Periodic Reporting for period 3 - SYNEME (Systems Neuroscience of Metabolism)
Reporting period: 2020-10-01 to 2022-03-31
Obesity represents an ever increasing global health burden. It results from the deregulation of energy intake and energy expenditure, ultimately causing a positive energy balance. Control over the coordinated regulation of energy balance is governed by highly specialised neurons in the central nervous system, specifically in the hypothalamus. Here, specialised neurons receive information about the energy state of the organism via hormones such as leptin and insulin. These neurons are characterised by the expression of certain messengers, i.e. neuropeptides, which in turn regulate food intake. In the hypothalamus two key neuron populations in this regulatory pathway comprise on one hand neurons, which when activated promote food intake (orexigenic neurons), while on the other hand anorexigenic neurons suppress food intake upon activation. A major population of these anorexigenic, food intake supressing neurons is characterised by the expression of the neuropeptide proopiomelanocortin (POMC). Inactivation of POMC accordingly results in massive obesity in both mice and humans. Thus, these specialised cells are key to the integrated regulation of energy homeostasis. While only 3000-5000 of these cells exist in mice and humans, recent experiments have indicated that these cells are heterogenous. However, the specific function and consequences of this heterogeneity remain unaddressed. Therefore, the overarching aim of this project is to define the molecular basis and functional significance of this heterogeneity in these critical metabolism-regulatory neurons, with the ultimate perspective to develop novel pharmacological modulators to target these specific cell types as a novel approach for the treatment of obesity and diabetes mellitus.
Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far
We have successfully further developed techniques in transgenic mice, which allowed us to specifcally identify subtypes of POMC neurons, as characterised by receptors for the fat derived hormone leptin or the gut derived hormone glucagon like peptide (GLP)-1. In summary, we found that POMC neurons expressing the Lepr (POMCLepr+) as well as POMC neurons expressing the Glp1r (POMCGlp1r+) exhibit distinct characteristics such as anatomical distribution patterns, basic electrophysiological properties and differentially express receptors for energy state communicating hormones and neurotransmitters. Moreover, we could demonstrate that both subpopulations of these key regulatory neurons exhibit a differential ability to suppress food intake upon activation. These findings provide the first proof of principle for the feasibility of this newly developed technology to unveil the molecular basis and functional consequences of cellular heterogeneity in defined neuronal circuits. Moreover, the developed technology will be applicable to general studies of cellular heterogeneity within other brain areas.
Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)
These results provide the first proof of principle on the molecular and functional heterogeneity of critical feeding regulatory neurons. Future studies will address, how specific subtypes of POMC neurons as defined in these experiments can be manipulated pharmacologically. Moreover, we aim to unravel the further characteristics of heterogenous POMC neuron populations beyond those characterised by the leptin and GLP-1 receptor.