MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency

被引：236

作者：

Clement, Karine ^{[1
]}

Biebermann, Heike ^{[2
,3
]}

Farooqi, I. Sadaf ^{[4
,5
]}

Van der Ploeg, Lex ^{[6
]}

Wolters, Barbara ^{[2
]}

Poitou, Christine ^{[1
]}

Puder, Lia ^{[2
,3
]}

Fiedorek, Fred ^{[6
]}

Gottesdiener, Keith ^{[6
]}

Kleinau, Gunnar ^{[3
,7
]}

Heyder, Nicolas ^{[3
,7
]}

Scheerer, Patrick ^{[3
,7
,8
]}

Blume-Peytavi, Ulrike ^{[3
,9
]}

Jahnke, Irina ^{[3
,9
]}

Sharma, Shubh ^{[6
]}

Mokrosinski, Jacek ^{[4
,5
]}

Wiegand, Susanna ^{[3
,10
]}

Mueller, Anne ^{[2
,3
]}

Weiss, Katja ^{[3
,11
]}

Mai, Knut ^{[3
,8
,12
,13
]}

Spranger, Joachim ^{[3
,8
,12
,13
]}

Grueters, Annette ^{[3
,14
]}

Blankenstein, Oliver ^{[2
,3
]}

Krude, Heiko ^{[2
,3
]}

Kuehnen, Peter ^{[2
,3
]}

机构：

[1] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, INSERM,NutriOm Team, Paris, France

[2] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Inst Expt Pediat Endocrinol, Berlin, Germany

[3] Berlin Inst Hlth, Berlin, Germany

[4] Univ Cambridge, Metab Res Labs, Cambridge, England

[5] Addenbrookes Hosp, Wellcome Trust MRC Inst Metab Sci, NIHR Cambridge Biomed Res Ctr, Cambridge, England

[6] Rhythm Pharmaceut, Boston, MA USA

[7] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Inst Med Phys & Biophys,Grp Prot Xray Crystallog, Berlin, Germany

[8] DZHK German Ctr Cardiovasc Res, Partner Site Berlin, Berlin, Germany

[9] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Clin Res Ctr Hair & Skin Sci,Dept Dermatol & Alle, Berlin, Germany

[10] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Ctr Chron Sick Children, Berlin, Germany

[11] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Dept Pediat Cardiol, Berlin, Germany

[12] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Dept Endocrinol Diabet & Nutr, Berlin, Germany

[13] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Charite Ctr Cardiovasc Res, Berlin, Germany

[14] Humboldt Univ, Freie Univ Berlin, Charite Univ Med Berlin, Dept Pediat Endocrinol & Diabet, Berlin, Germany

来源：

NATURE MEDICINE | 2018年 / 24卷 / 05期

基金：

英国惠康基金;

关键词：

PROTEIN-COUPLED RECEPTOR; MELANOCORTIN RECEPTORS; CRYSTAL-STRUCTURE; OBESITY; SETMELANOTIDE; THERAPIES;

D O I：

10.1038/s41591-018-0015-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Genetic defects underlying the melanocortin-4 receptor (MC4R) signaling pathway lead to severe obesity. Three severely obese LEPR-deficient individuals were administered the MC4R agonist setmelanotide, resulting in substantial and durable reductions in hyperphagia and body weight over an observation period of 45-61 weeks. Compared to formerly developed and tested MC4R agonists, setmelanotide has the unique capability of activating nuclear factor of activated T cell (NFAT) signaling and restoring function of this signaling pathway for selected MC4R variants. Our data demonstrate the potency of setmelanotide in treatment of individuals with diverse MC4R-related pathway deficiencies.

引用

页码：551 / +

页数：7

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