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ABSTRACT The global prevalences of obesity and type 2 diabetes mellitus have reached epidemic status, presenting a heavy burden on society. It is therefore essential to find novel mechanisms

and targets that could be utilized in potential treatment strategies and, as such, intracellular membrane trafficking has re-emerged as a regulatory tool for controlling metabolic

homeostasis. Membrane trafficking is an essential physiological process that is responsible for the sorting and distribution of signalling receptors, membrane transporters and hormones or

other ligands between different intracellular compartments and the plasma membrane. Dysregulation of intracellular transport is associated with many human diseases, including cancer,

neurodegeneration, immune deficiencies and metabolic diseases, such as type 2 diabetes mellitus and its associated complications. This Review focuses on the latest advances on the role of

endosomal membrane trafficking in metabolic physiology and pathology in vivo, highlighting the importance of this research field in targeting metabolic diseases. KEY POINTS * The endosomal

system controls signalling involved in metabolic physiology by tuning the trafficking and distribution of key proteins. * Some of the core machineries involved in the endosomal system are

altered in metabolic diseases. * Tuning the endosomal system could improve metabolic parameters in metabolic diseases. * Altering receptor trafficking through ligand-biased agonism is a

potential novel therapeutic strategy for metabolic pathologies. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS

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FAQs * Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS METABOLIC MESSENGERS: SMALL EXTRACELLULAR VESICLES Article 07 February 2025 REGULATION OF CARGO SELECTION IN EXOSOME

BIOGENESIS AND ITS BIOMEDICAL APPLICATIONS IN CANCER Article Open access 05 April 2024 CONTEXT-SPECIFIC REGULATION OF EXTRACELLULAR VESICLE BIOGENESIS AND CARGO SELECTION Article 10 February

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Download references ACKNOWLEDGEMENTS We thank R. Sekar, S. Herzig and T.D. Müller (all at The Institute for Diabetes and Cancer, Helmholtz Munich, Germany), J. Heeren (University Clinic

Hamburg Eppendorf, Hamburg, Germany), J.-F. Tanti and M. Cormont (both at the Université Côte d’Azur, INSERM UMR1065 C3M, Nice, France) and A. Schürmann (German Institute for Human Nutrition

Potsdam-Rehbruecke, Potsdam, Germany) for helpful discussions and critical comments to the review. We thank L. Harrison (The Institute for Diabetes and Cancer, Helmholtz Munich, Germany)

for creating the first drafts of the figures. The authors acknowledge the support of the DFG grants ZE1037/1-3 and ZE1037/3-2, H2020-MSCA-ITN 2020 Network grant ‘EndoConnect’ and the BMBF

grant 16LW0116K to A.Z., and of INSERM, the Université Côte d’Azur and the Young Investigator Program of the ANR to J.G. (ANR18-CE14-0035-01-GILLERON). AUTHOR INFORMATION Author notes *

These authors contributed equally: Jerome Gilleron, Anja Zeigerer. AUTHORS AND AFFILIATIONS * Université Côte d’Azur, Institut National de la Santé et de la Recherche Médicale (Inserm),

UMR1065 C3M, Team Cellular and Molecular Pathophysiology of Obesity, Nice, France Jerome Gilleron * Institute for Diabetes and Cancer, Helmholtz Center Munich, Neuherberg, Germany Anja

Zeigerer * German Center for Diabetes Research (DZD), Neuherberg, Germany Anja Zeigerer Authors * Jerome Gilleron View author publications You can also search for this author inPubMed Google

Scholar * Anja Zeigerer View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS J.G. and A.Z. contributed equally to all aspects of the article.

CORRESPONDING AUTHORS Correspondence to Jerome Gilleron or Anja Zeigerer. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing interest. PEER REVIEW PEER REVIEW

INFORMATION _Nature Reviews Endocrinology_ thanks Jacqueline Stöckli, Amira Klip and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. ADDITIONAL

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https://pan.ukbb.broadinstitute.org/ UK BIOBANK: http://www.nealelab.is/uk-biobank GLOSSARY * Metabolic syndrome A cluster of conditions that occur together, increasing the risk of heart

disease, stroke and type 2 diabetes mellitus. * Non-alcoholic fatty liver disease A generic term for liver steatosis unrelated to excessive alcoholic consumption. * Endocytosis A process

requiring complex molecular machineries to internalize plasma membrane-containing cargo. * Exocytosis A cellular mechanism by which various molecules or proteins are transported from

intracellular compartments towards the plasma membrane. * Endosomal system A complex network of interacting organelles that comprise early, late and recycling endosomes. * Early endosomes

Also called sorting endosomes, these are endosomal compartments dedicated to cargo sorting to recycling or degradation pathways. * Late endosomes Also called multivesicular bodies, these are

intermediate endosomal compartments between early endosomes and lysosomes dedicated to concentrating cargo for degradation within intraluminal vesicles (vesicles generated within the lumen

of endolysosomal organelles). * Recycling endosomes Endosomal compartments dedicated to the recycling of cargo to the plasma membrane. * Lysosomes Specialized organelles dedicated to the

degradation of cargo. * Receptor desensitization A process leading to a decrease in the responsiveness of downstream signalling of receptors. * Endolysosomal system A complex network of

interacting organelles that comprise the endosomal system plus lysosomes. * Endocytic system A complex network of all organelles involved in endocytosis and endocytic trafficking. *

Endosomal tubules Tubules that arise from endosomes. * Ubiquitination Post-translational modification that covalently links ubiquitin molecules to a protein. * Trans-Golgi network A

tubulovesicular network of membrane compartments located at the _trans_-side of the Golgi apparatus. * Intracellular storage pool A pool of receptors and transmembrane proteins

intracellularly stored within compartments that can be recruited at the plasma membrane in response to a specific signal. * Adaptor proteins Proteins that act as connecting molecules. During

endocytosis, adaptor proteins connect cargo to be internalized with the molecular machinery performing endocytosis. * Cargo A generic term referring to transmembrane proteins (receptors,

transporters, etc.), signalling ligands (hormones, growth factors, etc.) and internalized extracellular proteins or macromolecules (transferrin, lipoproteins, etc.). * Coat proteins Proteins

that act to shape and/or form vesicles. * Soluble _N_-ethylmaleimide-sensitive factor attachment protein receptors A large protein family whose members mediate vesicle fusion. * Endosomal

sorting complexes required for transport A large protein family whose members mediate intraluminal vesicle formation. * GTPase-activating proteins Proteins able to activate the GTPase

activity of proteins. * Dominant-negative RAB A mutant form of RAB that preferentially binds GDP and out-competes the endogenous RAB pool for the binding of regulatory elements. *

Endoplasmic reticulum-to-Golgi intermediate compartment A tubule-vesicular network of membrane compartments located at the interface between the endoplasmic reticulum and the Golgi

apparatus. * Non-alcoholic steatohepatitis A form of NAFLD in which, in addition to liver steatosis, liver inflammation and damage appears. * Transcytosis Cellular mechanism by which various

molecules or proteins are transported across the cell. RIGHTS AND PERMISSIONS Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under

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publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Gilleron, J., Zeigerer, A. Endosomal trafficking in metabolic homeostasis and diseases.

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