ITIH5 drives adipocyte differentiation and obesity-associated metabolic dysregulation via PI3K/AKT signaling activation.

Obesity markedly increases the risk of type 2 diabetes, highlighting the urgent need for novel therapeutic targets. The inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5), which is predominantly produced by the adipose tissue, has emerged as a potential regulatory factor in obesity; however, the specific underlying mechanisms remain unclear. In this study, we identified ITIH5 as a key factor upregulated in obesity and closely associated with adipocyte differentiation and metabolic regulation. ITIH5 expression was significantly elevated in the adipose tissue of obese mice. In vitro experiments revealed that ITIH5 knockdown suppressed 3T3-L1 adipocyte differentiation, lipid accumulation, and inflammatory cytokine secretion, whereas ITIH5 overexpression markedly enhanced these effects. Mechanistically, activation of the PI3K/AKT signaling pathway was found to mediate ITIH5-induced adipogenic differentiation and lipid synthesis. Consistent with these findings, in vivo knockdown of ITIH5 in the inguinal white adipose tissue alleviated high-fat diet-induced obesity, reduced adipocyte hypertrophy, improved glucose tolerance, and increased energy expenditure. Conversely, overexpression of ITIH5 aggravated metabolic dysfunction. Collectively, these findings indicate that ITIH5 promotes adipogenesis and obesity progression via the PI3K/AKT pathway, providing a potential therapeutic target for obesity intervention.