Disruption of mesothelial connections to the spleen inhibits splenic anti‐inflammatory responses and protects from the development of insulin resistance in rats

We have recently reported that stimulation of gastric acid secretion with NaHCO 3 promotes an anti‐inflammatory response in both rats and healthy human subjects. Importantly, disruption of ‘neuronal like’ mesothelial cell connections to spleen abolished this response. The Dahl salt‐sensitive (SS) rat model develops insulin resistance when fed a high salt diet. As low grade inflammation is thought to promote insulin resistance, we hypothesized that ‘Ingestion of NaHCO 3 would prevent the development of insulin resistance in Dahl SS rats and that this protection would be lost following surgical disruption of mesothelial connections to the spleen’. 9 week old male Dahl salt‐sensitive rats were anesthetized with isoflurane, an abdominal incision performed and either; mesothelial connections to the spleen physically disrupted (DISRUPTED) or; the spleen left untouched (SHAM). Following 1 wk of recovery from surgery, all rats were placed on an 8% high salt (HS) diet for 3 weeks. Upon starting the HS diet, the drinking water was replaced with either 0.1M NaHCO 3 (n=12 sham, n=10 disrupted) or equimolar NaCl solutions (n=11 sham, n=9 disrupted). An insulin tolerance test as performed at day 17 of HS feeding. Following 21 days of HS the spleen was harvested for flow cytometry analysis (n=6 each group). Ingestion of NaHCO 3 in SHAM rats resulted in significantly fewer splenic pro‐inflammatory M1 macrophages when compared to SHAM rats drinking NaCl (4.8±0.3 vs 7±0.5% splenocytes, ANOVA p=0.01, respectively) and this difference was abolished following mesothelial disruption (NaHCO 3 + DISRUPTED =7.2±0.5%, p=N.S). Insulin administration resulted in a decrease in blood glucose in all groups, however the decrease in blood glucose was significantly greater in the DISRUPTED + NaHCO 3 group when compared to all other groups (p=0.02). The % of splenic cells identified as myeloid dendritic cells mirrored the development of insulin resistance, with myeloid dendritic cells being significantly lower (p=0.02) only in the DISRUPTED + NaHCO 3 group. In agreement with our previous studies, ingestion of NaHCO 3 promoted an anti‐inflammatory response in the spleen which was abolished by surgical disruption of splenic mesothelial connections. Protection from the development of insulin resistance however, did not correlate with this anti‐inflammatory effect. Rather, the degree of insulin resistance was mirrored by differences in splenic myeloid dendritic cells. These data are important as they demonstrate that, despite promoting an inflammatory phenotype, disruption of mesothelial connections to the spleen can contribute to protection from the development of insulin resistance. As both NaHCO 3 ingestion and vagal nerve stimulation promote gastric acid secretion, and the anti‐inflammatory response to both stimuli can be inhibited by a nicotinic receptor antagonist, we speculate that these mesothelial connections mediate the anti‐inflammatory response to efferent vagal stimulation. Our data indicate however, that multiple signals are received by the spleen and that these act in combination to modulate immune responses resulting in varied functional effects. Support or Funding Information DK099548, P01HL134604 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .