Genetic deletion of ITIH5 leads to increased development of adipose tissue in mice

Adipose tissue, as a metabolically and endocrinologically active organ, plays a central role in energy regulation. In obesity, physiological homeostasis in adipose tissue can no longer be maintained, leading to metabolic diseases. ITIH5 was originally identified as a tumor suppressor in various cancers, but its role in adipose tissue and obesity has yet not been investigated. Earlier studies observed increased ITIH5 expression in the adipose tissue of obese individuals, which subsequently decreased after weight loss. This study investigated the hypothesis that ITIH5 serves as a negative regulator of adipocyte proliferation and differentiation. ITIH5 knockout mice were compared with wild-type mice to analyze its effects on adipose tissue development in vivo and in vitro. In addition to quantitative adipose tissue analysis and functional cell assays for proliferation and trilinear differentiation of ASCs, the release of inflammatory cytokines like IL-6 and MCP-1 was examined in an artificially induced inflammatory environment. ITIH5−/− mice exhibited increased relative fat mass. Cell culture experiments revealed enhanced proliferation, adipogenic, and chondrogenic differentiation in ITIH5−/− cells, while recombinant ITIH5 protein inhibited these effects in a concentration-dependent manner. Furthermore, rITIH5 protein reduced the elevated IL-6 and MCP-1 secretion caused by the knockout. These findings show that ITIH5 plays a key regulatory role in adipose tissue physiology by inhibiting adipose tissue expansion and controlling adipocyte proliferation and differentiation. ITIH5 also influences inflammatory processes within adipose tissue, highlighting its importance in regulating obesity and related metabolic disorders. The results indicate that ITIH5 helps maintain adipose tissue homeostasis and underscore its significance as a regulator of adipose tissue.