Principal Investigator, Cologne Biocenter
Prof. Dr. Matthias Hammerschmidt
During the course of evolution, many aspects of the neuroendocrine regulation of energy homeostasis have been preserved in both fish and humans. Even so, there are fundamental differences in that a fish reacts to increased energy supplies by growing in length, while a person puts on weight. Prof. Dr. Hammerschmidt’s research group is trying to extrapolate new findings in energy homeostasis to human metabolism.
Our research: Prof. Hammerschmidt and his team have pioneered basic systematic approaches to metabolic research in adult zebrafish and gained insight into related functional aspects. Systematic approaches to functional measurements of energy homeostasis in the zebrafish model are challenging, as there are no isogenic lines and considerable variation in the length, weight, and lifespan of individual fish. In addition, basic investigational methods, such as measuring food uptake and oxygen consumption, first had to be established. The key anatomical structure in this functional research is the hypothalamus, which regulates energy homeostasis in both fish and humans.
Our successes: Functional structures in the human hypothalamus for the regulation of energy homeostasis, such as POMC and AGRP neurons, as well as many second-order neurons, can also be demonstrated in zebrafish. By developing new systematic approaches, the team has succeeded in establishing the fish as a model organism for the basic research of metabolic regulatory networks.
Our goals: Based on the development of new systematic approaches, the research group intends to investigate in detail the regulatory processes of energy homeostasis emanating from the hypothalamus in the zebrafish model, and to extrapolate their findings to neuronal regulation in humans.
Our methods/techniques: Production of transgenic lines for network analysis and functional manipulation of specific neurons (optogenetics, cell ablation); production of genetic mutations in potential regulatory genes by means of CRIPR/Cas9 technology; forward genetics screens after random chemical mutagenesis to isolate mutants with decreased or increased body size.
Figure 1: A stable pomca:EGFPras transgenic line reveals the complex projection pattern of pomca neurons in the zebrafish larval brain. Anti-GFP immunohistochemistry of transgenic line at 7dpf, counterstained via in situ hybridization labeling of various second order neurons in the pre-optic region of the hypothalamus: oxtl (oxytocin-like); trh (thyrotropin-releasing hormone); crh (corticotropin-releasing hormone). ac: anterior commissure; poc: postoptic commissure.
Figure 2: Single pomca neurons innervate multiple target regions in the larval zebrafish brain. Genetic mosaic labeling was performed by injection of a BAC construct driving mCherry expression under the control of the pomca promoter into fertilized eggs of a stable Tg(pomca:EGFP) line. 15 dpf. The single neuron (purple) projects to all target regions of the pomca circuitry. Inset: magnification of cell body.
Figure 3: Dwarf mutants identified in an ENU F3-forward genetic screen. Comparison of body size of mutant fish (4D18-3) to wild-type sibling at 2 months of age.
Figure 4: Innervation of the pituitary by neuroendocrine cells of the hypothalamus. Live imaging of the hypothalamus-pituitary connection of an adult fish (6 months of age) carrying a otpb:EGFPras transgene (green), marking hypothalamic neurons and a prl:RFP transgene (purple), marking lactotropes of the anterior pituitary.