Reduced Serotonin Reuptake Transporter (SERT) Function Causes Insulin Resistance and Hepatic Steatosis Independent of Food Intake

Serotonin reuptake transporter (SERT) is a key regulator of serotonin neurotransmission and a major target of antidepressants. Antidepressants, such as selectively serotonin reuptake inhibitors (SSRIs), that block SERT function are known to affect food intake and body weight. Here, we provide genetic evidence that food intake and metabolism are regulated by separable mechanisms of SERT function. SERT-deficient mice ate less during both normal diet and high fat diet feeding. The reduced food intake was accompanied with markedly elevated plasma leptin levels. Despite reduced food intake, SERT-deficient mice exhibited glucose intolerance and insulin resistance, and progressively developed obesity and hepatic steatosis. Several lines of evidence indicate that the metabolic deficits of SERT-deficient mice are attributable to reduced insulin-sensitivity in peripheral tissues. First, SERT-deficient mice exhibited beta-cell hyperplasia and islet-mass expansion. Second, biochemical analyses revealed constitutively elevated JNK activity and diminished insulin-induced AKT activation in the liver of SERT-deficient mice. SERT-deficient mice exhibited hyper-JNK activity and hyperinsulinemia prior to the development of obesity. Third, enhancing AKT signaling by PTEN deficiency corrected glucose tolerance in SERT-deficient mice. These findings have potential implications for designing selective SERT drugs for weight control and the treatment of metabolic syndromes

Long-term effects of oxygen-enriched high-flow nasal cannula treatment in COPD patients with chronic hypoxemic respiratory failure

Line Hust Storgaard,1 Hans-Ulrich Hockey,2 Birgitte Schantz Laursen,3,4 Ulla Møller Weinreich1,3 1Department of Respiratory Diseases, Aalborg University Hospital, Aalborg, Denmark; 2Biometrics Matters Limited, Hamilton, New Zealand; 3Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; 4Clinical Nursing Research Unit, Aalborg University Hospital, Aalborg, Denmark Background: This study investigated the long-term effects of humidified high-flow nasal cannula (HFNC) in COPD patients with chronic hypoxemic respiratory failure treated with long-term oxygen therapy (LTOT).Patients and methods: A total of 200 patients were randomized into usual care ± HFNC. At inclusion, acute exacerbation of COPD (AECOPD) and hospital admissions 1 year before inclusion, modified Medical Research Council (mMRC) score, St George’s Respiratory Questionnaire (SGRQ), forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MWT) and arterial carbon dioxide (PaCO2) were recorded. Patients completed phone interviews at 1, 3 and 9 months assessing mMRC score and AECOPD since the last contact. At on-site visits (6 and 12 months), mMRC, number of AECOPD since last contact and SGRQ were registered and FEV1, FEV1%, PaCO2 and, at 12 months, 6MWT were reassessed. Hospital admissions during the study period were obtained from hospital records. Hours of the use of HFNC were retrieved from the high-flow device.Results: The average daily use of HFNC was 6 hours/day. The HFNC group had a lower AECOPD rate (3.12 versus 4.95/patient/year, p<0.001). Modeled hospital admission rates were 0.79 versus 1.39/patient/year for 12- versus 1-month use of HFNC, respectively (p<0.001). The HFNC group had improved mMRC scores from 3 months onward (p<0.001) and improved SGRQ at 6 and 12 months (p=0.002, p=0.033) and PaCO2 (p=0.005) and 6MWT (p=0.005) at 12 months. There was no difference in all-cause mortality.Conclusion: HFNC treatment reduced AECOPD, hospital admissions and symptoms in COPD patients with hypoxic failure. Keywords: COPD, high-flow heated and humidified oxygen, HFNC, exacerbation, AECOPD, modified Medical Research Council score, mMRC score, 6-minute walk test, 6MW