ITIH5 inhibits proliferation, adipogenic differentiation, and secretion of inflammatory cytokines of human adipose stem cells—A new key in treating obesity?

Inter-α-trypsin inhibitor heavy chain 5 (ITIH5) is widely expressed in the human body, and it is detected to be particularly abundant in adipose tissue. ITIH5 expression is increased in people with obesity compared to lean persons and is decreased by diet-induced weight loss. This suggests that ITIH5 may be involved in the development of adiposity and clinical metabolic variables, although its exact function remains unknown. We measured the protein concentration of ITIH5 in adipose samples from patients undergoing abdominoplasty and tested for correlation with the subjects' BMI as well as inflammatory mediators. We stimulated human adipose stem cells (ASCs) with recombinant (r)ITIH5 protein and tested for an effect on proliferation, differentiation, and immunosuppressive properties when the cells were exposed to an artificial inflammatory environment. We found positive correlations between ITIH5 levels and the BMI (p < .001) as well as concentrations of inflammatory cytokines (TNF-α, IL-6, and MCP-1) in adipose tissue (p < .01). Application of the rITIH5 protein inhibited both proliferation (p < .001) and differentiation of ASCs. Especially, the development of mature adipocytes was reduced by over 50%. Moreover, rITIH5 decreased the release of IL-6 and MCP-1 when the cells were exposed to TNF-α and IL-1β (p < .001). Our data suggest that ITIH5 is an adipokine that is increasingly released during human adipose tissue development, acting as a regulator that inhibits proliferation and adipogenic differentiation of ASCs. ITIH5 thus presents itself as a positive regulator of adipose tissue homeostasis, possibly protecting against both hyperplasia and hypertrophy of adipose tissue and the associated chronic inflammation.