1. Research Background

Obesity is a major health risk and affects an increasing population world-wide. Over the past decades, the brain, and specifically the hypothalamus and hindbrain, have been established as key regulators of energy homeostasis and food intake, highlighting the brain’s importance in the development of obesity. Energy-state correlated hormones such as leptin, which is secreted by adipocytes, reach leptin-receptor expressing neurons in the brain, which then control satiety and hunger. Mutations in key genes expressed in neurons involved the leptin signaling pathway such as the melanocortin-circuit in the hypothalamus, comprising e.g., Pro-opiomelanocortin (POMC) and Agouti-related peptide (AgRP) neurons, have been shown to cause severe obesity in humans. In recent years we and others have demonstrated that the hypothalamus comprises a vast number of different neuronal cell types, many of which play a role in energy homeostasis, behavior or other bodily functions, emphasizing the importance of characterizing neuronal circuits beyond the established models. Our research group employs methods from computational biology and bioinformatics to study the brain's role in regulating metabolism and energy balance. Our work focuses on characterizing the spectrum of neuronal cell types in the hypothalamus and hindbrain at the transcriptomic, epigenomic, metabolomic, and spatial level. We generate perturbation data sets to explore how different conditions, such as feeding state or obesity affect neurons in these brain regions and we work closely with other groups at the MPI for Metabolism Research to translate in-silico findings back into mechanistic biology, testing the hypotheses we derive from these large biological data sets. 

2. Research questions addressed by the group:

Cell type architecture of the hypothalamus and hindbrain

We develop multi-modal reference atlases to describe cell type diversity in the hypothalamus and hindbrain at high molecular and spatial resolution. Using machine learning methods, we integrate, cluster, and annotate OMICS data across different modalities and species to understand the conservation of cell types between humans and model organisms and to explore how gene expression is conserved and regulated in different neurons. To increase accessibility of our results, we develop novel visualization tools and approaches to make integrated multi-modal data easier to interpret. 

Effects of genetics and environment on metabolism-regulating cell types

We generate and analyze single-cell/nucleus transcriptomic and epigenomic data from mice subjected to various experimental conditions, studying how both neuronal and non-neuronal cells respond to environmental stimuli related to metabolism such as diet, feeding state or food perception. We aim to link human genetics data from rare variant studies and genome-wide association studies (GWAS) with our cross-species atlases to gain more mechanistic understanding of the effects of these variants in specific neurons and to prioritize both neuronal cell types, as well as, specific genes and their associated pathways and explore how these overlap with the cell types and pathways perturbed by experimental conditions. Utilizing cell type-specific epigenetic data we investigate how genetic variants, especially those in non-coding regions, affect gene regulation.

3. Possible project(s):

1. Multi-species atlas of the hypothalamus and hindbrain
   We are planning to generate multi-species transcriptomic atlases of hypothalamus and hindbrain that integrate our existing atlases with newly generated data and allow to define the conserved cross-species cell type architecture in these brain regions. This will enable to conduct a comprehensive and systematic investigation of gene expression and gene regulation across species within matched consensus cell types. This includes e.g. identifying differentially regulated gene modules across species and understanding functional differences in paralog gene usage. Lastly, we aim to connect the multi-species atlas with our metabolism research to e.g. investigate how central sensing of hormones evolved and how it differs between species.
    
2. Effect of obesity therapeutics on the endocrine system
   Using single-cell transcriptomics combined with other OMICs layers we want to study how the hypothalamus senses and responds to peripheral signals such as hormones and metabolites and how these responses are altered during treatment with obesity therapeutics. For this we want to simultaneously examine neuronal circuits in the hypothalamus as well as the metabolic state in peripheral organs such as liver, pancreas and adipose tissue using multi-omics approaches. 
   
   This involves generation of new data under different treatments, detailed in-silico analysis of gene expression and molecular pathway changes, as well as perturbations of cell-cell signaling and the metabolome. Ultimately, we aim to link molecular changes to functionally relevant cell types and confirming these results in-vivo.

4. Applied Methods and model organisms:

Methods:

• OMICs data analysis with a focus on the brain and neurons
• Single cell/nuclei & spatial transcriptomics
• Single-nuclei chromatin studies & analysis
• Human genetics
• Method development for single-cell and spatial data integration, clustering and visualization

5. Desirable skills and qualifications:

We seek a motivated PhD student interested in quantitative research and single-cell and spatial OMICS analysis, who wants to join a young, international team. A background or prior experience in bioinformatics, computational biology or systems biology will be advantageous.

6. References and key publications:

A comprehensive spatio-cellular map of the human hypothalamus
John A. Tadross*, Lukas Steuernagel*, Georgina K.C. Dowsett*, Katherine A. Kentistou, Sofia Lundh, Marta Porniece-Kumar, Paul Klemm, Kara Rainbow, Henning Hvid, Katarzyna Kania, Joseph Polex-Wolf, Lotte Bjerre-Knudsen, Charles Pyke, John R. B. Perry, Brian Y.H. Lam, Jens C. Brüning* & Giles S.H. Yeo*
Nature, 639, 708–716 (2025) 

Hypothalamic PNOC/NPY neurons constitute mediators of leptin‑controlled energy homeostasis
Marie H. Solheim, Sima Stroganov, Weiyi Chen, P. Sicilia Subagia, Corinna A. Bauder, Daria WnukLipinski, Almudena Del RíoMartín, Tamara SoteloHitschfeld, Cait A. Beddows, Paul Klemm, Garron T. Dodd, Sofia Lundh, Anna Secher, F. Thomas Wunderlich, Lukas Steuernagel & Jens C. Brüning
Cell, 188, 3550–3566.e22 (2025) 

HypoMap—a unified single-cell gene expression atlas of the murine hypothalamus
Lukas Steuernagel*, Brian Y. H. Lam*, Paul Klemm, Georgina K. C. Dowsett, Corinna A. Bauder, John A. Tadross, Tamara Sotelo Hitschfeld, Almudena del Rio Martin, Weiyi Chen, Alain J. de Solis, Henning Fenselau, Peter Davidsen, Irene Cimino, Sara N. Kohnke, Debra Rimmington, Anthony P. Coll, Andreas Beyer*, Giles S. H. Yeo* & Jens C. Brüning*
Nat Metab4, 1402–1419 (2022).