Folgueras AR, Freitas-Rodríguez S, Ramsay AJ, Garabaya C, Rodríguez F, Velasco G, López-Otín C. Nat Commun. 2018 Apr 10;9(1):1350 PDF
Commentary by Dr Gautam Rishi and Prof Nathan Subramaniam Liver Disease and Iron Disorders Research Group, Queensland University of Technology, Brisbane.
Iron dysfunction is associated with many clinical conditions including neurodegenerative disorders, cancers, the anemia associated with chronic disease, and many iron disorders. Several studies have also linked disturbed iron regulation with metabolic disorders including obesity; however in most cases it is linked to iron deficiency, with chronic inflammation identified as a possible cause. The iron regulatory hormone hepcidin is regulated by a number of proteins and various stimuli. Matriptase-2, encoded by TMPRSS6, is thought to be a repressor of hepcidin expression through its cleavage of the positive regulator, hemojuvelin (encoded by HJV). A deficiency of matriptase-2 in humans is associated with a form of anemia termed iron-refractory iron deficiency anemia (IRIDA).
This study by Folgueras et al, from the laboratory of Prof Carlos Lopez-Otin, demonstrates that mice with deficiency of matriptase-2 are protected from obesity induced by a high-fat diet. The authors demonstrate, and ascribe this protective effect to the increased breakdown of fat/lipids in matriptase-2 deficient mice resulting in decreased fat deposition. Surprisingly, the authors observed decreased levels of the “hunger hormone” leptin and a concomitant increase in food intake in matriptase-2 knockout mice which however showed decreased weight gain. Matriptase-2 knockout mice fed a high fat diet also had decreased liver steatosis and improved glucose tolerance. Decreasing hepcidin expression in matriptase-2 knockout mice through use of a neutralizing antibody against HJV reversed these effects. In summary these exciting studies demonstrate an important role for hepcidin and thus iron regulation in lipid homeostasis and function of adipocytes, opening new avenues in the fight against obesity.