Obesity elicits immune cell infiltration of adipose tissue provoking chronic low-grade inflammation. Regulatory T cells (Tregs) are specifically reduced in adipose tissue of obese animals. Since interleukin (IL)-21 plays an important role in inducing and maintaining immune-mediated chronic inflammatory processes and negatively regulates Treg differentiation/activity, we hypothesized that it could play a role in obesity-induced insulin resistance. We found IL-21 and IL-21R mRNA expression upregulated in adipose tissue of high-fat diet (HFD) wild-type (WT) mice and in stromal vascular fraction from human obese subjects in parallel to macrophage and inflammatory markers. Interestingly, a larger infiltration of Treg cells was seen in the adipose tissue of IL-21 knockout (KO) mice compared with WT animals fed both normal diet and HFD. In a context of diet-induced obesity, IL-21 KO mice, compared with WT animals, exhibited lower body weight, improved insulin sensitivity, and decreased adipose and hepatic inflammation. This metabolic phenotype is accompanied by a higher induction of interferon regulatory factor 4 (IRF4), a transcriptional regulator of fasting lipolysis in adipose tissue. Our data suggest that IL-21 exerts negative regulation on IRF4 and Treg activity, developing and maintaining adipose tissue inflammation in the obesity state.

In the originally published version of this article, the concentration reported for the sgp130fc injection was incorrectly reported as 20 mg/animal instead of 20 mg/animal.

Introduction: Hydroxyethyl starch (HES) has been associated with acute kidney injury (AKI) in people, but there is limited evidence in dogs. We present the protocol and feasibility analysis of an ongoing prospective randomized blinded phase II clinical trial. Methods: Dogs at a university hospital prescribed a fluid bolus for clinical reasons were randomized to receive at least 10 mL/kg of HES 130/0.4 or Hartmann's solution. After 40 mL/kg of study fluid further fluid administration was open-label. Urine for neutrophil gelatinase-associated lipocalin and cystatin C was collected prior to and 6, 12, and 24 hours after the first study fluid bolus. Serum creatinine was measured daily for 7 days or until discharge. Target sample size was 20 per group. Screening and enrolment targets were 7 and 2 per week, respectively. Population characteristics and feasibility outcomes for the first 17 weeks of enrolment are reported. Results: Thirty-six dogs were logged as screened (2.1 per week) with 15 enrolled (0.9 per week). Reasons for exclusion included dehydration (4/21), transfusion required (4/21), consent declined (3/21), insufficient time to enroll (2/21), and predicted hospitalization < 24 hours (2/21). Twelve out of 15 dogs that were enrolled were administered the intervention. One was taken home against medical advice, one was administered a transfusion in place of the intervention, and one no longer required the intervention. For the 12 dogs administered the intervention, median (range) APPLE fast score was 23.5 (20-38) and 4 were septic. Median (range) volume of intervention fluid was 22.9 mL/kg (10.0-57.1 mL/kg). There were four major protocol violations, all relating to volume of intervention fluid administered. Nine of 12 dogs completed blood and urine sampling for all time points. Two out of 12 dogs developed AKI during hospitalization based on Veterinary Acute Kidney Injury scoring (one stage 1, one stage 2). Nine out of 12 dogs survived to discharge (2 died, 1 euthanized due to prognosis). Conclusion: Recruitment rate was lower than projected, mainly due to lower number of dogs screened. The investigators are satisfied that the enrolled cases are representative of the population of clinical interest. Drop-out after enrolment and protocol violations highlight the challenges of performing clinical interventional studies in emergency medicine.

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