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Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signalling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine-Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signalling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signalling. In vivo, shRNA-mediated SWELL1 knockdown and adipose-targeted SWELL1 knockout reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.

Background: The clinical significance of Chiari’s network identified by echocardiogram is not yet established. A few authors have hypothesized that Chiari’s network may be associated with a patent foramen ovale, atrial septal aneurysm and paradoxical embolism. We set out to better understand the relationships of arterial embolic events and echocardiographic diagnosis of Chiari’s network in our adult population. Methods: We reviewed unique subject-adult transesophageal echocardiograms (TEE) performed at UIHC between November 2010 and March 2015 (n=3,703); we identified subjects with transesophageal echocardiographic diagnosis of Chiari’s network. Chiari’s network was observed in 6.2% of all TEE studies (n=229); males represented 59.8% with mean age of 61.5±16.3 years and mean left ventricular ejection fraction 53.8% ± 13.6%. Retrospective chart review was then performed to evaluate clinical variables encompassing a median [IQR] follow up of 8 months [2-19]. Results: Patent foramen ovale and atrial septal aneurysm were present in 22.3% and 11.4% subjects respectively. Approximately one half of patients (n=115, 50.2%) experienced at least one systemic embolic event by the end of the follow up period. Of these, 84 (36.7%) and 30 (13.1%) patients suffered stroke and transient ischemic events respectively. The all-cause mortality rate was high at 13.5%. Atrial tachyarrhythmia was present in 59 subjects (25.8%). The rate of systemic embolic events was higher in those without atrial tachyarrhythmia compared to those with atrial tachyarrhythmia (58.2% vs. 27.1%, p=0.000; OR (95% CI),0.267 (0.139-0.511). Antithrombotic therapy was prescribed in 79% of all subjects, 86.4% of patients with atrial tachyarrhythmia and 95.5% of patients with systemic embolic events. Conclusions: Patients with Chiari’s network have a high incidence of atrial tachyarrhythmia and systemic embolic events, primarily embolic stroke and transient ischemic events. Systemic embolic events occurred at significantly higher rates in subjects with Chiari’s network and no atrial tachyarrhythmia than those with atrial tachyarrhythmia. Future studies are warranted to further elucidate the risk of thromboembolic events in patients with Chiari’s network.

SUMMARY Adipocytes undergo considerable volumetric expansion in the setting of obesity. It has been proposed that such marked increases in adipocyte size may be sensed via adipocyte-autonomous mechanisms to mediate size-dependent intracellular signaling. Here, we show that SWELL1 (LRRC8a), a member of the Leucine Rich Repeat Containing protein family, is an essential component of a volume-sensitive ion channel (VRAC) in adipocytes. We find that SWELL1-mediated VRAC is augmented in hypertrophic murine and human adipocytes in the setting of obesity. SWELL1 regulates adipocyte insulin-PI3K-AKT2-GLUT4 signaling, glucose uptake and lipid content via SWELL1 C-terminal leucine-rich repeat domain interactions with GRB2/Cav1. Silencing GRB2 in SWELL1 KO adipocytes rescues insulin-pAKT2 signaling. In vivo, shRNA-mediated SWELL1 knock-down and adipose-targeted SWELL1 knock-out reduce adiposity and adipocyte size in obese mice while impairing systemic glycaemia and insulin-sensitivity. These studies identify SWELL1 as a cell-autonomous sensor of adipocyte size that regulates adipocyte growth, insulin sensitivity and glucose tolerance.

Previous studies have indicated that inhibitors of the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) protect against ischemia reperfusion injury (IRI) in the brain and heart. However, the role of endogenous 20-HETE in renal IRI has not been well characterized. The present study compared the susceptibility to IRI in Dahl salt-sensitive (S) rats in which the renal formation of 20-HETE is impaired versus that seen in normal Sprague-Dawley (SD) rats and in SS.5LEW 4A+ (4A+) congenic and SS.BN5 (BN5) consomic strains in which the CYP4A region of chromosome 5 was transferred from the Lewis or Brown Norway rats into the S genetic background. S, 4A+ and BN5 rats were fed a low salt diet and SD rats were fed a standard diet. IRI was induced by bilateral renal ischemia for 30 minutes followed by reperfusion. The 20-HETE production was measured using liquid chromatography-mass spectrometry (LC/MS). The renal production level of 20-HETE was significantly greater in SD, 4A+ and BN5 rats as compared to S rats and renal 20-HETE levels rose to a greater extent in these strains than in S rats following renal ischemia reperfusion. Plasma creatinine concentration rose to 3.7 ± 0.1 (n=6), 2.0 ± 0.4 (n=6), 1.9 ± 0.3 (n=6) and 2.2 ± 0.3 (n=6) mg/dl 24 hours following renal ischemia in S, 4A+, BN5 and SD rats, respectively. The kidney of S rats following IRI exhibited renal tubular necrosis and protein casts. The % of necrotic tubules in the corticomedullary regions of S rats (42.5 ± 3.5 %) was significantly higher than that seen in 4A+ (10.8 ± 3.8 %) or BN5 (10.2 ± 1.5 %) rats. The number of apoptotic tubular cells in the corticomedullary regions of S rats (125.3 ± 8.2 cells/field) was significantly higher than that seen in BN5 rats (46.8 ± 5.1 cells/field). Administration of the 20-HETE antagonist (6, 15-20-hydroxyeicosadecanoic acid) or the 20-HETE synthesis inhibitor (HET0016) abolished the resistance of 4A+ and BN5 rats to renal IRI and plasma creatinine levels rose to 4.0 ± 0.4 (n=4) and 3.8 ± 0.1 (n=4) mg/dl, respectively. The % of necrotic tubules respectively increased to 33.6 ± 6.9 % and 38.5 ± 5.5 % in 4A+ and BN5 rats and the number of apoptotic tubular cells increased to 119.2 ± 10.7 cells/field in BN5 rats. These data indicate that endogenously released 20-HETE plays a protective role in renal IRI.

Chiari network and atrial septal aneurysm (ASA) are considered “normal” anatomic variants though ASA has been associated with embolic events. The relationship of these variants with cardiomyopathy, cardiac conduction abnormalities and arrhythmias has not been described. From all adult patients