Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kaineder, K.
Continuous Focal Drug Delivery to Assess the Pharmacological Role of Liraglutide on Energy Homeostasis in the Hypothalamus
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Graz Medical University; 2017. pp.
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- Autor*innen der Med Uni Graz:
- Kaineder Katrin
- Betreuer*innen:
- Pieber Thomas
- Sattler Wolfgang
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- Abstract:
- Liraglutide is a glucagon-like peptide-1 receptor (GLP-1R) agonist and is approved by the FDA and EMA for use in chronic weight management and glycaemic control. Liraglutide possibly exerts its anorectic effects via the GLP-1R in the brain, especially in the hypothalamus. The hypothalamus plays a pivotal role in the maintenance of body weight by regulating appetite and energy expenditure. Animal studies show that acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms underlying the chronic liraglutide-induced weight loss are still under investigation. In this study, we aimed to evaluate the difference between peripherally (subcutaneous – SC) and centrally (intrahypothalamic – IH) injected liraglutide on body weight regulation in both a chronic and an acute administration. We examined whether energy expenditure, in terms of thermogenesis and browning of adipose tissue or hypothalamic appetite centres are involved in the liraglutide-induced weight loss. Therefore, healthy and lean male Sprague Dawley rats (N=32) were separated in 4 groups, 2 treatment and 2 control groups. For the chronic study design, we continuously administered liraglutide either intrahypothalamically (IH; 10 µg/day) or subcutaneously (SC; 200 µg/kg/day) for 28 days. For the 24-hours acute study we injected liraglutide (IH liraglutide) or placebo (IH control) once into the hypothalamus of healthy lean rats (N=16). For both studies, we assessed changes in body weight and adipose tissue mass. Adipocyte size of three different adipose tissue depots was evaluated for the chronic study setup. The distribution of subcutaneous and visceral adipose tissues after chronic liraglutide administration was analysed by using micro-CT. For both studies, we examined mRNA signature of markers for browning, thermogenic and adipocyte differentiation in adipose tissue depots as well as markers specific for neurons regulating appetite. The results show that chronic IH liraglutide administration induced an 8% body weight reduction at day 9 compared to the corresponding control group (P<0.01) and a 7% body weight loss at day 9 compared to SC liraglutide treatment (P<0.01). Epididymal and inguinal adipose tissue mass were significantly reduced after chronic IH liraglutide treatment compared to the control group (P<0.05). Moreover, our data show that chronic IH liraglutide treatment triggered an 18-fold induction of the hypothalamic melanocortin 4 receptor (P<0.01). Circulating plasma parameters for glucose and fat metabolism were unaffected by both treatments, apart from a significant increase of circulating thyroxine levels (P<0.05) after chronic IH liraglutide treatment. Both acute IH and chronic SC liraglutide treatment were did not trigger an anorectic effect. Thus we conclude that chronic IH liraglutide is more effective than SC liraglutide treatment in triggering an anorectic effect, by reducing body weight and adipose tissue mass. We further state that this profound reduction in body weight and adipose tissue mass is most likely mediated by the hypothalamic melanocortin 4 receptor system rather than by improved thermogenesis. Further investigations will be needed to assess the role of the central GLP-1R in the regulation of body weight.