Membrane-Bound sn-1,2-Diacylglycerols Explain the Dissociation of Hepatic Insulin Resistance from Hepatic Steatosis in MTTP Knockout Mice

Microsomal triglyceride transfer protein (MTTP) deficiency results in a syndrome of hypolipidemia and accelerated NAFLD. Animal models of decreased hepatic MTTP activity have revealed an unexplained dissociation between hepatic steatosis and hepatic insulin resistance. Here, we performed comprehensive metabolic phenotyping of liver-specific MTTP knockout (L-Mttp(-/-)) mice and age-weight matched wild-type control mice. Young (10-12-week-old) L-Mttp(-/-) mice exhibited hepatic steatosis and increased DAG content; however, the increase in hepatic DAG content was partitioned to the lipid droplet and was not increased in the plasma membrane. Young L-Mttp(-/-) mice also manifested normal hepatic insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamps, no PKC epsilon activation, and normal hepatic insulin signaling from the insulin receptor through AKT Ser/Thr kinase. In contrast, aged (10-month-old) L-Mttp(-/-) mice exhibited glucose intolerance and hepatic insulin resistance along with an increase in hepatic plasma membrane sn-1,2-DAG content and PKC epsilon activation. Treatment with a functionally liver-targeted mitochondrial uncoupler protected the aged L-Mttp(-/-) mice against the development of hepatic steatosis, increased plasma membrane sn-1,2-DAG content, PKC epsilon activation, and hepatic insulin resistance. Furthermore, increased hepatic insulin sensitivity in the aged controlled-release mitochondrial protonophore-treated L-Mttp(-/-) mice was not associated with any reductions in hepatic ceramide content. Taken together, these data demonstrate that differences in the intracellular compartmentation of sn-1,2-DAGs in the lipid droplet versus plasma membrane explains the dissociation of NAFLD/lipid-induced hepatic insulin resistance in young L-Mttp(-/-) mice as well as the development of lipid-induced hepatic insulin resistance in aged L-Mttp(-/-) miceThis work was supported by National Institutes of Health Grants R01 DK116774, R01 DK119968, R01 DK114793, R01 DK113984, K23 DK10287, P30 DK045735, DK121490, and HL137202 and the Veterans Health Administration Merit Review Awards I01 BX000901 and BX004113. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the U.S. Department of Veterans Affair

Research Review: Do parent ratings of infant negative emotionality and self‐regulation predict psychopathology in childhood and adolescence? A systematic review and meta‐analysis of prospective longitudinal studies

Background Identifying low‐cost and easy to implement measures of infant markers of later psychopathology may improve targeting of early intervention for prevention. Because of their early manifestation, relative stability and overlap with constructs central to affect‐based dimensions of child and adolescent psychopathology, negative emotionality and self‐regulation have been the focus of this research. We conducted a meta‐analysis of longitudinal studies examining the prospective association between infant temperament measured with parent ratings and child/adolescent psychopathology. Methods A systematic literature search for prospective longitudinal studies, which included measures of questionnaire‐assessed infant temperament (negative emotionality, self‐regulation, behavioural inhibition, surgency/extraversion, activity level) and symptoms of child or adolescent mental health (externalising, internalising) and neurodevelopmental problems (attention deficit/hyperactivity disorder [ADHD], autism spectrum disorder [ASD]), was conducted. Standardised estimates of association were calculated and pooled in meta‐analyses. Results Twenty‐five studies (n = 28,425) met inclusion criteria. Small associations were seen between psychopathology aggregated across all domains and infant negative emotionality (r = .15; p < .001) and self‐regulation (r = −.19; p = .007). Effects were also significant but weaker for behavioural inhibition (r = .10; p = .027) and activity level (r = .08; p = .016). Surgency/extraversion was not significantly associated with psychopathology in general (r = −.04; p = .094); however, it was negatively associated with ASD (r = −.10, p = .015). Significant correlations were observed with some outcomes isomorphic with predictors, internalising problems and behavioural inhibition (r = .10; p = .013), ADHD symptoms and activity level (r = .19; p = .009). Conclusion Questionnaire‐based assessments of infant negative emotionality may have transdiagnostic potential to contribute to a risk index of later childhood psychopathology. Behavioural inhibition, surgency/extraversion and activity ratings may provide more specific predictive power. More data from prospective studies are required before the potential of self‐regulation and surgency/extraversion can be properly gauged

Linking the Gut Microbial Ecosystem with the Environment: Does Gut Health Depend on Where We Live?

Global comparisons reveal a decrease in gut microbiota diversity attributed to Western diets, lifestyle practices such as caesarian section, antibiotic use and formula-feeding of infants, and sanitation of the living environment. While gut microbial diversity is decreasing, the prevalence of chronic inflammatory diseases such as inflammatory bowel disease, diabetes, obesity, allergies and asthma is on the rise in Westernized societies. Since the immune system development is influenced by microbial components, early microbial colonization may be a key factor in determining disease susceptibility patterns later in life. Evidence indicates that the gut microbiota is vertically transmitted from the mother and this affects offspring immunity. However, the role of the external environment in gut microbiome and immune development is poorly understood. Studies show that growing up in microbe-rich environments, such as traditional farms, can have protective health effects on children. These health-effects may be ablated due to changes in the human lifestyle, diet, living environment and environmental biodiversity as a result of urbanization. Importantly, if early-life exposure to environmental microbes increases gut microbiota diversity by influencing patterns of gut microbial assembly, then soil biodiversity loss due to land-use changes such as urbanization could be a public health threat. Here, we summarize key questions in environmental health research and discuss some of the challenges that have hindered progress toward a better understanding of the role of the environment on gut microbiome development

Characterization of 18-Fluorodeoxyglucose Uptake Pattern in Infective Endocarditis After Transcatheter Aortic Valve Implantation

n/

Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes

Impaired insulin-mediated suppression of hepatic glucose production (HGP) plays a major role in the pathogenesis of type 2 diabetes (T2D), yet the molecular mechanism by which this occurs remains unknown. Using a novel in vivo metabolomics approach, we show that the major mechanism by which insulin suppresses HGP is through reductions in hepatic acetyl CoA by suppression of lipolysis in white adipose tissue (WAT) leading to reductions in pyruvate carboxylase flux. This mechanism was confirmed in mice and rats with genetic ablation of insulin signaling and mice lacking adipose triglyceride lipase. Insulin\u27s ability to suppress hepatic acetyl CoA, PC activity, and lipolysis was lost in high-fat-fed rats, a phenomenon reversible by IL-6 neutralization and inducible by IL-6 infusion. Taken together, these data identify WAT-derived hepatic acetyl CoA as the main regulator of HGP by insulin and link it to inflammation-induced hepatic insulin resistance associated with obesity and T2D