CB2 stimulation of adipose resident ILC2s orchestrates immune balance and ameliorates type 2 diabetes mellitus.

Development of type 2 diabetes mellitus (T2DM) is associated with low-grade chronic type 2 inflammation and disturbance of glucose homeostasis. Group 2 innate lymphoid cells (ILC2s) play a critical role in maintaining adipose homeostasis via the production of type 2 cytokines. Here, we demonstrate that CB 2 , a G-protein-coupled receptor (GPCR) and member of the endocannabinoid system, is expressed on both visceral adipose tissue (VAT)-derived murine and human ILC2s. Moreover, we utilize a combination of ex vivo and in vivo approaches to explore the functional and therapeutic impacts of CB 2 engagement on VAT ILC2s in a T2DM model. Our results show that CB 2 stimulation of ILC2s protects against insulin-resistance onset, ameliorates glucose tolerance, and reverses established insulin resistance. Our mechanistic studies reveal that the therapeutic effects of CB 2 are mediated through activation of the AKT, ERK1/2, and CREB pathways on ILC2s. The results reveal that the CB 2 agonist can serve as a candidate for the prevention and treatment of T2DM. [Display omitted] • CB 2 is expressed on adipose-resident ILC2s • CB 2 signaling is mediated via the AKT, ERK1/2, and CREB pathways • CB 2 stimulation of ILC2s protects against and reverses metabolic distress in T2DM • CB 2 induces type 2 cytokine production by human ILC2s, supporting its therapeutic potential CB 2 is highly expressed on adipose-resident ILC2s. Shafiei-Jahani et al. reveal that CB 2 agonists stimulate murine and human ILC2s, enhancing their proliferation and cytokine production through the AKT, ERK1/2, and CREB pathways. This activation promotes an IL-13-dependent mechanism that prevents insulin resistance, enhances glucose tolerance, and reverses established conditions in T2DM. [ABSTRACT FROM AUTHOR]