Exp Clin Endocrinol Diabetes 2014; 122 - P139
DOI: 10.1055/s-0034-1372156

CNS impact of the GLP-1-Estrogen conjugate on food-motivated behavior

S Wolf 1, H Vogel 1, C Rabasa 1, SL Dickson 1, B Finan 2, MH Tschöp 2, A Schürmann 3, KP Skibicka 1
  • 1Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • 2Institute for Diabetes and Obesity, Helmholtz Zentrum München and Department of Medicine, Technische Universität München, Munich, Germany
  • 3German Institute of Human Nutrition Potsdam-Rehbrücke, Department of Experimental Diabetology, Nuthetal, Germany

Introduction: Recent findings suggest that the GLP-1-estrogen (GE) conjugate may be a new strategy to treat diabesity. The anti-obesity action of GE is proposed to be mediated by its direct action on the CNS GLP-1 and estrogen receptors, which are co-expressed in several brain areas regulating metabolic control and feeding behavior, but also in the mesolimbic system in underlying food reward control. Therefore we hypothesized that the GE-induced anorexia involves direct action of GE on central receptors and may also involve changes in food-motivated behavior.

Methods: The progressive ratio (PR) was used to assess the role of GE stimulation on food reward in rats. To target the CNS cannulas were implanted into lateral ventricle (LV), ventral tegmental area (VTA) and nucleus accumbens (NA).

Results: A single peripheral injection of GE significantly decreased body weight and food intake in comparison to vehicle-treated animals, whereas administration of matching doses of unconjugated GLP-1 failed to reduce either parameter indicating a synergistic effect of GE combination. Moreover conjugate-injected rats reduced responding for sucrose to greater extent than rats treated with vehicle or GLP-1 alone. Similar results were obtained when injections were restricted to the CNS, suggesting that CNS GLP-1 and estrogen receptors are sufficient for the anorexic, food-reward and body weight reducing effect of GE. To determine the target area for central GE effects, we assessed the breaking point after VTA and NA drug administration. Direct VTA and NA GE injection failed to suppress body weight, food intake and reward to a higher degree than GLP-1 alone suggesting that the synergistic effect of GE is derived from a CNS-site other than the VTA or NA.

Conclusion: The body weight-lowering efficacy of GE is mediated through central effects and involves changes in reward behavior. The direct site of action for GE-driven food intake and food-motivated behavior remains to be elucidated.