Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-Associated Steatohepatitis Development.

BACKGROUND AND AIMS: REversion inducing Cysteine rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. METHODS: We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. RESULTS: Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild type mice. Hepatocyte-RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (A Disintegrin And Metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. CONCLUSION: Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlight its potential as a novel therapeutic in MASH.

Metabolic effects of an essential amino acid supplement in adolescents with PCOS and obesity.

OBJECTIVE: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism, insulin resistance, and hepatic steatosis (HS). Because dietary essential amino acid (EAA) supplementation has been shown to decrease HS in various populations, this study's objective was to determine whether supplementation would decrease HS in PCOS. METHODS: A randomized, double-blind, crossover, placebo-controlled trial was conducted in 21 adolescents with PCOS (BMI 37.3 ± 6.5 kg/m2, age 15.6 ± 1.3 years). Liver fat, very low-density lipoprotein (VLDL) lipogenesis, and triacylglycerol (TG) metabolism were measured following each 28-day phase of placebo or EAA. RESULTS: Compared to placebo, EAA was associated with no difference in body weight (p = 0.673). Two markers of liver health improved: HS was lower (-0.8% absolute, -7.5% relative reduction, p = 0.013), as was plasma aspartate aminotransferase (AST) (-8%, p = 0.004). Plasma TG (-9%, p = 0.015) and VLDL-TG (-21%, p = 0.031) were reduced as well. VLDL-TG palmitate derived from lipogenesis was not different between the phases, nor was insulin sensitivity (p > 0.400 for both). Surprisingly, during the EAA phase, participants reported consuming fewer carbohydrates (p = 0.038) and total sugars (p = 0.046). CONCLUSIONS: Similar to studies in older adults, short-term EAA supplementation in adolescents resulted in significantly lower liver fat, AST, and plasma lipids and thus may prove to be an effective treatment in this population. Additional research is needed to elucidate the mechanisms for these effects.

Relationship between serum ß-hydroxybutyrate and hepatic fatty acid oxidation in individuals with obesity and NAFLD.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excess lipid accumulation that can progress to inflammation (nonalcoholic steatohepatitis, NASH), and fibrosis. Serum ß-hydroxybutyrate (ß-HB), a product of the ketogenic pathway, is commonly used as a surrogate marker for hepatic fatty acid oxidation (FAO). However, it remains uncertain whether this relationship holds true in the context of NAFLD in humans. We compared fasting serum ß-HB levels with direct measurement of liver mitochondrial palmitate oxidation in humans stratified based on NAFLD severity (n = 142). Patients were stratified based on NAFLD activity score (NAS): NAS = 0 (no disease), NAS = 1-2 (mild), NAS = 3-4 (moderate), and NAS ≥ 5 (advanced). Moderate and advanced NAFLD is associated with reductions in liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2), serum ß-HB, but not 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL) mRNA, relative to no disease. Worsening liver mitochondrial complete palmitate oxidation corresponded with lower HMGCS2 mRNA but not total (complete + incomplete) palmitate oxidation. Interestingly, we found that liver HMGCS2 mRNA and serum ß-HB correlated with liver mitochondrial ß-hydroxyacyl-CoA dehydrogenase (ß-HAD) activity and CPT1A mRNA. Also, lower mitochondrial mass and markers of mitochondrial turnover positively correlated with lower HMGCS2 in the liver. These data suggest that liver ketogenesis and FAO occur at comparable rates in individuals with NAFLD. Our findings support the utility of serum ß-HB to serve as a marker of liver injury and hepatic FAO in the context of NAFLD.NEW & NOTEWORTHY Serum ß-hydroxybutyrate (ß-HB) is frequently utilized as a surrogate marker for hepatic fatty acid oxidation; however, few studies have investigated this relationship during states of liver disease. We found that the progression of nonalcoholic fatty liver disease (NAFLD) is associated with reductions in circulating ß-HB and liver 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2). As well, decreased rates of hepatic fatty acid oxidation correlated with liver HMGCS2 mRNA and serum ß-HB. Our work supports serum ß-HB as a potential marker for hepatic fatty acid oxidation and liver injury during NAFLD.

Gamification to Promote Physical Activity in Youth and Mothers With Obesity.

PURPOSE: Physical inactivity and sugar-sweetened beverage (SSB) consumption are associated with obesity. Gamification and self-monitoring to promote physical activity in youth is unknown, but evidence of effectiveness is present in adults. This study examined the effects of a gamification intervention on increased steps per day among parent-adolescent dyads with obesity compared with digital self-monitoring and if self-monitored SSB intake differed between these arms. METHODS: Youth ages 10-16 years and their mothers (N = 39 pairs), both with obesity, were randomized to a self-monitoring (N = 18) or a self-monitoring plus gamification arm (N = 21) for 9 weeks. The step goal was set and incrementally increased each week and was measured with Fitbit devices. Mixed effects linear regression examined changes in steps and SSB consumption per day, per week by study arm. RESULTS: During run-in, mothers averaged 8317 and youth 7508 steps per day. Compared with self-monitoring alone, gamification did not increase daily steps in mothers or youth beyond baseline levels. On average, SSB intake decreased in mothers by approximately 0.5 servings per day; occurred in both arms and persisted throughout the intervention. CONCLUSION: Gamification did not promote physical activity levels in mother-youth dyads with obesity. SSB intake declined in mothers with obesity in both study arms.

Isotope Labeling and Biochemical Assessment of Liver-Triacylglycerol in Patients with Different Levels of Histologically-Graded Liver Disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) prevalence is rapidly growing, and fatty liver has been found in a quarter of the US population. Increased liver lipids, particularly those derived from the pathway of de novo lipogenesis (DNL), have been identified as a hallmark feature in individuals with high liver fat. This has led to much activity in basic science and drug development in this area. No studies to date have investigated the contribution of DNL across a spectrum of disease, although it is clear that inhibition of DNL has been shown to reduce liver fat. OBJECTIVES: The purpose of this study was to determine whether liver lipid synthesis increases across the continuum of liver injury. METHODS: Individuals (n = 49) consumed deuterated water for 10 d before their scheduled bariatric surgeries to label DNL; blood and liver tissue samples were obtained on the day of the surgery. Liver lipid concentrations were quantitated, and levels of protein and gene expression assessed. RESULTS: Increased liver DNL, measured isotopically, was significantly associated with liver fatty acid synthase protein content (R = 0.470, P = 0.003), total steatosis assessed by histology (R = 0.526, P = 0.0008), and the fraction of DNL fatty acids in plasma very low-density lipoprotein-triacylglycerol (R = 0.747, P < 0.001). Regression analysis revealed a parabolic relationship between fractional liver DNL (percent) and NAFLD activity score (R = 0.538, P = 0.0004). CONCLUSION: These data demonstrate that higher DNL is associated with early to mid stages of liver disease, and this pathway may be an effective target for the treatment of NAFLD and nonalcoholic steatohepatitis. This study was registered at clinicaltrials.gov as NCT03683589.

Medications and conditions associated with weight loss in patients prescribed semaglutide based on real-world data.

OBJECTIVE: Approved by the Food and Drug Administration (FDA) in 2017 for diabetes and in 2021 for weight loss, semaglutide has seen widespread use among individuals who aim to lose weight. The aim of this study was to evaluate weight loss and the influence of clinical factors on semaglutide patients in real-world clinical practice. METHODS: Using data from 10 health systems within the Greater Plains Collaborative (a PCORnet Clinical Research Network), nearly 4000 clinical factors encompassing demographic, diagnosis, and prescription information were extracted for semaglutide patients. A gradient-boosting, machine-learning classifier was developed for weight-loss prediction and identification of the most impactful factors via SHapley Additive exPlanations (SHAP) value extrapolation. RESULTS: A total of 3555 eligible patients (539 of whom were observed 52 weeks following exposure) from March 2017 to April 2022 were studied. On average, individuals lost 4.44% (male individuals, 3.66%; female individuals, 5.08%) of their initial weight. History of diabetes mellitus diagnosis was associated with less weight loss, whereas prediabetes and linaclotide use were associated with more pronounced weight loss. CONCLUSIONS: Weight loss in patients prescribed semaglutide from real-world evidence was strong but attenuated compared with previous clinical trials. Machine-learning analysis of electronic health record data identified factors that warrant further research and consideration when tailoring weight-loss therapy.

Labeled breath tests in patients with NASH: Octanoate oxidation relates best to measures of glucose metabolism.

In vivo methods to estimate human liver mitochondrial activity are lacking and this project's goal was to use a non-invasive breath test to quantify complete mitochondrial fat oxidation and determine how test results changed when liver disease state was altered over time. Patients with suspected non-alcoholic fatty liver disease (NAFLD; 9 men, 16 women, 47 ± 10 years, 113 ± 23 kg) underwent a diagnostic liver biopsy and liver tissue was histologically scored by a pathologist using the NAFLD activity score (0-8). To assess liver oxidation activity, a labeled medium chain fatty acid was consumed orally (23.4 mg 13C4-octanoate) and breath samples collected over 135 min. Total CO2 production rates were measured using breath 13CO2 analysis by isotope ratio mass spectrometry. Fasting endogenous glucose production (EGP) was measured using an IV infusion of 13C6-glucose. At baseline, subjects oxidized 23.4 ± 3.9% (14.9%-31.5%) of the octanoate dose and octanoate oxidation (OctOx) was negatively correlated with fasting plasma glucose (r = -0.474, p = 0.017) and EGP (r = -0.441, p = 0.028). Twenty-two subjects returned for repeat tests 10.2 ± 1.0 months later, following lifestyle treatment or standardized care. OctOx (% dose/kg) was significantly greater across all subjects (p = 0.044), negatively related to reductions in EGP (r = -0.401, p = 0.064), and tended to correlate with reduced fasting glucose (r = -0.371, p = 0.090). Subjects exhibited reductions in steatosis (p = 0.007) which tended to correlate with increased OctOx (% of dose/kg, r = -0.411, p = 0.058). Based on our findings, the use of an 13C-octanoate breath test may be an indicator of hepatic steatosis and glucose metabolism, but these relationships require verification through larger studies in NAFLD populations.

Circulating indian hedgehog is a marker of the hepatocyte-TAZ pathway in experimental NASH and is elevated in humans with NASH.

Background & Aims: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is emerging as the most common cause of liver disease. For evaluation of therapies, there is a pressing need to identify non-invasive, mechanism-based biomarkers. A pro-fibrotic process relevant to human NASH involves a pathway in which a transcriptional regulator called TAZ (WWTR1) in hepatocytes induces the secretion of pro-fibrotic Indian hedgehog (IHH). We therefore reasoned that circulating IHH may be a useful mechanism-based marker to assess changes in NASH fibrosis. Methods: Circulating IHH was assessed in wild-type and hepatocyte-TAZ-silenced NASH mice and in three separate cohorts of patients with mild-moderate NASH. Results: Circulating IHH was elevated in mice with diet-induced NASH compared with chow-fed mice or with NASH mice in which hepatocyte TAZ was silenced, which is an effective means to decrease NASH fibrosis. In patients with fatty liver disease with or without NASH, NASH fibrosis was associated with increased concentrations of circulating IHH. Conclusions: The results of these analyses support further investigation to determine whether circulating IHH may be useful as a mechanism-based indicator of target engagement in anticipated future clinical trials testing NASH fibrosis therapies that block the IHH pathway. Impact and implications: Non-alcoholic steatohepatitis (NASH)-induced liver fibrosis is a common cause of liver disease. Circulating biomarkers that reflect liver fibrosis in NASH would be very useful to evaluate therapies. One mechanism of NASH fibrosis with potential as a therapeutic target involves a liver-secreted protein called Indian hedgehog (IHH). We report that circulating levels of IHH in experimental and human NASH associates with NASH and NASH-associated liver fibrosis, providing the premise for further investigation into using circulating IHH to evaluate anticipated future NASH therapies that block the IHH pathway in liver.

Relationship between hepatic and mitochondrial ceramides: a novel in vivo method to track ceramide synthesis.

Ceramides (CERs) are key intermediate sphingolipids implicated in contributing to mitochondrial dysfunction and the development of multiple metabolic conditions. Despite the growing evidence of CER role in disease risk, kinetic methods to measure CER turnover are lacking, particularly using in vivo models. The utility of orally administered 13C3, 15N l-serine, dissolved in drinking water, was tested to quantify CER 18:1/16:0 synthesis in 10-week-old male and female C57Bl/6 mice. To generate isotopic labeling curves, animals consumed either a control diet or high-fat diet (HFD; n = 24/diet) for 2 weeks and varied in the duration of the consumption of serine-labeled water (0, 1, 2, 4, 7, or 12 days; n = 4 animals/day/diet). Unlabeled and labeled hepatic and mitochondrial CERs were quantified using liquid chromatography tandem MS. Total hepatic CER content did not differ between the two diet groups, whereas total mitochondrial CERs increased with HFD feeding (60%, P < 0.001). Within hepatic and mitochondrial pools, HFD induced greater saturated CER concentrations (P < 0.05) and significantly elevated absolute turnover of 16:0 mitochondrial CER (mitochondria: 59%, P < 0.001 vs. liver: 15%, P = 0.256). The data suggest cellular redistribution of CERs because of the HFD. These data demonstrate that a 2-week HFD alters the turnover and content of mitochondrial CERs. Given the growing data on CERs contributing to hepatic mitochondrial dysfunction and the progression of multiple metabolic diseases, this method may now be used to investigate how CER turnover is altered in these conditions.

African American mothers' perceptions of infant body size are prospectively associated with infant growth and BMI.

OBJECTIVES: The effect of mothers' perceptions of infant body size on infant growth and later BMI is poorly understood. We aimed to assess whether maternal perceptions were associated with infant BMI and weight gain and to identify factors that may influence maternal perceptions. METHODS: We analyzed data from a prospective, longitudinal study of pregnant African American women living with healthy weight (BMI < 25 kg/m2 ) or obesity (BMI ≥ 30 kg/m2 ). We collected sociodemographic, feeding mode, perceived stress, depression, and food insecurity information. The African American Infant Body Habitus Scale assessed maternal perceptions of infant body size at age 6 months. A "maternal satisfaction with infant body size" score was derived. Infant BMI z-scores (BMIZ) were calculated at 6 and 24 months. RESULTS: Maternal perception and satisfaction scores did not differ between obese (n = 148) and healthy weight (n = 132) groups. Perception of infant size at 6 months was positively associated with infant BMIZ at 6 and 24 months. A positive association of maternal satisfaction scores with change in infant BMIZ from 6 to 24 months indicated that BMIZ changed less for infants whose mothers preferred them to be smaller at 6 months. Perception and satisfaction scores were not associated with feeding variables, maternal stress, depression, socioeconomic status, or food security status. CONCLUSION: Mothers' perceptions of and satisfaction with infant size correlated with current and later infant BMI. However, mother's perceptions were not associated with maternal weight status or other factors explored for their potential to impact maternal perceptions. Further work is needed to elucidate factors linking maternal perception/satisfaction and infant growth.

Impact of sex and diet-induced weight loss on vascular insulin sensitivity in type 2 diabetes.

Vascular insulin resistance, a major characteristic of obesity and type 2 diabetes (T2D), manifests with blunting of insulin-induced vasodilation. Although there is evidence that females are more whole body insulin sensitive than males in the healthy state, whether sex differences exist in vascular insulin sensitivity is unclear. Also uncertain is whether weight loss can reestablish vascular insulin sensitivity in T2D. The purpose of this investigation was to 1) establish if sex differences in vasodilatory responses to insulin exist in absence of disease, 2) determine whether female sex affords protection against the development of vascular insulin resistance with long-term overnutrition and obesity, and 3) examine if diet-induced weight loss can restore vascular insulin sensitivity in men and women with T2D. First, we show in healthy mice and humans that sex does not influence insulin-induced femoral artery dilation and insulin-stimulated leg blood flow, respectively. Second, we provide evidence that female mice are protected against impairments in insulin-induced dilation caused by overnutrition-induced obesity. Third, we show that men and women exhibit comparable levels of vascular insulin resistance when T2D develops but that diet-induced weight loss is effective at improving insulin-stimulated leg blood flow, particularly in women. Finally, we provide indirect evidence that these beneficial effects of weight loss may be mediated by a reduction in endothelin-1. In aggregate, the present data indicate that female sex confers protection against obesity-induced vascular insulin resistance and provide supportive evidence that, in women with T2D, vascular insulin resistance can be remediated with diet-induced weight loss.

"Sorry, I Didn't Mean to Kiss at You": A Descriptive Analysis of Tourette Syndrome in Interpersonal Interactions.

Recent research has begun to explore the specific social challenges experienced by persons with Tourette syndrome (TS); however, it does not specifically address the challenges that often arise interpersonally as part of people's communicative interactions and these interactions socially construct the individual and collective well-being of all involved. This study conducted semi-structured interviews with 18 adults who identified as having TS in order to investigate the ways in which others respond behaviorally to TS behaviors and the ways TS behaviors are misinterpreted within interpersonal interactions. Thematic analysis was used to identify themes common within participant responses. All participants reported receiving unwanted attention from others in response to their TS symptoms. Unwanted attention was further divided into six emergent subthemes, including verbal harassment, physical abuse, staring, general bullying, getting into trouble, and being kicked out. Three types of misunderstandings were also reported in interpersonal interactions: misunderstanding communicative intention, misunderstanding TS, and misunderstanding the cause of TS behaviors. Applying attribution theory, it is determined that it is ultimately the misattribution of communicative intent to TS behaviors that causes many misunderstandings reported by adults with TS and leads to a plethora of interpersonal, communicative challenges. Importantly, these misunderstandings are what ultimately contribute to much of the unwanted attention described by the participants in this study and documented in previous work, highlighting the value of a greater awareness of how misunderstandings take place with respect to TS.

Measurement of lipid flux to advance translational research: evolution of classic methods to the future of precision health.

Over the past 70 years, the study of lipid metabolism has led to important discoveries in identifying the underlying mechanisms of chronic diseases. Advances in the use of stable isotopes and mass spectrometry in humans have expanded our knowledge of target molecules that contribute to pathologies and lipid metabolic pathways. These advances have been leveraged within two research paths, leading to the ability (1) to quantitate lipid flux to understand the fundamentals of human physiology and pathology and (2) to perform untargeted analyses of human blood and tissues derived from a single timepoint to identify lipidomic patterns that predict disease. This review describes the physiological and analytical parameters that influence these measurements and how these issues will propel the coming together of the two fields of metabolic tracing and lipidomics. The potential of data science to advance these fields is also discussed. Future developments are needed to increase the precision of lipid measurements in human samples, leading to discoveries in how individuals vary in their production, storage, and use of lipids. New techniques are critical to support clinical strategies to prevent disease and to identify mechanisms by which treatments confer health benefits with the overall goal of reducing the burden of human disease.

Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period.

In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m2/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.

Research gaps and opportunities in precision nutrition: an NIH workshop report.

Precision nutrition is an emerging concept that aims to develop nutrition recommendations tailored to different people's circumstances and biological characteristics. Responses to dietary change and the resulting health outcomes from consuming different diets may vary significantly between people based on interactions between their genetic backgrounds, physiology, microbiome, underlying health status, behaviors, social influences, and environmental exposures. On 11-12 January 2021, the National Institutes of Health convened a workshop entitled "Precision Nutrition: Research Gaps and Opportunities" to bring together experts to discuss the issues involved in better understanding and addressing precision nutrition. The workshop proceeded in 3 parts: part I covered many aspects of genetics and physiology that mediate the links between nutrient intake and health conditions such as cardiovascular disease, Alzheimer disease, and cancer; part II reviewed potential contributors to interindividual variability in dietary exposures and responses such as baseline nutritional status, circadian rhythm/sleep, environmental exposures, sensory properties of food, stress, inflammation, and the social determinants of health; part III presented the need for systems approaches, with new methods and technologies that can facilitate the study and implementation of precision nutrition, and workforce development needed to create a new generation of researchers. The workshop concluded that much research will be needed before more precise nutrition recommendations can be achieved. This includes better understanding and accounting for variables such as age, sex, ethnicity, medical history, genetics, and social and environmental factors. The advent of new methods and technologies and the availability of considerably more data bring tremendous opportunity. However, the field must proceed with appropriate levels of caution and make sure the factors listed above are all considered, and systems approaches and methods are incorporated. It will be important to develop and train an expanded workforce with the goal of reducing health disparities and improving precision nutritional advice for all Americans.

Role of adropin in arterial stiffening associated with obesity and type 2 diabetes.

Adropin is a peptide largely secreted by the liver and known to regulate energy homeostasis; however, it also exerts cardiovascular effects. Herein, we tested the hypothesis that low circulating levels of adropin in obesity and type 2 diabetes (T2D) contribute to arterial stiffening. In support of this hypothesis, we report that obesity and T2D are associated with reduced levels of adropin (in liver and plasma) and increased arterial stiffness in mice and humans. Establishing causation, we show that mesenteric arteries from adropin knockout mice are also stiffer, relative to arteries from wild-type counterparts, thus recapitulating the stiffening phenotype observed in T2D db/db mice. Given the above, we performed a set of follow-up experiments, in which we found that 1) exposure of endothelial cells or isolated mesenteric arteries from db/db mice to adropin reduces filamentous actin (F-actin) stress fibers and stiffness, 2) adropin-induced reduction of F-actin and stiffness in endothelial cells and db/db mesenteric arteries is abrogated by inhibition of nitric oxide (NO) synthase, and 3) stimulation of smooth muscle cells or db/db mesenteric arteries with a NO mimetic reduces stiffness. Lastly, we demonstrated that in vivo treatment of db/db mice with adropin for 4 wk reduces stiffness in mesenteric arteries. Collectively, these findings indicate that adropin can regulate arterial stiffness, likely via endothelium-derived NO, and thus support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.NEW & NOTEWORTHY Arterial stiffening, a characteristic feature of obesity and type 2 diabetes (T2D), contributes to the development and progression of cardiovascular diseases. Herein we establish that adropin is decreased in obese and T2D models and furthermore provide evidence that reduced adropin may directly contribute to arterial stiffening. Collectively, findings from this work support the notion that "hypoadropinemia" should be considered as a putative target for the prevention and treatment of arterial stiffening in obesity and T2D.

A social media intervention for the families of young Black men with obstructive sleep apnoea.

Objective: To address positive airway pressure (PAP) adherence in adolescents diagnosed with obstructive sleep apnoea (OSA) by pilot testing a novel, online, facilitated, peer-support and health education programme for families. Design Setting and Methods: Families participated in separate Facebook peer-groups (adolescent [n=6] and parent [n=6]) for four weeks, followed by face-to-face interviews. Participants received OSA and PAP educational videos and posts, engaged with questions and polls, and viewed de-identified postings of peer PAP use data. Results: Adolescent participants were young Black males aged 13-17 years (n=6) with obesity (n=5), severe sleep apnoea (100%) and 4-15 months of prior PAP use. Parent participants were mothers (n=4) and fathers (n=2). Four of six young males increased their mean PAP use during the intervention period. Overall, parents were more engaged with the Facebook group page than adolescents, but interviews revealed the online group/peer-support and education provided was highly regarded and appreciated by families. Parents were particularly appreciative of being involved in care and diagnosis in this way. Conclusion: Results of this pilot trial provide important data regarding intervention design, content, and delivery approaches to be considered in the development of future interventions aiming to engage families and improve adolescent PAP adherence.

The Utility and Diagnostic Accuracy of Transient Elastography in Adults with Morbid Obesity: A Prospective Study.

Patients with morbid obesity are at high risk for nonalcoholic fatty liver disease (NAFLD) complicated by liver fibrosis. The clinical utility of transient elastography (TE) by Fibroscan in patients with morbid obesity (body mass index (BMI) ≥ 40 kg/m2) is not well-defined. We examined the diagnostic accuracy of Fibroscan in predicting significant liver fibrosis (fibrosis stage ≥2) in morbidly obese patients (BMI ≥ 40 kg/m2). Patients scheduled for bariatric surgery were prospectively enrolled. Intraoperative liver biopsy, liver-stiffness measurement (LSM) by Fibroscan (XL probe), and biochemical evaluation were all performed on the same day. The endpoint was significant liver fibrosis defined as fibrosis stage ≥2 based on the Nonalcoholic Steatohepatitis Clinical Research Network. The optimal LSM cutoff value for detecting significant fibrosis was determined by using the Youden Index method. Routine clinical, laboratory, and elastography data were analyzed by stepwise logistic regression analysis to identify predictors of significant liver fibrosis and build a predictive model. An optimal cutoff point of the new model's regression formula for predicting significant fibrosis was determined by using the Youden index method. One hundred sixty-seven patients (mean age, 46.4 years) were included, of whom 83.2% were female. Histological assessment revealed the prevalence of steatohepatitis and significant fibrosis of 40.7% and 11.4%, respectively. The median LSM was found to be significantly higher in the significant fibrosis group compared to those in the no or non-significant fibrosis group (18.2 vs. 7.7 kPa, respectively; p = 0.0004). The optimal LSM cutoff for predicting significant fibrosis was 12.8 kPa, with an accuracy of 71.3%, sensitivity of 73.7%, specificity of 70.9%, positive predictive value of 24.6%, negative predictive value of 95.5%, and ROC area of 0.723 (95% CI: 0.62-0.83). Logistic regression analysis identified three independent predictors of significant fibrosis: LSM, hemoglobin A1c, and alkaline phosphatase. A risk score was developed by using these three variables. At an optimal cutoff value of the regression formula, the risk score had an accuracy of 79.6% for predicting significant fibrosis, sensitivity of 89.5%, specificity of 78.4%, positive predictive value of 34.7%, negative predictive value of 98.3%, and ROC area of 0.855 (95% CI: 0.76-0.95). Fibroscan utility in predicting significant liver fibrosis in morbidly obese subjects is limited with accuracy of 71.3%. A model incorporating hemoglobin A1c and alkaline phosphatase with LSM improves accuracy in detecting significant fibrosis in this patient population.

Compromised hepatic mitochondrial fatty acid oxidation and reduced markers of mitochondrial turnover in human NAFLD.

BACKGROUND AND AIMS: NAFLD and its more-advanced form, steatohepatitis (NASH), is associated with obesity and is an independent risk factor for cardiovascular, liver-related, and all-cause mortality. Available human data examining hepatic mitochondrial fatty acid oxidation (FAO) and hepatic mitochondrial turnover in NAFLD and NASH are scant. APPROACH AND RESULTS: To investigate this relationship, liver biopsies were obtained from patients with obesity undergoing bariatric surgery and data clustered into four groups based on hepatic histopathological classification: Control (CTRL; no disease); NAFL (steatosis only); Borderline-NASH (steatosis with lobular inflammation or hepatocellular ballooning); and Definite-NASH (D-NASH; steatosis, lobular inflammation, and hepatocellular ballooning). Hepatic mitochondrial complete FAO to CO2 and the rate-limiting enzyme in ß-oxidation (ß-hydroxyacyl-CoA dehydrogenase activity) were reduced by ~40%-50% with D-NASH compared with CTRL. This corresponded with increased hepatic mitochondrial reactive oxygen species production, as well as dramatic reductions in markers of mitochondrial biogenesis, autophagy, mitophagy, fission, and fusion in NAFL and NASH. CONCLUSIONS: These findings suggest that compromised hepatic FAO and mitochondrial turnover are intimately linked to increasing NAFLD severity in patients with obesity.

How safe is adolescent bariatric surgery? An analysis of short-term outcomes.

BACKGROUND: The prevalence of childhood obesity in the U.S. has tripled over the last three decades. However, fewer than 1% of children with severe obesity undergo surgical weight loss interventions each year. MATERIALS AND METHODS: All patients age 10 to 19 years old who underwent laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) from 2015 through 2018 in the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database were included in this retrospective cohort analysis. The primary outcomes were mortality and overall complications. Procedural trends, readmission and reoperation rates were also examined using a multivariate regression model. RESULTS: Patients had a mean BMI of 47.3 kg/m2 and 80.0% were either 18 or 19 years old (n = 4,051). There were two reported deaths. Reoperation within 30 days occurred in 1.1% of patients, readmission in 3.5%, and complications in 1.2%. Among all readmissions, primary reasons included nausea/vomiting or nutritional depletion (41.3%) and abdominal pain (16.3%). RYGB was associated with higher odds for readmission (p = 0.006) and complications (p = 0.005). Higher BMI and younger age were not associated with an increased likelihood to experience poorer outcomes. The proportion of patients undergoing SG increased yearly over RYGB from 73.9% in 2015 to 84.3% in 2018. CONCLUSIONS: Bariatric surgery appears to be low risk for adolescents and SG has become the operation of choice. More research on early consideration of surgical therapy in adolescents with severe obesity is needed given the safety profile. LEVEL OF EVIDENCE: III.