mTORC1 controls murine postprandial hepatic glycogen synthesis via Ppp1r3b.

In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.

Analysis of Social Media Involvement in Violent Injury.

This cross-sectional study uses police agency­collected information to quantify the association among social media involvement, crime, and violence.

Loss of FOXO transcription factors in the liver mitigates stress-induced hyperglycemia.

OBJECTIVE: Stress-induced hyperglycemia is associated with poor outcomes in nearly all critical illnesses. This acute elevation in glucose after injury or illness is associated with increased morbidity and mortality, including multiple organ failure. Stress-induced hyperglycemia is often attributed to insulin resistance as controlling glucose levels via exogenous insulin improves outcomes, but the mechanisms are unclear. Forkhead box O (FOXO) transcription factors are direct targets of insulin signaling in the liver that regulate glucose homeostasis via direct and indirect pathways. Loss of hepatic FOXO transcription factors reduces hyperglycemia in chronic insulin resistance; however, the role of FOXOs in stress-induced hyperglycemia is unknown. METHODS: We subjected mice lacking FOXO transcription factors in the liver to a model of injury known to cause stress-induced hyperglycemia. Glucose, insulin, glycerol, fatty acids, cytokines, and adipokines were assessed before and after injury. Liver and adipose tissue were analyzed for changes in glycogen, FOXO target gene expression, and insulin signaling. RESULTS: Stress-induced hyperglycemia was associated with reduced hepatic insulin signaling and increased hepatic FOXO target gene expression while loss of FOXO1, 3, and 4 in the liver attenuated hyperglycemia and prevented hyperinsulinemia. Mechanistically, the loss of FOXO transcription factors mitigated the stress-induced hyperglycemia response by directly altering gene expression and glycogenolysis in the liver and indirectly suppressing lipolysis in adipose tissue. Reductions were associated with decreased IL-6, TNF-α, and follistatin and increased FGF21, suggesting that cytokines and FOXO-regulated hepatokines contribute to the stress-induced hyperglycemia response. CONCLUSIONS: This study implicates FOXO transcription factors as a predominant driver of stress-induced hyperglycemia through means that include cross-talk between the liver and adipose, highlighting a novel mechanism underlying acute hyperglycemia and insulin resistance in stress.

Hepatic AKT orchestrates adipose tissue thermogenesis via FGF21-dependent and -independent mechanisms.

Organismal stressors such as cold exposure require a systemic response to maintain body temperature. Brown adipose tissue (BAT) is a key thermogenic tissue in mammals that protects against hypothermia in response to cold exposure. Defining the complex interplay of multiple organ systems in this response is fundamental to our understanding of adipose tissue thermogenesis. In this study, we identify a role for hepatic insulin signaling via AKT in the adaptive response to cold stress and show that liver AKT is an essential cell-nonautonomous regulator of adipocyte lipolysis and BAT function. Mechanistically, inhibition of forkhead box O1 (FOXO1) by AKT controls BAT thermogenesis by enhancing catecholamine-induced lipolysis in the white adipose tissue (WAT) and increasing circulating fibroblast growth factor 21 (FGF21). Our data identify a role for hepatic insulin signaling via the AKT-FOXO1 axis in regulating WAT lipolysis, promoting BAT thermogenic capacity, and ensuring a proper thermogenic response to acute cold exposure.

Risk factors for postdischarge venous thromboembolism among bariatric surgery patients and the evolving approach to extended thromboprophylaxis with enoxaparin.

BACKGROUND: Venous thromboembolism (VTE) is one of the most common causes of postoperative mortality following bariatric surgery. The majority of VTE events occur after discharge from the hospital. Little consensus exists regarding who should receive extended enoxaparin thromboprophylaxis or how they should be dosed, namely whether to use weight-based or BMI-stratified dosing strategies. OBJECTIVES: Provide an overview of the risk factors associated with VTE in procedures among bariatric patients including the use of predictive tools to stratify risk and the various approaches to enoxaparin chemoprophylaxis in obesity. SETTING: Multiple centers. METHODS: A review of the literature identified studies evaluating risk factors for VTE including demographic characteristics, co-morbidities, and operative factors. The use of calculators to stratify patients by risk and approaches to extended thromboprophylaxis in obesity were evaluated as well. RESULTS: VTE was associated with increased age, weight, male sex, and prior history of VTE, all frequently included in risk calculators. Outside of those major risk factors, there is little consensus about the importance of patient diagnoses. Weight-based dosing was often superior to standardized dosing in studies across disciplines in generating target anti-Xa levels however there is no consistent association of reduced risk of VTE with therapeutic anti-Xa levels. CONCLUSIONS: Risk calculators may be a valuable tool for identifying patients at high-risk for VTE, but their efficacy depends on the rating algorithm and inclusion of various risk factors and is methodologically limited by prophylactic interventions. Future work should consider if biochemical factors should be included in patient stratification approaches in particular when defining the ideal chemoprophylaxis approach. Transparency and consistency in data collection and reporting is needed to better assess and inform the ideal dosing strategy to prevent VTE following bariatric surgery.

A Contemporary Analysis of Delayed Diagnoses After Traumatic Injury : The Role of Operative Therapy.

BACKGROUND: Factors associated with delayed injury diagnosis (DID) have been examined, but incompletely researched. METHODS: We evaluated demographics, mechanism, and measures of mental status and injury severity among 10 years' worth of adult trauma patients at our center for association with DID in a multivariable regression model. Descriptions of DID injuries were reviewed to highlight characteristics of these injuries. RESULTS: We included 13 509 patients, 89 (0.7%) of whom had a recognized DID. In regression analysis, ISS (OR 1.04 per point, 95% CI 1.02-1.06) and number of injuries (OR 1.08 per injury, 95% CI 1.04-1.11) were associated with DID. Operative patients had twice the odds of DID (OR 2.02, 95% CI 1.18-3.44). The most common category of DID was orthopedic extremity injury (22/89). CONCLUSION: DID is associated with injury severity and operative intervention. This suggests that the presence of an injury requiring operation may distract the trauma team from additional injuries.