Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity

Carmelo Quarta, Christoffer Clemmensen, Zhimeng Zhu, Bin Yang, Sini S. Joseph, Dominik Lutter, Chun Xia Yi, Elisabeth Graf, Cristina García-Cáceres, Beata Legutko, Katrin Fischer, Robert Brommage, Philippe Zizzari, Bernardo S. Franklin, Martin Krueger, Marco Koch, Sabine Vettorazzi, Pengyun Li, Susanna M. Hofmann, Mostafa BakhtiAimée Bastidas-Ponce, Heiko Lickert, Tim M. Strom, Valerie Gailus-Durner, Ingo Bechmann, Diego Perez-Tilve, Jan Tuckermann, Martin Hrabě de Angelis, Darleen Sandoval, Daniela Cota, Eicke Latz, Randy J. Seeley, Timo D. Müller, Richard D. DiMarchi, Brian Finan, Matthias H. Tschöp

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Chronic inflammation has been proposed to contribute to the pathogenesis of diet-induced obesity. However, scarce therapeutic options are available to treat obesity and the associated immunometabolic complications. Glucocorticoids are routinely employed for the management of inflammatory diseases, but their pleiotropic nature leads to detrimental metabolic side effects. We developed a glucagon-like peptide-1 (GLP-1)-dexamethasone co-agonist in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells. GLP-1-dexamethasone lowers body weight up to 25% in obese mice by targeting the hypothalamic control of feeding and by increasing energy expenditure. This strategy reverses hypothalamic and systemic inflammation while improving glucose tolerance and insulin sensitivity. The selective preference for GLP-1 receptor bypasses deleterious effects of dexamethasone on glucose handling, bone integrity, and hypothalamus-pituitary-adrenal axis activity. Thus, GLP-1-directed glucocorticoid pharmacology represents a safe and efficacious therapy option for diet-induced immunometabolic derangements and the resulting obesity. Quarta et al. develop a tissue-specific anti-inflammatory drug in which GLP-1 selectively delivers dexamethasone to GLP-1 receptor-expressing cells, bypassing many of the deleterious side effects of chronic dexamethasone treatment. The GLP-1/Dexa anti-inflammatory agent improves metabolism and lowers body weight up to 25% in obese mice through both central and peripheral effects.

Original languageEnglish
Pages (from-to)620-632.e6
JournalCell Metabolism
Volume26
Issue number4
DOIs
StatePublished - 3 Oct 2017

Keywords

  • GLP-1
  • anti-inflammatory
  • co-agonist
  • conjugate
  • dexamethasone
  • drug delivery
  • hypothalamic inflammation
  • obesity
  • type 2 diabetes

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