Acute Activation of GFRAL in the Area Postrema Contributes to Glucose Regulation Independent of Weight.

GDF15 regulates energy balance and glucose homeostasis in rodents by activating its receptor GFRAL, expressed in the area postrema of the brain. However, whether GDF15-GFRAL signaling in the area postrema regulates glucose tolerance independent of changes in food intake and weight and contributes to the glucose-lowering effect of metformin remain unknown. Herein, we report that direct, acute GDF15 infusion into the area postrema of rats fed a high-fat diet increased intravenous glucose tolerance and insulin sensitivity to lower hepatic glucose production independent of changes in food intake, weight, and plasma insulin levels under conscious, unrestrained, and nonstressed conditions. In parallel, metformin infusion concurrently increased plasma GDF15 levels and glucose tolerance. Finally, a knockdown of GFRAL expression in the area postrema negated administration of GDF15, as well as metformin, to increase glucose tolerance independent of changes in food intake, weight, and plasma insulin levels. In summary, activation of GFRAL in the area postrema contributes to glucose regulation of GDF15 and metformin in vivo.

Metformin triggers a kidney GDF15-dependent area postrema axis to regulate food intake and body weight.

Metformin, the most widely prescribed medication for obesity-associated type 2 diabetes (T2D), lowers plasma glucose levels, food intake, and body weight in rodents and humans, but the mechanistic site(s) of action remain elusive. Metformin increases plasma growth/differentiation factor 15 (GDF15) levels to regulate energy balance, while GDF15 administration activates GDNF family receptor α-like (GFRAL) that is highly expressed in the area postrema (AP) and the nucleus of the solitary tract (NTS) of the hindbrain to lower food intake and body weight. However, the tissue-specific contribution of plasma GDF15 levels after metformin treatment is still under debate. Here, we found that metformin increased plasma GDF15 levels in high-fat (HF) fed male rats through the upregulation of GDF15 synthesis in the kidney. Importantly, the kidney-specific knockdown of GDF15 expression as well as the AP-specific knockdown of GFRAL expression negated the ability of metformin to lower food intake and body weight gain. Taken together, we unveil the kidney as a target of metformin to regulate energy homeostasis through a kidney GDF15-dependent AP axis.

Comparing the Effect of Resilience Skills Training and Metacognitive Therapy on Job Stress in Nurses: An Experimental Study.

Background: Nursing is one of the stressful professions. The work-related stressful factors have affected the physical and mental health of nurses seriously. This study aimed to compare the effect of resilience skills training and metacognitive therapy on nurses' job stress. Materials and Methods: This experimental study was conducted on 54 nurses working in intensive care units and the emergency department of Valiasr Hospital, Birjand, Iran, in 2018. Selected participants were allocated via permuted block randomization into three groups: resilience skills training, metacognitive therapy, and control (n = 18 for each group). Both resilience and metacognitive therapy programs were held in eight sessions of 45-mintraining classes twice a week. The control group received no intervention. The data were collected using a demographic characteristics form and the Expanded Nursing Stress Scale (ENSS) before, immediately after, and one month after the intervention. The data were analyzed using Chi-square, Fisher's exact test, Analysis of Variance (ANOVA), and repeated measures ANOVA in the Statistical Package for Social Science (SPSS) software. Results: Job stress significantly decreased in both resilience (F2,51 = 123.5, p < 0.001) and metacognitive therapy (F2,51= 29.2, p = 0.002) groups over time. However, this decrease was not significantly different between the two groups (p > 0.05). Also, the control group's job stress mean score increased over time (F2,51 = 9.35, p < 0.001). Conclusions: The findings suggest that both resilience skills training and metacognitive therapy can reduce the job stress of emergency and intensive care nurses. Therefore, it is recommended that both programs be taken into account by managers to reduce nurses' job stress.

Vascepa protects against high-fat diet-induced glucose intolerance, insulin resistance, and impaired ß-cell function.

Omega-3 fatty acid prescription drugs, Vascepa (≥96% eicosapentaenoic acid [EPA] ethyl ester) and Lovaza (46.5% EPA and 37.5% docosahexaenoic acid ethyl ester) are known therapeutic regimens to treat hypertriglyceridemia. However, their impact on glucose homeostasis, progression to type 2 diabetes, and pancreatic beta cell function are not well understood. In the present study, mice were treated with Vascepa or Lovaza for one week prior to six weeks of high-fat diet feeding. Vascepa but not Lovaza led to reduced insulin resistance, reduced fasting insulin and glucose, and improved glucose intolerance. Vascepa improved beta cell function, reduced liver triglycerides with enhanced expression of hepatic fatty acid oxidation genes, and altered microbiota composition. Vascepa has protective effects on diet-induced insulin resistance and glucose intolerance in mice.

Small intestinal taurochenodeoxycholic acid-FXR axis alters local nutrient-sensing glucoregulatory pathways in rats.

OBJECTIVE: The mechanism of nutrient sensing in the upper small intestine (USI) and ileum that regulates glucose homeostasis remains elusive. Short-term high-fat (HF) feeding increases taurochenodeoxycholic acid (TCDCA; an agonist of farnesoid X receptor (FXR)) in the USI and ileum of rats, and the increase of TCDCA is prevented by transplantation of microbiota obtained from the USI of healthy donors into the USI of HF rats. However, whether changes of TCDCA-FXR axis in the USI and ileum alter nutrient sensing remains unknown. METHODS: Intravenous glucose tolerance test was performed in rats that received USI or ileal infusion of nutrients (i.e., oleic acids or glucose) via catheters placed toward the lumen of USI and/or ileum, while mechanistic gain- and loss-of-function studies targeting the TCDCA-FXR axis or bile salt hydrolase activity in USI and ileum were performed. RESULTS: USI or ileum infusion of nutrients increased glucose tolerance in healthy but not HF rats. Transplantation of healthy microbiome obtained from USI into the USI of HF rats restored nutrient sensing and inhibited FXR via a reduction of TCDCA in the USI and ileum. Further, inhibition of USI and ileal FXR enhanced nutrient sensing in HF rats, while inhibiting USI (but not ileal) bile salt hydrolase of HF rats transplanted with healthy microbiome activated FXR and disrupted nutrient sensing in the USI and ileum. CONCLUSIONS: We reveal a TCDCA-FXR axis in both the USI and ileum that is necessary for the upper small intestinal microbiome to govern local nutrient-sensing glucoregulatory pathways in rats.