Systems genetics reveals ITIH5 as a key mediator of adipocyte–Endothelial crosstalk
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.
Authors
- Hosung Bae (ORCID: https://orcid.org/0000-0001-5848-7972)
- Cholsoon Jang (ORCID: https://orcid.org/0000-0001-6651-4213)
- Lior Pachter (ORCID: https://orcid.org/0000-0002-9164-6231)
- Paul Petrus (ORCID: https://orcid.org/0000-0001-8297-3874)
- Lambda Moses (ORCID: https://orcid.org/0000-0002-7092-9427)
- Rémi Buisson (ORCID: https://orcid.org/0000-0002-7196-8209)
- Marcus Seldin (ORCID: https://orcid.org/0000-0001-8026-4759)
- Miklós Péterfy (ORCID: https://orcid.org/0000-0002-5280-0216)
- Mona Fouladi
- Douglas Arneson (ORCID: https://orcid.org/0000-0002-9464-2586)
- Dequina Nicholas (ORCID: https://orcid.org/0000-0003-4996-2190)
- Ivan Marazzi (ORCID: https://orcid.org/0000-0003-3376-0922)
- Amandine Verlande (ORCID: https://orcid.org/0000-0001-6794-4119)
- Farah Gamie
- Lillian Mott
- Andrea Hevener
- Mingqi Zhou
- Casey D. Johnson
- Xia YANG (ORCID: https://orcid.org/0009-0001-2642-9505)
- Danica Kwan
- Selma Masri
- Aldons Jake Lusis
- Christy M. Nguyen
- Leandro M. Velez
Institutions
- California Institute of Technology (US)
- Bristol-Myers Squibb (Germany) (DE)
- University of California, Los Angeles (US)
- University of California, Irvine (US)
- University of California System (US)
- Karolinska Institutet (SE)
- University of California, Davis (US)
- Western University of Health Sciences (US)
Publication Details
- Journal
- Molecular Metabolism
- Published
- 2026-04-21
- DOI
- https://doi.org/10.1016/j.molmet.2026.102373
- Primary Topic
- Angiogenesis and VEGF in Cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- NIH Office of the Director
- National Institute of Diabetes and Digestive and Kidney Diseases