title: GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany, robert.schwenk@dife.de.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schwenk
authors.forename: Christian
authors.initials: C
authors.lastname: Baumeier
authors.forename: Brian
authors.initials: B
authors.lastname: Finan
authors.forename: Oliver
authors.initials: O
authors.lastname: Kluth
authors.forename: Christine
authors.initials: C
authors.lastname: Brauer
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.forename: Richard D
authors.initials: RD
authors.lastname: DiMarchi
authors.forename: Matthias H
authors.initials: MH
authors.lastname: Tschöp
authors.forename: Annette
authors.initials: A
authors.lastname: Schürmann
mesh_terms: D000818:Animals; D004967:Estrogens / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1 / Q000627:therapeutic use*; D006963:Hyperphagia / Q000188:drug therapy* / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009520:New Zealand
chemical_list: D004967:Estrogens; D052216:Glucagon-Like Peptide 1