Tanycyte/arcuate Neuron communications in the regulation of energy balance

Project Information

TANGO

Grant agreement ID: 948196

DOI

10.3030/948196

EC signature date 18 November 2020

Start date 1 March 2021

End date 31 July 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

UNIVERSITE DE LAUSANNE
Switzerland

Periodic Reporting for period 3 - TANGO (Tanycyte/arcuate Neuron communications in the regulation of energy balance)

Reporting period: 2024-03-01 to 2025-08-31

Summary of the context and overall objectives of the project

The balance between energy intake and expenditure is essential to life and remains a central theme in biology, with significant ramifications for the pathogenesis and treatment of metabolic diseases, including obesity and diabetes. The escalating pandemic of these diseases (nearly tripled since 1975) in Western and developing countries represents one of the most pressing and costly biomedical challenges confronting modern society, prioritizing research in this field.

The regulation of energy balance partly relies on the central detection of metabolic cues, which informs the brain about the nutritional status of the body. Considered the "master metabolic integrator", the arcuate nucleus of the hypothalamus (located at the ventral part of the brain) integrates a substantial part of this metabolic information through a rich cellular network. Indeed, the emerging view is that neurons do not act alone to detect metabolic information but require the support of other cell types, such as glia, to perform as an integrated metabolic sensing network.

In this perspective, peculiar glial cells called tanycytes have begun to attract considerable attention. Tanycytes are special elongated and polarized ependymal cells in the arcuate nucleus and interact with neurons to regulate energy balance. Over the last years, numerous studies have elegantly demonstrated that tanycytes can detect variations of metabolic cues and communicate this information to neurons. Although these functions are now indisputable, many mechanistic questions remain, and further investigations are required to assess the dialog between tanycytes and neurons in the context of energy balance. The overall objective of this project is to elucidate the molecular, structural, and functional organization of tanycyte/arcuate neuron communications to control energy balance adequately, thanks to multidisciplinary approaches, including neuroanatomy, molecular biology, and physiology. In detail, the project aims to understand the molecular structures behind these interactions, the signals used for the communications, the cell biology necessary for the secretion of these signals, and its plasticity to respond to energy imbalance.

The elucidation of tanycyte/neuron communications will be essential to explain the regulation of energy balance and to allow the development of new therapeutic strategies for obesity and associated metabolic syndromes.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The overall objective of this project is to elucidate the molecular, structural, and functional organization of tanycyte/arcuate neuron communications to control energy balance adequately.

To shed light on the molecules behind tanycyte/neuron interaction, we combine high-throughput single-cell transcriptomics, inference of cell-cell communications, and neuroanatomical analysis. So far, we mainly defined 1- different tanycyte and neuron subpopulations in this brain region, 2- their specific molecular profile, and 3- the potential interactions by analyzing ligand-receptor couples between these cells. This high-throughput approach allowed us to sort candidate genes, which will be characterized in functional studies. Additionally, we also developed bioinformatical tools to analyze the tanycyte population, developing pseudospatial analysis, for instance, and validated these novel approaches on brain tissue using neuroanatomy.

To study signals secreted by tanycytes in these glia-neuron communications, we are currently evaluating the impact of annexin a1 (ANXA1) on hypothalamic neuronal functions and mouse physiology using complementary in vitro and in vivo approaches. First, we characterized the regulation of ANXA1 expression in tanycytes in response to energy imbalance (physiological variations such as fasting and pathological conditions such as diet-induced obesity) and inflammation levels in the hypothalamus. Second, combining single-cell transcriptomics and neuroanatomy, we analyzed which cell populations may be targeted by tanycytic ANXA1 and what the impacts on their functions are. Finally, we studied the impact of ANXA1 on mouse physiology, especially food intake, temperature, and anxiety.

To decipher the cell biology behind these tanycyte/neuron communications, we are analyzing the possibility of local translation: such mechanisms will allow quick and specific communications. So far, we have done a massive analysis by electron microscopy to visualize the machinery necessary for local translation in different metabolic conditions and revealed a link with calcium signaling in tanycytes. We are also implementing an approach to visualize the mRNA transport and translation in tanycytes depending on calcium response.

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)

The proposed research project addresses fundamental and challenging questions in metabolic neuroendocrinology, with high translational interest from basic scientists to clinicians. So far, our results first yielded new fundamental knowledge on the molecular basis for communication between tanycytes and neurons. The high-throughput analysis gave us numerous ligand-receptor couples that may be involved in the regulation of energy balance, whereas the study of ANXA1 detailed one peculiar signaling pathway. These analyses being done in different metabolic conditions, including physiological and pathological ones, the candidate genes we obtained may become targets to treat metabolic diseases.

Additionally, our results brought key knowledge regarding the tanycyte intracellular arrangement and how the tanycyte-neuron interface is organized. It allowed us to seek a more profound understanding of calcium signaling in these cell types.
Finally, our data gave rise to a new concept in the field. Indeed, the organization of the arcuate nucleus is much more complex than a neuron-tanycyte partnership. We observed back-and-forth communications with numerous other cell types, such as microglia and endothelial cells, enlarging our view into a tanycyte connectome.

Dancing with tanycytes: neuronal partnership