JAK Signaling Inhibitor Induces Browning of White Adipose Tissue, and Improves Systemic Metabolic Health In Vivo

[Speaker] Kikid R. Qurania:1
[Co-author] Koji Ikeda:2, Keiko Yagi:2, Ken-Ichi Hirata:1, Noriaki Emoto:2
1:Department of Internal Medicine, Division of Cardiovascular Medicine, Kobe University, Japan, 2:Department of Clinical Pharmacy, Kobe Pharmaceutical University, Japan

Obesity as global epidemic contributes greatly to the incidence of cardiovascular disease and strongly related to metabolic disorders. Obesity is caused by an imbalance between energy intake and energy consumption. One strategy to tackle obesity is to pharmacologically convert the energy storing white adipocyte into the energy-consuming brown adipocyte. Recently, it has been reported that JAK inhibitor induced browning of white adipose tissue (WAT) in vitro; however, this has not been proven in vivo studies. Here, we report the in vivo effects of JAK inhibition on browning of WAT and systemic metabolic homeostasis.
In this in vivo study, we used C57BL/6 mice given high-fat diet for 4 weeks to mimic obese mice and subsequently divided into 2 groups; JAK inhibitor-treatment group and vehicle-treatment group. The administration of JAK inhibitor drug (Tofacitinib) was performed through an osmotic pump implanted subcutaneously for 8 weeks. At the end of treatment, insulin sensitivity was assessed by insulin tolerance test.
Body weight in JAK inhibitor group showed a tendency toward decrease, though not statistically significant. JAK inhibition significantly improved the insulin sensitivity in mice compared with vehicle-treated group despite the similar body weight. Of note, JAK inhibition induced the browning of both subcutaneous and visceral WAT assessed by increased expression of brown adipocyte markers such as UCP-1 and PRDM16. Adipocyte size was reduced in WAT of JAK inhibitor groups, but chronic inflammation in WAT was not different between the groups.
We revealed that JAK inhibition could induce the browning of WAT and improved the systemic metabolic health in vivo. Though detailed molecular mechanisms remain to be elucidated, our data defined that JAK signaling is an attracting pharmacotherapeutic target for the treatment of obesity and its related metabolic disorders.

Advanced Search