Fat Metabolism and Cancer Progression

In mammals, there are two main types of adipose tissue: white and brown. White fat plays a crucial role in systemic homeostasis, serving as an energy reservoir that stores triglycerides. Brown fat burns lipids to generate heat, particularly in response to cold temperatures or dietary stimuli. Brown-like adipocytes, known as “beige” cells, can also emerge within white adipose tissue through a process known as "browning". Recent evidence supports the existence of functional brown and beige fat in adult humans. Promoting brown fat development in both humans and experimental mouse models increases energy expenditure without causing tissue dysfunction, making fat manipulation an attractive therapeutic strategy.

The gut microbiota, which develops in concert with the host, is influenced by a variety of physiological changes and, in turn, regulates systemic metabolism through its impact on energy balance.

These metabolic axes have a profound impact on virtually all aspects of our functioning, influencing not only the metabolic health but also the immune system and even cancer.

©TRAJKOVSKI/UNIGE. Left) The human gut microbiota catalogue developed by the Trajkovski lab. Middle) Transversal [¹⁸F]FDG PET-CT images of adipose tissue from mice after microbiota transplantation. Right) Advanced metabolic profiling.

RESEARCH AIMS

Our research focuses on developing novel strategies to improve insulin sensitivity, induce weight loss and fat browning, and assess the importance of the immune system and the gut microbiota-host signalling axes in regulating metabolism and cancer. Using multiorgan integrative approaches and mice as a model organism, in combination with in vitro systems, computational biology and bioinformatics, and cohorts of human patients, we identified new physiological stimuli that lead to fat browning, established that the gut microbiota contributes to these processes, and identified molecular axes of these interactions. In a complementary line of research, we focus on the bone and the gastrointestinal tract, and how we can modulate its resorptive capacity.

With our microbiota-related line of research, we first focus on identifying how the microbiota modulates metabolic health, particularly the host's response to shifts in microbial composition. The second area focuses on developing advanced computational tools for microbiota analysis that can be used in diagnostics, personalised medicine, and for mechanistic assessments.

Our group also explores immunometabolism and the role of adipose tissue and the gut in the broader regulation of metabolism and cancer. We integrate advanced technologies and methodologies, aiming to develop new strategies for treating dyslipidaemia, diabetes, obesity, as well as cancer.

A deeper understanding of the interplay between microbiota, host metabolism and immune responses is crucial for improving therapeutic approaches to metabolic disorders and promoting long-term health.

EXPERTISE

Metagenomics, single-cell RNA sequencing, spatial transcriptomics, immunofluorescence, flow cytometry, in vivo, ex vivo and in vitro metabolic assays.

SELECTED PUBLICATIONS

Chevalier C, Stojanović O, Colin DJ, Suarez-Zamorano N, Tarallo V, Veyrat-Durebex C, Rigo D, Fabbiano S, Stevanović A, Hagemann S, Montet X, Seimbille Y, Zamboni N, Hapfelmeier S, Trajkovski M. Gut Microbiota Orchestrates Energy Homeostasis during Cold. Cell. 2015 Dec 3;163(6):1360-74. doi: 10.1016/j.cell.2015.11.004. PMID: 26638070.
Fabbiano S, Suárez-Zamorano N, Chevalier C, Lazarević V, Kieser S, Rigo D, Leo S, Veyrat-Durebex C, Gaïa N, Maresca M, Merkler D, Gomez de Agüero M, Macpherson A, Schrenzel J, Trajkovski M. Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements. Cell Metab. 2018 Dec 4;28(6):907-921.e7. doi: 10.1016/j.cmet.2018.08.005. Epub 2018 Aug 30. PMID: 30174308;
Chevalier C, Kieser S, Çolakoğlu M, Hadadi N, Brun J, Rigo D, Suárez-Zamorano N, Spiljar M, Fabbiano S, Busse B, Ivanišević J, Macpherson A, Bonnet N, Trajkovski M. Warmth Prevents Bone Loss Through the Gut Microbiota. Cell Metab. 2020 Oct 6;32(4):575-590.e7. doi: 10.1016/j.cmet.2020.08.012. Epub 2020 Sep 10. PMID: 32916104;
Spiljar M, Steinbach K, Rigo D, Suárez-Zamorano N, Wagner I, Hadadi N, Vincenti I, Page N, Klimek B, Rochat MA, Kreutzfeldt M, Chevalier C, Stojanović O, Bejuy O, Colin D, Mack M, Cansever D, Greter M, Merkler D, Trajkovski M. Cold exposure protects from neuroinflammation through immunologic reprogramming. Cell Metab. 2021 Nov 2;33(11):2231-2246.e8. doi: 10.1016/j.cmet.2021.10.002. Epub 2021 Oct 22. PMID: 34687652;
Trajkovski M, Hausser J, Soutschek J, Bhat B, Akin A, Zavolan M, Heim MH, Stoffel M. MicroRNAs 103 and 107 regulate insulin sensitivity. Nature. 2011 Jun 8;474(7353):649-53. doi: 10.1038/nature10112. PMID: 21654750.
Stojanović O, Altirriba J, Rigo D, Spiljar M, Evrard E, Roska B, Fabbiano S, Zamboni N, Maechler P, Rohner-Jeanrenaud F, Trajkovski M. Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα. Nat Commun. 2021 Dec 2;12(1):7031. doi: 10.1038/s41467-021-27133-7. PMID: 34857752;
Stojanović O, Miguel-Aliaga I, Trajkovski M. Intestinal plasticity and metabolism as regulators of organismal energy homeostasis. Nat Metab. 2022 Nov;4(11):1444-1458. doi: 10.1038/s42255-022-00679-6. Epub 2022 Nov 17. PMID: 36396854.