One main focus area constitute in vitro structure and function studies of 7TM G protein coupled receptors involved in metabolic homeostasis and glucose metabolism. This includes the molecular basis for ligand recognition, potency and efficacy and phenomena such as constitutive receptor activity, allosteric ligand function, and signal transduction pathway biased signaling etc. The molecular pharmacology is closely integrated with computational chemistry (Thomas Frimurer at CPR, SUND), with medicinal chemistry (Annette Beck-Sickinger, Leipzig University), with cell biology (Nick Holliday, University of Nottingham, UK) and currently being integrated with biophysic methods (Tom Sakmar, Rockefeller University). We are mainly focusing on following metabolic 7TM receptors as model systems: Ghrelin receptor, GPR39, melanocortin receptors, neurotensin receptors and melatonin receptors
In vivo Metabolic Receptology
We are currently focusing on hormones (ghrelin, PYY etc.) and receptors involved in the gut brain communication axis controlling food intake and energy expenditure. In particular the interaction with the homeostatic appetite regulating center in hypothalamus but also interaction with the central reward systems (with David Woldbye, INF, SUND, KU), control of the endocrine pancreas (ghrelin R, GPR39 etc.) and in adipocyte metabolism – pt. focusing on 7TM receptors in the control of lipolysis (especially GPR39, adrenoceptors, GPR81 and GPR109A) is important. We are using and establishing various forms of transgenic animal models (for example with Jeff Zigmann, South Western Medical School, Dallas, USA) as well as testing in vivo novel pharmacological tool compounds to determine the metabolic function of 7TM receptors. An important part of the in vivo studies are integrating and probing knowledge from basic molecular pharmacology Molecular Pharmacology Laboratory 30 Annual Report 2012(see above) with in vivo endocrinology and pharmacology. One example is to probe the physiological, in vivo importance of the constitutive receptor activities originally discovered in the ghrelin receptor system by novel inverse agonists and transgenic models including adenovirus models. Another example is to probe the in vivo importance of biased agonists that are characterized by selectively coupling only a few of the possible signaling pathways. Several biased agonist has been developed for the ghrelin receptor and our group are currently characterizing the physiological role of these agonists compared to un-biased agonists. Metabolic characterization of the orphan ghrelin receptor family member, GPR39 in the function of pancreatic beta-cells, adipocytes constitute another important research area.
Rodent Metabolic Phenotyping Center
BH has founded and is head of “Rodent Metabolic Phenotyping Center”, an in vivo laboratory or core facility at SUND specialized in testing metabolic functions of mice and rats, which is being used for a variety of rodent models of especially obesity and diabetes as well as for testing the metabolic phenotype of various transgenic mouse models and the effects of hormones, drugs, drug candidates and pharmacological tool compounds. The equipment and capabilities at the center includes: 1) TSE calometry test systems – i.e. cages to measure food intake, energy expenditure (CO2 production, O2 consumption etc.), locomoter activity done under variable temperature 2) MRI scanner for measuring body composition and composition of tissue samples, biopsies etc 3) Specialized cages for studies of food intake in real time in rats and mice and “chipped”, group-housed mice and 4) Intellicages – specialized cages for measuring animal behavior, i.e. especially reward, food intake related behavior. Collaborative projects:
- Gether and Kjærulff lab INF – probe the metabolic importance to the intracellular protein PICK1 for secretion of peptide hormones.
- Harald Hansen lab “old FARMA” – Study the regulation of lipid metabolites important for energy homeostasis and food intake
- Lars Bo Nielsen – Study of ApoM for energy and brown fat homeostasis and fat accumulation
- Kristian Helin and Karl Agger – importance of histone demethylases for energy homeostasis and fat accumulation
- Anders Hay Smith – The importance of Neuroglobulin for body weight and energy homoestasis. 6. Bente Klarlund, Pernille Højlund and Klaus – FSTL3 electroporation and effect on energy homeostasis. 7. Axel Kornerup and Britt T. Christensen. 8. Thomas Mandrup Poulsen and Jacob Bondo Hansen – importance of the Fe transporter for beta cell function.
For testing the in vitro and ex vivo basic metabolism of cells (cell lines, isolated adipocytes, muscle cells, hepatocytes, pancreatic islets etc.) as well as isolated mitochondria.
Birgitte Holst, Professor
2200 Copenhagen N
Phone +45 3532 7699