New AI framework maps systemic obesity damage at cellular resolution

Researchers at Helmholtz Munich, the Ludwig Maximilians University Munich (LMU) and collaborating institutions have developed an artificial intelligence (AI) framework that maps disease-related changes throughout the entire mouse body at cellular resolution. Using the new platform, called MouseMapper, the researchers uncovered widespread inflammation and previously unrecognized damage to facial sensory nerves caused by obesity. Importantly, they also identified corresponding molecular signatures in human tissue, suggesting that key features of obesity-associated nerve damage are conserved across species. The findings are published today in the journal Nature.

Obesity affects far more than metabolism and fat storage. It alters immune activity, nerve structure, and tissue organization across multiple organ systems, increasing the risk of diseases including type 2 diabetes, cardiovascular disease, stroke, neuropathy and cancer. Yet despite these systemic effects, researchers have lacked tools capable of studying disease-associated changes across the entire body in intact organisms and at high resolution.

A team led by Prof. Ali Ertürk, Director of the Institute for Biological Intelligence (iBIO) at Helmholtz Munich and Professor at the LMU, has now developed MouseMapper, a suite of foundation-model-based deep-learning algorithms designed to analyze whole-body biological imaging data. The framework automatically segments 31 organs and tissue types while quantitatively mapping nerves and immune cells throughout the body, enabling comprehensive multi-system analysis in intact mice.

MouseMapper is built on a foundation model, which means it generalizes far beyond the data it was originally trained on." 

Ying Chen, co-first author of the study

Looking inside an entire transparent mouse

To create whole-body maps, the researchers labeled nerves and immune cells in mice with fluorescent markers visible under the microscope. They then used tissue-clearing techniques to render the animals transparent while preserving the fluorescent signals, allowing imaging deep inside intact bodies.

Using specialized light-sheet microscopy, the team captured detailed three-dimensional images of entire mice, producing datasets containing tens of millions of cellular structures across organs and tissues. MouseMapper then analyzed these data automatically, identifying nerves, immune-cell clusters, and anatomical regions throughout the body.

This allowed the researchers to determine precisely where inflammation and structural damage occur across different tissues – including fat, muscle, liver, and peripheral nerves – without requiring researchers to preselect specific regions of interest.

New insights into obesity, from mouse to human

To investigate how obesity reshapes the body, the researchers fed mice a high-fat diet that induced obesity and metabolic dysfunction similar to that observed in humans. Applying MouseMapper revealed widespread changes in both immune-cell organization and nerve architecture across the body.

One of the most striking findings was a structural change to part of the trigeminal nerve, a major facial nerve that is responsible for facial sensation and motor functions. In obese mice, these sensory nerves had far fewer endings and branches, suggesting a loss of normal nerve function. Behavioral experiments further showed that the animals responded less to sensory stimulation than lean mice, linking the structural damage to impaired sensory function.

The researchers next examined the trigeminal ganglion, the structure containing the cell bodies of facial sensory neurons. Using spatial proteomics, they identified molecular alterations associated with nerve remodeling and inflammation. Remarkably, many of the same molecular signatures were also detected in trigeminal tissue from people with obesity, suggesting that the obesity-associated nerve alterations observed in mice also occur in humans.

"We revealed previously unknown structural and molecular changes in the trigeminal ganglion and its facial branches, and the same molecular signature was conserved in human tissue. This kind of finding simply cannot emerge from studying one organ at a time" says Dr. Doris Kaltenecker, senior scientist at the Institute for Diabetes and Cancer (IDC) at Helmholtz Munich and first author of the study.

A platform for studying systemic disease

Beyond obesity, the researchers believe MouseMapper could transform the study of complex diseases that affect multiple organs systems simultaneously, including diabetes, cancer, neurodegeneration and autoimmune disorders. Unlike earlier methods focused on selected organs or tissues, MouseMapper provides an integrated whole-body analysis platform capable of identifying disease "hotspots" throughout the organism.

The team has made whole-body datasets publicly available online, allowing scientists worldwide to explore obesity-associated changes across tissues and organ systems.

"Our goal is to create a comprehensive framework for understanding how diseases affect the body as an interconnected system," says Ali Ertürk. "Our long-term vision is to build truly realistic digital twins of mice in health and disease: cell-level atlases that we can query, perturb and screen in silico computationally. That would let us pinpoint the earliest changes a disease causes, design interventions to prevent them, and accelerate the discovery of new treatments while reducing the number of physical experiments we need to run."