GLP-1–oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice

Robert W. Schwenk, Christian Baumeier, Brian Finan, Oliver Kluth, Christine Brauer, Hans Georg Joost, Richard D. DiMarchi, Matthias H. Tschöp, Annette Schürmann

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Aims/hypothesis: Oestrogens have previously been shown to exert beta cell protective, glucose-lowering effects in mouse models. Therefore, the recent development of a glucagon-like peptide-1 (GLP-1)–oestrogen conjugate, which targets oestrogen into cells expressing GLP-1 receptors, offers an opportunity for a cell-specific and enhanced beta cell protection by oestrogen. The purpose of this study was to compare the effects of GLP-1 and GLP-1–oestrogen during beta cell failure under glucolipotoxic conditions.

Methods: Male New Zealand obese (NZO) mice were treated with daily s.c. injections of GLP-1 and GLP-1–oestrogen, respectively. Subsequently, the effects on energy homeostasis and beta cell integrity were measured. In order to clarify the targeting of GLP-1–oestrogen, transcription analyses of oestrogen-responsive genes in distinct tissues as well as microarray analyses in pancreatic islets were performed.

Results: In contrast to GLP-1, GLP-1–oestrogen significantly decreased food intake resulting in a substantial weight reduction, preserved normoglycaemia, increased glucose tolerance and enhanced beta cell protection. Analysis of hypothalamic mRNA profiles revealed elevated expression of Pomc and Leprb. In livers from GLP-1–oestrogen-treated mice, expression of lipogenic genes was attenuated and hepatic triacylglycerol levels were decreased. In pancreatic islets, GLP-1–oestrogen altered the mRNA expression to a pattern that was similar to that of diabetes-resistant NZO females. However, conventional oestrogen-responsive genes were not different, indicating rather indirect protection of pancreatic beta cells.

Conclusions/interpretation: GLP-1–oestrogen efficiently protects NZO mice against carbohydrate-induced beta cell failure by attenuation of hyperphagia. In this regard, targeted delivery of oestrogen to the hypothalamus by far exceeds the anorexigenic capacity of GLP-1 alone.

Original languageEnglish
Pages (from-to)604-614
Number of pages11
JournalDiabetologia
Volume58
Issue number3
DOIs
StatePublished - Mar 2015
Externally publishedYes

Keywords

  • Beta cells
  • GLP-1
  • Liver fat
  • NZO
  • Oestrogen
  • Pomc

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