc Res Ctr, Div Chron Inflammat & Canc, D-69120 Heidelberg, Germany

[14] Charite, Inst Expt Pediat Endocrinol, D-13353 Berlin, Germany

[15] Univ Munich, Inst Cardiovasc Prevent, Dept Med, D-80336 Munich, Germany

[16] Univ Alabama Birmingham, Comprehens Diabet Ctr, Birmingham, AL 35294 USA

[17] Univ Alabama Birmingham, Dept Med Endocrinol Diabet & Metab, Birmingham, AL 35294 USA

[18] German Res Ctr Environm Hlth GmbH, Helmholtz Zentrum Munchen, Helmholtz Diabet Ctr, Inst Diabet & Regenerat, D-85764 Neuherberg, Germany

[19] Calibrium LLC, Carmel, IN 46032 USA

[20] Charite, Inst Expt Endocrinol, D-13353 Berlin, Germany

[21] Tech Univ Munich, Sch Life Sci Weihenstephan, Chair Expt Genet, D-85353 Freising Weihenstephan, Germany

[22] Klinikum LMU, Med Klin & Poliklin 4, D-80336 Munich, Germany

[23] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Pathol, D-85764 Neuherberg, Germany

[24] Univ Copenhagen, Dept Nutr Exercise & Sports, Sect Mol Physiol, Fac Sci, DK-2200 Copenhagen, Denmark

[25] German Ctr Cardiovascular Res DZHK, Partner Site Munich Heart Alliance MHA, D-80336 Munich, Germany

[26] Maastricht Univ, Cardiovasc Res Inst Maastricht CARIM, Dept Biochem, NL-6200 MD Maastricht, Netherlands

来源：

CELL | 2016年 / 167卷 / 03期

基金：

欧洲研究理事会;

关键词：

GROWTH-FACTOR; 21; BODY-WEIGHT; RECEPTOR; FGF21; ACTIVATION; PROTECTS; OBESITY; TRIIODOTHYRONINE; ATHEROSCLEROSIS; CHOLESTEROL;

D O I：

10.1016/j.cell.2016.09.014

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Glucagon and thyroid hormone (T-3) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T-3 actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T-3 reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T-3 action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T-3 action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.

引用

页码：843 / +

页数：29

共 53 条

[1] Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes [J].

Baxter, John D. ;

Webb, Paul .

NATURE REVIEWS DRUG DISCOVERY, 2009, 8 (04) :308-320

[2] INTRACELLULAR CONVERSION OF THYROXINE TO TRIIODOTHYRONINE IS REQUIRED FOR THE OPTIMAL THERMOGENIC FUNCTION OF BROWN ADIPOSE-TISSUE [J].

BIANCO, AC ;

SILVA, JE .

JOURNAL OF CLINICAL INVESTIGATION, 1987, 79 (01) :295-300

[3] GLUCAGON IN PHYSIOLOGICAL CONCENTRATIONS STIMULATES BROWN FAT THERMOGENESIS INVIVO [J].

BILLINGTON, CJ ;

BRIGGS, JE ;

LINK, JG ;

LEVINE, AS .

AMERICAN JOURNAL OF PHYSIOLOGY, 1991, 261 (02) :R501-R507

[4] TRα Protects Against Atherosclerosis in Male Mice: Identification of a Novel Anti-Inflammatory Property for TRα in Mice [J].

Billon, Cyrielle ;

Canaple, Laurence ;

Fleury, Sebastien ;

Deloire, Alexandre ;

Beylot, Michel ;

Dombrowicz, David ;

del Carmine, Peggy ;

Samarut, Jacques ;

Gauthier, Karine .

ENDOCRINOLOGY, 2014, 155 (07) :2735-2745

[5] CLONING AND SEQUENCE-ANALYSIS OF THE MURINE GLUCAGON RECEPTOR-ENCODING GENE [J].

BURCELIN, R ;

LI, J ;

CHARRON, MJ .

GENE, 1995, 164 (02) :305-310

[6] A new glucagon and GLP-1 co-agonist eliminates obesity in rodents [J].

Day, Jonathan W. ;

Ottaway, Nickki ;

Patterson, James T. ;

Gelfanov, Vasily ;

Smiley, David ;

Gidda, Jas ;

Findeisen, Hannes ;

Bruemmer, Dennis ;

Drucker, Daniel J. ;

Chaudhary, Nilika ;

Holland, Jenna ;

Hembree, Jazzminn ;

Abplanalp, William ;

Grant, Erin ;

Ruehl, Jennifer ;

Wilson, Hilary ;

Kirchner, Henriette ;

Lockie, Sarah Haas ;

Hofmann, Susanna ;

Woods, Stephen C. ;

Nogueiras, Ruben ;

Pfluger, Paul T. ;

Perez-Tilve, Diego ;

DiMarchi, Richard ;

Tschoep, Matthias H. .

NATURE CHEMICAL BIOLOGY, 2009, 5 (10) :749-757

[7] EFFECTS OF MATERNAL HYPOTHYROIDISM ON THE WEIGHT AND THYROID-HORMONE CONTENT OF RAT EMBRYONIC-TISSUES, BEFORE AND AFTER ONSET OF FETAL THYROID-FUNCTION [J].

DEESCOBAR, GM ;

PASTOR, R ;

OBREGON, MJ ;

DELREY, FE .

ENDOCRINOLOGY, 1985, 117 (05) :1890-1900

[8] How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease [J].

Diamond, David M. ;

Ravnskov, Uffe .

EXPERT REVIEW OF CLINICAL PHARMACOLOGY, 2015, 8 (02) :201-210

[9] Apparent thermogenic effect of injected glucagon is not due to a direct effect on brown fat cells [J].

Dicker, A ;

Zhao, J ;

Cannon, B ;

Nedergaard, J .

AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY, 1998, 275 (05) :R1674-R1682

[10] Fibroblast Growth Factor 21 and Thyroid Hormone Show Mutual Regulatory Dependency but Have Independent Actions In Vivo [J].

Domouzoglou, Eleni M. ;

Fisher, Ffolliott Martin ;

Astapova, Inna ;

Fox, Elliott C. ;

Kharitonenkov, Alexei ;

Flier, Jeffrey S. ;

Hollenberg, Anthony N. ;

Maratos-Flier, Eleftheria .

ENDOCRINOLOGY, 2014, 155 (05) :2031-2040

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