CORDIS - EU research results

Systems Neuroscience of Metabolism

Periodic Reporting for period 4 - SYNEME (Systems Neuroscience of Metabolism)

Reporting period: 2022-04-01 to 2022-09-30

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 the 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 was 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.
We have successfully further developed techniques in transgenic mice, which allowed us to specifically 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. Moreover, we have employed these novel mouse models to identify entirely novel feeding regulatory neurons in the hypothalamus, which are activated upon obesity development, and which thus serve as potential new targets for the treatment of this prevalent metabolic disease.

Moreover, we have developed a unified molecular atlas of hypothalamic cell types in mice (HypoMap). This resource integrates 17 publicly available single cell and single nucleus sequencing data sets of the murine hypothalamus with an in house generated new single nucleus data set, harmonizing the results across different experiments to allow a unified annotation of hypothalamic cell types. This resource will serve as a reference for the entire field to functionally validate the role of specific neuronal populations in control of metabolism and thereby potentially identify novel drug targets for the treatment of metabolic diseases.
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. In addition, HypoMap will aid the entire field of neuroendocrinology of metabolism for the unified characterization of metabolism-regulatory neurocircuits.