Engineered neurobiological tools for the manipulation of cellular activity, such as chemogenetics and optogenetics, have become a cornerstone of modern neuroscience research. These tools are invaluable for the interrogation of the central control of metabolism as they provide a direct means to establish a causal relationship between brain activity and biological processes at the cellular, tissue and organismal levels. The utility of these methods has grown substantially due to advances in cellular-targeting strategies, alongside improvements in the resolution and potency of such tools. Furthermore, the potential to recapitulate endogenous cellular signalling has been enriched by insights into the molecular signatures and activity dynamics of discrete brain cell types. However, each modulatory tool has a specific set of advantages and limitations; therefore, tool selection and suitability are of paramount importance to optimally interrogate the cellular and circuit-based underpinnings of metabolic outcomes within the organism. Here, we describe the key principles and uses of engineered neurobiological tools. We also highlight inspiring applications and outline critical considerations to be made when using these tools within the field of metabolism research. We contend that the appropriate application of these biotechnological advances will enable the delineation of the central circuitry regulating systemic metabolism with unprecedented potential.
Neurobiological tools facilitate the probing of the interaction between discrete cell populations of the brain and systemic metabolism with unprecedented potential.
Chemogenetic and optogenetic tools have different properties, which enables their complementary use to optimize the testing of the necessity and sufficiency of metabolic neural circuitry.
The relative advantages and drawbacks of chemogenetic and optogenetic tools are important considerations as they dictate the ideal experimental conditions under which these tools should be used.
The delineation and subsequent dissection of the complex neural circuitry underlying metabolism can leverage novel translational elements and pharmacological strategies for the treatment of metabolic diseases.
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We thank Marielle Minère, Thomas Wunderlich and Sophie Steculorum (Max Planck Institute for Metabolism Research) for helpful discussions and comments on the manuscript. H.F. has received funding from the European Research Council (ERC) under the European Union Horizon 2020 Research and Innovation Programme (grant agreement ID 851778), research funds through collaboration agreements with Novo Nordisk (Denmark), and funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; grant IDs 409551513 and 505389599) and within the Excellence Initiative by German Federal and State Governments (CECAD).
The authors declare no competing interests.
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Mirabella, P.N., Fenselau, H. Advanced neurobiological tools to interrogate metabolism. Nat Rev Endocrinol 19, 639–654 (2023). https://doi.org/10.1038/s41574-023-00885-6