Visceral adipose tissue mast cell infiltration defines a clinically-meaningful favorable sub-phenotype of people with obesity and diabetes

Nir Goldstein ^1,3 Yarden Kezerle ² Yftach Gepner ³ Yulia Haim ¹ Tal Pecht ¹ Roi Gazit ^4,5 Vera Polischuk ⁶ Idit F Liberty ⁶ Boris Kirshtein ⁶ Ruthy Shaco-Levy ² Matthias Blüher ⁷ Assaf Rudich ^1,5

¹Department of Clinical Biochemistry and Pharmacology,, Ben-Gurion University of the Negev, Israel
²Institute of Pathology, Soroka University Medical Center Ben-Gurion University of the Negev, Israel
³Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine and Sylvan Adams Sports Institute, Tel Aviv University, Israel
⁴The Shraga Segal Department of Microbiology Immunology and Genetics Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁵The National Institute of Biotechnology in the Negev, Ben-Gurion University of the Negev, Israel
⁶Soroka Academic Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Israel
⁷Department of Medicine, University of Leipzig, Germany

Aims and hypothesis
Identification of obesity sub-types may improve the clinical management, and uncover previously-unrecognized mechanisms. Adipose tissue (AT) inflammation is associated with a more metabolically-adverse obesity phenotype. Here we hypothesized that AT-mast cells (MC) estimation could contribute to human obesity sub-phenotyping, both cross-sectionally and prospectively.
Methods
A cohort of 65 persons with obesity who underwent elective abdominal (mainly bariatric) surgery was established. Visceral AT (VAT) and subcutaneous (SAT) MC infiltration was estimated by gene expression and histologically, and associations with cardiometabolic risk and the response to bariatric surgery were assessed.
Results
VAT-MC (but not SAT-MC) gene expression (KIT, TPSB2, CMA1) was associated with a better metabolic profile, especially in persons with obesity and type 2 diabetes: higher expression of MC genes (`MC^high`) associated with lower fasting glucose, HbA1c, triglycerides, alkaline-phosphatase and higher HOMA-β compared to low expression (`MC^low`). We next treated HepG2 cells with conditioned media (CM) from VAT explants MC^high versus MC^low. VAT-MC^low-CM-treated hepatocytes were more insulin resistant, compared to AT-MC^high-CM-treated hepatocytes. Finally, VAT-MC^high patients prospectively lost more weight six months after bariatric surgery compared to VAT-MC^low patients.
Conclusions
High VAT-MC infiltration may define an obesity sub-phenotype that is associated with a “healthier” cardiometabolic risk profile and a greater weight-loss response to bariatric surgery.