EXPLORING THE CROSSTALK BETWEEN IRON HOMEOSTASIS AND ADIPOSE METABOLISM

The normal functioning of many tissues relies on the tight regulation of both iron concentration and distribution within cells and tissues. Studies have shown that changes in adipocyte iron alter several aspects of adipose metabolism. Here we focus on understanding how Tmprss6, a hepatic serine protease, influences lipid metabolism and its potential implications for treating obesity and metabolic disorders. The loss of Tmprss6 in mice is protective against diet-induced obesity and promotes lipolysis; however, the mechanism is unclear. Utilizing a GalNac-conjugated Tmprss6 antisense oligonucleotide (ASO) to achieve Tmprss6 deficiency in mice, revealed a stark reduction in fat mass. Two hypotheses are being explored to understand the mechanisms behind the fat-reducing effects of Tmprss6-ASO:

 

Hepcidin-Dependent Mechanism:

   - Tmprss6-ASO induces hepcidin, retaining iron in adipose stromal vascular fraction (SVF) macrophages. This reduces iron availability to adipocytes lowering lipid absorption in the gut.

   - The study aims to confirm the necessity of hepcidin for the observed fat-reducing effects using hepcidin knockout (KO) mice.

 

Hepcidin-Independent Mechanism:

   - As a type II transmembrane serine protease (TTSP), Tmprss6 may activate hepatocyte growth factor (HGF). Activated HGF serves as a hepatokine linked to adipose metabolism.

   - Here we investigate whether Tmprss6-ASO inhibits the proteolytic activation of HGF, leading to reduced body fat by reducing adipogenesis in various adipose depots.

 

In summary, the study seeks to determine whether Tmprss6 influences lipid metabolism through hepcidin or independently via altered adipocyte HGF/c-Met signaling. Understanding these mechanisms could unveil novel therapeutic targets for obesity and metabolic disorders.