Interleukin-1β Regulates Fat-Liver Crosstalk in Obesity by Auto-Paracrine Modulation of Adipose Tissue Inflammation and Expandability

• DOI: 10.1371/journal.pone.0053626
• Publication Date: 2013-01-16T22:10:33Z
• Authors: Ori Nov; Hagit Shapiro; Hilla Ovadia; Tanya Tarnovscki; Irit Dvir; Elad Shemesh; Julia Kovsan; Ilan Shelef; Yaron Carmi; Elena Voronov; Ron N. Apte; Eli Lewis; Yulia Haim; Daniel Konrad; Nava Bashan; Assaf Rudich
• Keywords: Adipose tissue macrophages

The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role IL-1β was clinically demonstrated to mediate only pancreatic beta-cell demise, and mice mainly intra-hepatic manifestations obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed function locally, could regulate dysfunctional inter-organ crosstalk Here we show that High-fat-fed (HFF) exhibited preferential increase portal compared systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted lower pyruvate-glucose flux receiving wild-type (WT) transplant. These results raised putative endocrine for visceral fat-derived regulating hepatic gluconeogenic flux. on HFF minor or no adipose expression pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures CD11b-F4/80-double-positive macrophages, all which were markedly increased WT-HFF mice. Further consistent with autocrine/paracrine functions within tissue, tissue lipid content mice, but significantly less Ex-vivo, explants co-cultured primary hepatocytes WT IL-1-receptor (IL-1RI)-KO suggested direct effect adipose-derived hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly WT-HFF, they had larger depots similar degree adipocyte hypertrophy. Furthermore, adipogenesis markers (pparg, cepba, fabp4, glut4) decreased by WT, paradoxically elevated IL-1βKO-HFF local alterations inflammation expansion correlated liver size, steatosis, preserved sensitivity. Collectively, demonstrate promoting limiting expandability, supports ectopic accumulation adipose-tissue contributing impaired fat-liver nutritional