A new glucagon and GLP-1 co-agonist eliminates obesity in rodents

被引：481

作者：

Day, Jonathan W. ^{[1
]}

Ottaway, Nickki ^{[2
]}

Patterson, James T. ^{[1
]}

Gelfanov, Vasily ^{[1
]}

Smiley, David ^{[1
]}

Gidda, Jas ^{[3
]}

Findeisen, Hannes ^{[4
]}

Bruemmer, Dennis ^{[4
]}

Drucker, Daniel J. ^{[5
]}

Chaudhary, Nilika ^{[2
]}

Holland, Jenna ^{[2
]}

Hembree, Jazzminn ^{[2
]}

Abplanalp, William ^{[2
]}

Grant, Erin ^{[2
]}

Ruehl, Jennifer ^{[2
]}

Wilson, Hilary ^{[2
]}

Kirchner, Henriette ^{[2
]}

Lockie, Sarah Haas ^{[2
]}

Hofmann, Susanna ^{[6
]}

Woods, Stephen C. ^{[2
]}

Nogueiras, Ruben ^{[2
]}

Pfluger, Paul T. ^{[2
]}

Perez-Tilve, Diego ^{[2
]}

DiMarchi, Richard ^{[1
]}

Tschoep, Matthias H. ^{[2
,6
]}

机构：

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

[2] Univ Cincinnati, Dept Psychiat, Obes Res Ctr, Cincinnati, OH USA

[3] Marcadia Biotech, Carmel, IN USA

[4] Univ Kentucky, Coll Med, Div Endocrinol & Mol Med, Lexington, KY USA

[5] Univ Toronto, Mt Sinai Hosp, Dept Med, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada

[6] Univ Cincinnati, Div Endocrinol, Cincinnati, OH USA

来源：

NATURE CHEMICAL BIOLOGY | 2009年 / 5卷 / 10期

关键词：

SECONDARY STRUCTURE ANALYSES; FOOD-INTAKE; ADIPOSE-TISSUE; PEPTIDE-1; OXYNTOMODULIN; WEIGHT; OVERWEIGHT; EFFICACY; INSULIN; SAFETY;

D O I：

10.1038/nchembio.209

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：

We report the efficacy of a new peptide with agonism at the glucagon and GLP-1 receptors that has potent, sustained satiation-inducing and lipolytic effects. Selective chemical modification to glucagon resulted in a loss of specificity, with minimal change to inherent activity. The structural basis for the co-agonism appears to be a combination of local positional interactions and a change in secondary structure. Two co-agonist peptides differing from each other only in their level of glucagon receptor agonism were studied in rodent obesity models. Administration of PEGylated peptides once per week normalized adiposity and glucose tolerance in diet-induced obese mice. Reduction of body weight was achieved by a loss of body fat resulting from decreased food intake and increased energy expenditure. These preclinical studies indicate that when full GLP-1 agonism is augmented with an appropriate degree of glucagon receptor activation, body fat reduction can be substantially enhanced without any overt adverse effects.

引用

页码：749 / 757

页数：9

共 34 条

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