IL18 is a pleiotropic cytokine that is expressed in cardiovascular disease-relevant macrophages, smooth muscle cells, endothelial cells, and adipocytes. Il18-/- mice but not Il18r-/- mice showed reduced atherosclerosis. These unexplained observations inspired the discovery that IL18 uses two receptors: IL18r and NCC (Na-Cl

co-transporter), a 12-transmembrane domain ion channel protein. The role of IL18 in obesity and diabetes remains uncertain. Adipocytes, skeletal muscle, and inflammatory cells in white adipose tissues (WAT) produce IL18. Plasma IL18 levels are elevated in obese and diabetic patients, correlate with HbA1C, and predict the risk of type 1 diabetes (T1D), type 2 diabetes (T2D). Paradoxically, results from several studies indicate that IL18 deficiency exacerbated obesity and diabetes in mice. Il18-/- and Il18r-/- mice on a chow diet gained more weight than wild-type mice, suggesting that IL18 is a homeostatic regulator that is elevated in obesity to oppose excess energy, analogous to insulin and adipokine leptin. Our preliminary studies suggest that IL18r and NCC mediate IL18 activities in distinct cell types. IL18 and NCC (but not IL18r) are expressed predominantly in BAT or in beige adipocytes. Their expression was reduced in mice on a high fat diet (HFD) or increased after thermogenic stimulation with CL316243. Deficiency of NCC (but not IL18r) reduced energy expenditure and BAT or beige adipocyte thermogenic program. BAT-selective IL18 deficiency aggravated obesity and diabetes. In WAT from HFD-fed and CL316243-treated mice, and in beige adipocytes from WAT, the expression of IL18 and IL18r (but not NCC) was increased. In WAT adipocytes, IL18 induced the expression of IL18r (but not NCC) and insulin signaling. Insulin receptor (IR�) formed an immunocomplex with IL18r, but not with NCC. In pancreas, we detected selective expression of IL18 in a-cells, NCC in �-cells, and IL18r in acinar cells. In HFD-induced T2D and streptozotocin-induced T1D, NCC or IL18r deficiency reduced pancreas islet count and insulin production and signaling with concurrent increase of islet macrophage content.�-cell NCC is required for islet insulin secretion and signaling, whereas IL18r on acinar cells is required for islet insulin secretion and to block exocrine acinus macrophage accumulation. a-cell-selective IL18 depletion or �- cell-selective NCC deficiency exacerbated HFD-induced obesity or diabetes. Our current program is to test the hypothesize that NCC in BAT controls thermogenesis, IL18r in WAT controls insulin signaling, NCC in islet �- cells controls �-cell insulin secretion and signaling and islet inflammation, and IL18r in acinar cells controls exocrine acinus inflammation and indirectly controls islet insulin secretion.