Journal article
Systems genetics reveals ITIH5 as a key mediator of adipocyte–Endothelial crosstalk
Molecular metabolism (Germany), Vol.108, p.102373
06/01/2026
DOI: 10.1016/j.molmet.2026.102373
PMID: 42025695
Abstract
Proper adipose tissue homeostasis is essential for systemic metabolic health, and its disruption promotes insulin resistance, inflammation, and cardiometabolic risk. Using unbiased systems genetics analyses in mice and humans identified ITIH5 as a central regulator of adipose homeostasis and whole-body metabolism. Acute administration of recombinant ITIH5 with pan-organ sequencing revealed a local adipose function, suppressing recruitment of circulating immune cells. Consistently, ITIH5 treatment in human endothelial cells reduced leukocyte recruitment. We generated temporally controlled, adipocyte-specific ITIH5 overexpression models in mice, which improved adipose architecture, glucose metabolism under high-fat diet conditions, while consistently reducing left ventricular mass and cardiac output regardless of dietary group. Spatial transcriptomics of adipose tissue showed that elevated ITIH5 signaling to endothelia selectively impairs dendritic cell (DC) and B cell activation pathways. Collectively, these findings identify a mechanism whereby natural genetic variation in an adipocyte-secreted protein modulates endothelial–immune interactions in fat, influencing cardiometabolic homeostasis in a diet-dependent manner.
•Multi-tissue network and genetic centrality identify ITIH5 as a regulator linking adipose coordination to systemic homeostasis.•Adipocyte-specific AAV models show ITIH5 enhances adipocyte–endothelial signaling and reduces hypertrophy and glucose intolerance.•Spatial transcriptomics maps adipocyte–endothelial–immune crosstalk, showing ITIH5 suppresses adipose immune activation.•Integrated spatial and physiological data link ITIH5 immune suppression in adipose to protection against cardiac remodeling.
Details
- Title: Subtitle
- Systems genetics reveals ITIH5 as a key mediator of adipocyte–Endothelial crosstalk
- Creators
- Mingqi Zhou - University of California, IrvineLeandro M. Velez - University of California, IrvineDanica Kwan - University of California, IrvineLambda Moses - California Institute of TechnologyCasey D. Johnson - University of California, IrvineChristy M. Nguyen - University of California, IrvineLillian Mott - University of California, DavisFarah Gamie - University of California, IrvineMona Fouladi - University of California, Los AngelesHosung Bae - University of California, IrvineAmandine Verlande - University of California, IrvineDouglas Arneson - Bristol-Myers Squibb (Germany)Paul Petrus - Karolinska InstitutetMiklós Péterfy - Western University of Health SciencesAndrea Hevener - University of California, Los AngelesRemi Buisson - University of California, IrvineXia Yang - University of California, Los AngelesLior Pachter - California Institute of TechnologyAldons Jake Lusis - University of California, Los AngelesSelma Masri - University of California, IrvineDequina A. Nicholas - University of California, IrvineCholsoon Jang - University of California, IrvineIvan Marazzi - University of California, IrvineMarcus Seldin - University of California, Irvine
- Resource Type
- Journal article
- Publication Details
- Molecular metabolism (Germany), Vol.108, p.102373
- DOI
- 10.1016/j.molmet.2026.102373
- PMID
- 42025695
- NLM abbreviation
- Mol Metab
- ISSN
- 2212-8778
- eISSN
- 2212-8778
- Publisher
- Elsevier GmbH
- Language
- English
- Date published
- 06/01/2026
- Academic Unit
- Internal Medicine
- Record Identifier
- 9985217133602771
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