Systems genetics reveals ITIH5 as a key mediator of adipocyte-Endothelial crosstalk PMID: 42025695

ADC Targets in Oncology

2026-04-10

Systems genetics reveals ITIH5 as a key mediator of adipocyte-Endothelial crosstalk

Mol Metab. 2026 Jun:108:102373. doi: 10.1016/j.molmet.2026.102373.

Mingqi Zhou ¹ , Leandro M Velez ¹ , Danica Kwan ¹ , Lambda Moses ² , Casey D Johnson ¹ , Christy M Nguyen ¹ , Lillian Mott ³ , Farah Gamie ¹ , Mona Fouladi ⁴ , Hosung Bae ¹ , Amandine Verlande ¹ , Douglas Arneson ⁵ , Paul Petrus ⁶ , Miklós Péterfy ⁷ , Andrea Hevener ⁸ , Remi Buisson ¹ , Xia Yang ⁹ , Lior Pachter ¹⁰ , Aldons Jake Lusis ⁴ , Selma Masri ¹ , Dequina A Nicholas ¹¹ , Cholsoon Jang ¹ , Ivan Marazzi ¹ , Marcus Seldin ¹²

Affiliations

1. Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, USA.
2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA; Department of Statistics and Irving Institute of Cancer Dynamics, Columbia University, New York, USA.
3. Department of Pharmacology, University of California Davis, Davis, CA, USA.
4. Department of Medicine, Division of Cardiology, University of California, Los Angeles, USA.
5. Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA; Informatics and Predictive Sciences, Bristol Myers Squibb, San Diego, CA, USA.
6. Department of Medicine (H7), Karolinska Institutet, Stockholm 141 86, Sweden.
7. Department of Biomedical Sciences, Western University of Health Sciences, Pomona, CA, USA.
8. Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles Los Angeles CA, USA.
9. Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
10. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, USA.
11. Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, USA; Department of Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, Irvine CA, USA.
12. Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, USA. Electronic address: [email protected].

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.

Keywords

Adipose cell crosstalk; Adipose-endothelial signaling; ITIH5; Systems genetics.