Baricitinib Inhibition of Jak/STAT Pathway Changed Immune Composition in Adipose Tissue and Improved Metabolism in Diet-Induced Obese Mice

ABSTRACT

Jak/STAT pathway plays key roles in inflammation and is highly activated in adipose tissue (AT) in obesity. Recently, inhibition of the Jak/STAT pathway with baricitinib, a Jak1/Jak2 inhibitor, has been demonstrated to accelerate clinical improvements in a trial of hospitalized patients with COVID-19, who had a mean BMI of 32. Currently, we aimed to examine effects of long-term treatment with baricitinib on AT inflammation and metabolism in diet-induced obese mice. Starting from 3 months old, male C57BL/6J mice were fed high fat diet (HFD) and concurrently received daily oral gavage of baricitinib (10mg/kg) or vehicle for 12 weeks. Compared to vehicle control, baricitinib treatment significantly improved insulin resistance examined by insulin tolerance test and increased UCP1 (a key browning marker) expression in perigonadal (pAT) and inguinal AT (iAT), but did not affect weight gain and AT mass. Strikingly, total T cells were reduced by ~50% in iAT and pAT in baricitinib group vs. control group. CD4+ IFNγ-expressing Th1 cells, IL5-expressing Th2 cells, and TNFα-expressing T cells were decreased in pAT, but not in iAT, of mice from baricitinib group vs. control group. Unexpectedly, percentage of TNFα-expressing cells in CD8+ T cells were higher in iAT of baricitinib-treated mice than controls. Finally, baricitinib compared to control reduced M1/M2 ratio in pAT, but not iAT, and reduced eosinophils in iAT and pAT. Baricitinib inhibition of Jak/STAT pathway in diet-induced obese mice improved insulin sensitivity and changed immune cells in AT, with dramatic reductions of T cells in particular, indicating an important role of Jak/STAT-mediated inflammation in metabolism in obesity. Given the fact that obesity and insulin resistance are associated with increased severity of COVID-19, our data also point to the need for further studies on AT immune cells, COVID-19, and baricitinib.