Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high-fat diet (HFD)-induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno-associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD-induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9-hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD-induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans

Increased Levels of Interleukin-36 in Obesity and Type 2 Diabetes Fuel Adipose Tissue Inflammation by Inducing Its Own Expression and Release by Adipocytes and Macrophages

Interleukin (IL)-36 is a recently described cytokine with well-known functions in the regulation of multiple inflammatory diseases. Since no data exists on how this cytokine regulates adipose tissue (AT) homeostasis, we aimed to explore the function of a specific isoform, IL-36γ, an agonist, in human obesity and obesity-associated type 2 diabetes as well as in AT inflammation and fibrosis. Plasma IL-36γ was measured in 91 participants in a case-control study and the effect of weight loss was evaluated in 31 patients with severe obesity undergoing bariatric surgery. Gene expression levels of IL36G and its receptor were analyzed in relevant human metabolic tissues. The effect of inflammatory factors and IL-36γ was determined in vitro in human adipocytes and macrophages. We found, for the first time, that the increased (P<0.05) circulating levels of IL-36γ in patients with obesity decreased (P<0.001) after weight and fat loss achieved by Roux-en-Y gastric bypass and that gene expression levels of IL36G were upregulated in the visceral AT (P<0.05) and in the peripheral blood mononuclear cells (P<0.01) from patients with obesity. We also demonstrated increased (P<0.05) expression levels of Il36g in the epididymal AT from diet-induced obese mice. IL36G was significantly enhanced (P<0.001) by LPS in human adipocytes and monocyte-derived macrophages, while no changes were found after the incubation with anti-inflammatory cytokines. The addition of IL-36γ for 24 h strongly induced (P<0.01) its own expression as well as key inflammatory and chemoattractant factors with no changes in genes associated with fibrosis. Furthermore, adipocyte-conditioned media obtained from patients with obesity increased (P<0.01) the release of IL-36γ and the expression (P<0.05) of cathepsin G (CTSG) in monocyte-derived macrophages. These findings provide, for the first time, evidence about the properties of IL-36γ in the regulation of AT-chronic inflammation, emerging as a link between AT biology and the obesity-associated comorbidities

Bipolar disorder and antibodies against the N-methyl-d-aspartate receptor: A gate to the involvement of autoimmunity in the pathophysiology of bipolar illness.

The high prevalence of comorbidity between bipolar disorder (BD) and other medical conditions, including autoimmune diseases, supports the hypothesis of the nature of BD as a biological illness category. Hence, an immune dysregulation process may play an important role in the development of at least certain subtypes of BD. Increasing evidence also suggests that the N-methyl-d-aspartate receptor (NMDAR) may be relevant in the pathophysiology of BD. A possible key mechanism underlying the physiopathology of certain autoimmune diseases that may present with affective symptoms might be the production of anti-NMDAR auto-antibodies (auto-Abs). The best characterized autoimmune anti-NMDAR disease is the anti-NMDAR encephalitis. It has been found that 4% of these patients present isolated, mostly affective, psychiatric manifestations during their illness. An interesting suggestion emerged from this overview is that the same mechanisms that trigger affective symptoms in patients with increased anti-NMDAR auto-Abs levels could be involved in the physiopathology of at least a subgroup of BD. Future studies are needed to characterize the relationship between anti-NMDAR auto-Abs and BD.The authors ofthis report wouldlike to acknowledge the support of the Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III (CP08/00140 and PI 12/00910), CIBERSAM (Exp. CB07/ 09/0004), the Spanish Ministry of Education and the Comissionat per a Universitats i Recerca del DIUE de la Generalitat de Catalunya to the Bipolar Disorders Group (2014 SGR 398)

Conservative management of perforated duodenal diverticulum: A case report and review of the literature

Duodenal diverticula are a relatively common condition. They are asymptomatic, unless they become complicated, with perforation being the rarest but most severe complication. Surgical treatment is the most frequently performed approach. We report the case of a patient with a perforated duodenal diverticulum, which was diagnosed early and treated conservatively with antibiotics and percutaneous drainage of secondary retroperitoneal abscesses. We suggest this method could be an acceptable option for the management of similar cases, provided that the patient is in good general condition and without septic signs