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.

Histological improvements following energy restriction and exercise: The role of insulin resistance in resolution of MASH.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common liver diseases worldwide and is characterized by multi-tissue insulin resistance. The effects of a 10-month energy restriction and exercise intervention on liver histology, anthropometrics, plasma biochemistries, and insulin sensitivity were compared to standard of care (control) to understand mechanisms that support liver health improvements. METHODS: Following medical diagnosis of MASH, individuals were randomized to treatment (n = 16) or control (n = 8). Liver fat (magnetic resonance spectroscopy), 18-hour plasma biochemical measurements, and isotopically labeled hyperinsulinemic-euglycemic clamps were completed pre- and post-intervention. Body composition and cardiorespiratory fitness (VO2peak) were also measured mid-intervention. Those in the treatment group were counseled to reduce energy intake and completed supervised, high-intensity interval training (3x/week) for 10 months. Controls continued physician-directed care. RESULTS: Treatment induced significant (p <0.05) reductions in body weight, fat mass, and liver injury, while VO2peak (p <0.05) and non-esterified fatty acid suppression (p = 0.06) were improved. Both groups exhibited reductions in total energy intake, hemoglobin A1c, hepatic insulin resistance, and liver fat (p <0.05). Compared to control, treatment induced a two-fold increase in peripheral insulin sensitivity which was significantly related to higher VO2peak and resolution of liver disease. CONCLUSIONS: Exercise and energy restriction elicited significant and clinically meaningful treatment effects on liver health, potentially driven by a redistribution of excess nutrients to skeletal muscle, thereby reducing hepatic nutrient toxicity. Clinical guidelines should emphasize the addition of aerobic exercise in lifestyle treatments for the greatest histologic benefit in individuals with advanced MASH. IMPACT AND IMPLICATIONS: The mechanisms that underpin histologic improvement in individuals with metabolic dysfunction-associated steatohepatitis (MASH) are not well understood. This study evaluated the relationship between liver and metabolic health, testing how changes in one may affect the other. We investigated the effects of energy restriction and exercise on the association between multi-tissue insulin sensitivity and histologic improvements in participants with biopsy-proven MASH. For the first time, these results show that an improvement in peripheral (but not hepatic) insulin sensitivity and systemic markers of muscle function (i.e. cardiorespiratory fitness) were strongly related to resolution of liver disease. Extrahepatic disposal of substrates and improved fitness levels supported histologic improvement, confirming the addition of exercise as crucial to lifestyle interventions in MASH. CLINICAL TRIAL NUMBER: NCT03151798.

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.

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.

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.

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.

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.

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.

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.

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.

High-throughput LC-MS method to investigate postprandial lipemia: considerations for future precision nutrition research.

Elevated postprandial lipemia is an independent risk factor for cardiovascular disease, yet methods to quantitate postmeal handling of dietary lipids in humans are limited. This study tested a new method to track dietary lipid appearance using a stable isotope tracer (2H11-oleate) in liquid meals containing three levels of fat [low fat (LF), 15 g; moderate fat (MF), 30 g; high fat (HF), 60 g]. Meals were fed to 12 healthy men [means ± SD, age 31.3 ± 9.2 yr, body mass index (BMI) 24.5 ± 1.9 kg/m2] during four randomized study visits; the HF meal was administered twice for reproducibility. Blood was collected over 8 h postprandially, triglyceride (TG)-rich lipoproteins (TRL), and particles with a Svedberg flotation rate >400 (Sf > 400, n = 8) were isolated by ultracentrifugation, and labeling of two TG species (54:3 and 52:2) was quantified by LC-MS. Total plasma TRL-TG concentrations were threefold greater than Sf > 400-TG. Both Sf > 400- and TRL-TG 54:3 were present at higher concentrations than 52:2, and singly labeled TG concentrations were higher than doubly labeled. Furthermore, TG 54:3 and the singly labeled molecules demonstrated higher plasma absolute entry rates differing significantly across fat levels within a single TG species (P < 0.01). Calculation of fractional entry showed no significant differences in label handling supporting the utility of either TG species for appearance rate calculations. These data demonstrate the utility of labeling research meals with stable isotopes to investigate human postprandial lipemia while simultaneously highlighting the importance of examining individual responses. Meal type and timing, control of prestudy activities, and effects of sex on outcomes should match the research goals. The method, optimized here, will be beneficial to conduct basic science research in precision nutrition and clinical drug development.NEW & NOTEWORTHY A novel method to test human intestinal lipid handling using stable isotope labeling is presented and, for the first time, plasma appearance and lipid turnover were quantified in 12 healthy men following meals with varying amounts of fat. The method can be applied to studies in precision nutrition characterizing individual response to support basic science research or drug development. This report discusses key questions for consideration in precision nutrition that were highlighted by the data.

Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities.

BACKGROUND AND AIMS: Elevated hepatic de novo lipogenesis (DNL) is a key distinguishing characteristic of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. In rodent models of NAFLD, treatment with a surrogate of TVB-2640, a pharmacological fatty acid synthase inhibitor, has been shown to reduce hepatic fat and other biomarkers of DNL. The purpose of this phase I clinical study was to test the effect of the TVB-2640 in obese men with certain metabolic abnormalities that put them at risk for NAFLD. APPROACH AND RESULTS: Twelve subjects (mean ± SEM, 42 ± 2 years, body mass index 37.4 ± 1.2 kg/m2 , glucose 103 ± 2 mg/dL, triacylglycerols 196 ± 27 mg/dL, and elevated liver enzymes) underwent 10 days of treatment with TVB-2640 at doses ranging from 50-150 mg/day. Food intake was controlled throughout the study. Hepatic DNL was measured before and after an oral fructose/glucose bolus using isotopic labeling with 1-13 C1 -acetate intravenous infusion, followed by measurement of labeled very low-density lipoprotein palmitate via gas chromatography mass spectometry. Substrate oxidation was measured by indirect calorimetry. Across the range of doses, fasting DNL was reduced by up to 90% (P = 0.003). Increasing plasma concentrations of TVB-2640 were associated with progressive reductions in the percent of fructose-stimulated peak fractional DNL (R2  = -0.749, P = 0.0003) and absolute DNL area under the curve 6 hours following fructose/glucose bolus (R2  = -0.554, P = 0.005). For all subjects combined, alanine aminotransferase was reduced by 15.8 ± 8.4% (P = 0.05). Substrate oxidation was unchanged, and safety monitoring revealed that the drug was well tolerated, without an increase in plasma triglycerides. Alopecia occurred in 2 subjects (reversed after stopping the drug), but otherwise no changes were observed in fasting glucose, insulin, ketones, and renal function. CONCLUSION: These data support the therapeutic potential of a fatty acid synthase inhibitor, TVB-2640 in particular, in patients with NAFLD and nonalcoholic steatohepatitis.

Modest sleep restriction does not influence steps, physical activity intensity or glucose tolerance in obese adults.

Sleep restriction (SR) (<6 h) and physical activity (PA) are risk factors for obesity, but little work has examined the inter-related influences of both risk factors. In a free-living environment, 13 overweight/obese adults were sleep restricted for five nights to 6 h time-in-bed each night, with and without regular exercise (45 min/65% VO2 max; counterbalanced design). Two days of recovery sleep followed SR. Subjects were measured during a mixed meal tolerance test (MMT), resting metabolic rate, cognitive testing and fat biopsy (n=8). SR increased peak glucose response (+7.3 mg/dl, p = .04), elevated fasting non-esterified fatty acid (NEFA) concentrations (+0.1 mmol/L, p = .001) and enhanced fat oxidation (p < .001) without modifying step counts or PA intensity. Inclusion of daily exercise increased step count (+4,700 steps/day, p < .001) and decreased the insulin response to a meal (p = .01) but did not prevent the increased peak glucose response or elevated NEFA levels. The weekend recovery period improved fasting glucose (p = .02), insulin (p = .02), NEFA concentrations (p = .001) and HOMA-IR (p < .01) despite reduced steps (p < .01) and increased sedentary time (p < .01). Abdominal adipose tissue (AT) samples, obtained after baseline, SR and exercise, did not differ in lipolytic capacity following SR. Fatty acid synthase protein content tended to increase following SR (p = .07), but not following exercise. In a free-living setting, SR adversely affected circulating NEFAs, fuel oxidation and peak glucose response but did not directly affect glucose tolerance or AT lipolysis. SR-associated metabolic impairments were not mitigated by exercise, yet recovery sleep completely rescued its adverse effects on glucose metabolism.

Don't give up when communication is difficult: Online well-being advice for caregivers of people with Alzheimer's and dementia.

Sixteen million people in the United States are unpaid caregivers to people with Alzheimer's or dementia. Although caregiver investment is associated with personal and relational benefits, there are also emotional, mental, relational, and physical costs. This study explores online well-being advice for nonprofessional caregivers of people with Alzheimer's and dementia, resulting in 332 online resources that offer informational support for nonprofessional caregivers. Although competent communication directly impacts the well-being of caregiving relationships, only 39 of these texts offered advice related to communication strategies. Thematic analysis of these 39 sources resulted in 1,024 discrete pieces of caregiver advice related to three overarching themes: Daily Routine, Care Recipient Well-Being, and Caregiver Self-Care. We examine the Caregiver Self-Care theme to understand informational support available to caregivers. These self-care advice themes reveal a need for intentional focus on the home health quality of nonprofessional caregivers about ways that communication impacts their everyday lives.

Perspectives of adolescents with severe obesity on social Media in Preparation for weight-loss surgery: a qualitative study.

BACKGROUND: Currently the most effective treatment for severe obesity in adolescents is weight-loss surgery coupled with lifestyle behavior change. In preparation for weight-loss surgery, adolescents are required to make changes to eating and activity habits (lifestyle changes) to promote long term success. Social media support groups, which are popular among adolescents, have the potential to augment preoperative lifestyle changes. The purpose of this study was to qualitatively assess the perceived role of social media as a support tool for weight-loss, and to identify motivators and constraints to lifestyle changes and social media use in adolescents preparing for weight-loss surgery. METHODS: Thematic analysis of social media comments from 13 (3 male, 10 female) adolescents aged 16 ± 1.3 years with a body mass index (BMI) 45 ± 7.3 kg/m2 enrolled in a weight-management program preparing for bariatric surgery and who participated in a 12-week pilot social media intervention was performed. Participants commented on moderator posts and videos of nutrition, physical activity, and motivation that were shared three to four times per week. Social media comments were coded using NVivo 11.0 to identify recurrent themes and subthemes. RESULTS: 1) Social media provided accountability, emotional support, and shared behavioral strategies. 2) Motivators for lifestyle changes included family support, personal goals, and non-scale victories. 3) Challenges included negative peers, challenges with planning and tracking, and time constraints. CONCLUSION: Adolescents considering bariatric surgery identified social media as a tool for social support and reinforcement of strategies for successful behavior change. Important motivators and challenges to lifestyle changes were identified.

Conducting a Pilot Randomized Controlled Trial on a Medical Inpatient Unit Utilizing Cognitive Remediation Therapy for Adolescents with Restrictive Eating Disorders: Protocol Updates and Reflections on Feasibility.

We conducted a pilot randomized control trial (RCT) to simultaneously examine the feasibility of effectively implementing Cognitive Remediation Therapy (CRT) for adolescents with anorexia nervosa (AN) during medical hospitalization at a single-site hospital center. Employment of this protocol occurred on a general medical unit with diverse medical admitting diagnoses, not an eating disorder floor of a hospital and not part of a structured inpatient anorexia nervosa treatment program. This was the first time an RCT for a psychosocial intervention was implemented on this unit with patients with eating disorders. Here, we describe the process of piloting the study, including modifications that needed to be made to the original protocol. We also describe the feedback from major stakeholders regarding the process of conducting the pilot study. We summarize lessons learned and steps to take for smooth integration of an RCT of a therapeutic intervention on medical unit.Trial registration: ClinicalTrials.gov Identifier NCT02883413.

Antibiotic Exposure During the First 6 Months of Life and Weight Gain During Childhood.

IMPORTANCE: Early-life antibiotic exposure has been associated with increased adiposity in animal models, mediated through the gut microbiome. Infant antibiotic exposure is common and often inappropriate. Studies of the association between infant antibiotics and childhood weight gain have reported inconsistent results. OBJECTIVE: To assess the association between early-life antibiotic exposure and childhood weight gain. DESIGN AND SETTING: Retrospective, longitudinal study of singleton births and matched longitudinal study of twin pairs conducted in a network of 30 pediatric primary care practices serving more than 200,000 children of diverse racial and socioeconomic backgrounds across Pennsylvania, New Jersey, and Delaware. PARTICIPANTS: Children born between November 1, 2001, and December 31, 2011, at 35 weeks' gestational age or older, with birth weight of 2000 g or more and in the fifth percentile or higher for gestational age, and who had a preventive health visit within 14 days of life and at least 2 additional visits in the first year of life. Children with complex chronic conditions and those who received long-term antibiotics or multiple systemic corticosteroid prescriptions were excluded. We included 38,522 singleton children and 92 twins (46 matched pairs) discordant in antibiotic exposure. Final date of follow-up was December 31, 2012. EXPOSURE: Systemic antibiotic use in the first 6 months of life. MAIN OUTCOMES AND MEASURES: Weight, measured at preventive health visits from age 6 months through 7 years. RESULTS: Of 38,522 singleton children (50% female; mean birth weight, 3.4 kg), 5287 (14%) were exposed to antibiotics during the first 6 months of life (at a mean age of 4.3 months). Antibiotic exposure was not significantly associated with rate of weight change (0.7%; 95% CI, -0.1% to 1.5%; P = .07, equivalent to approximately 0.05 kg; 95% CI, -0.004 to 0.11 kg of added weight gain between age 2 years and 5 years). Among 92 twins (38% female; mean birth weight, 2.8 kg), the 46 twins who were exposed to antibiotics during the first 6 months of life received them at a mean age of 4.5 months. Antibiotic exposure was not significantly associated with a weight difference (-0.09 kg; 95% CI, -0.26 to 0.08 kg; P = .30). CONCLUSIONS AND RELEVANCE: Exposure to antibiotics within the first 6 months of life compared with no exposure was not associated with a statistically significant difference in weight gain through age 7 years. There are many reasons to limit antibiotic exposure in young, healthy children, but weight gain is likely not one of them.

Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls). METHODS: We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat. Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis. RESULTS: Subjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher concentrations of insulin than subjects with LowLF (3.1% ± 2.7%; P = .04 and P < .001, respectively). No differences were observed between groups in adipose flux of FFAs (414 ± 195 µmol/min for HighLF vs 358 ± 105 µmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 µmol/min vs 4.34 ± 1.82 µmol/min; P = .77). In contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57 ± 1.53 µmol/min vs 0.78 ± 0.42 µmol/min; P = .001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2% ± 7.9% vs 10.1% ± 6.7%; P < .001); this level was independently associated with the level of intrahepatic triacylglycerol (r = 0.53; P = .007). CONCLUSIONS: By administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans.

PURPOSE OF REVIEW: Different sources of fatty acids (FA) used for VLDL-triglyceride synthesis include dietary FA that clear to the liver via chylomicron uptake, FA synthesized de novo in the liver from carbohydrates, nonesterified fatty acids derived from adipose tissue, nonesterified fatty acids derived from the spillover of chylomicron-triglyceride in the fasted and fed states, and FA stored in liver lipid droplets. RECENT FINDINGS: Data have amassed on the contributions of each of these sources to liver-triglyceride accrual, VLDL-triglyceride synthesis, and hypertriglyceridemia. Discussed here is the timing of use of FA from each of these sources for synthesis of VLDL-triglyceride. Secondly, as all of these FA sources have been shown to contribute significantly to nonalcoholic fatty liver disease (NAFLD), data are presented demonstrating how poor handling of FA and glucose in the periphery can contribute to NAFLD. Lastly, we highlight how the stress of excess FA availability on the liver can be corrected by reduction of dietary intake of sugars and fats, weight loss, and increased physical activity. SUMMARY: A better understanding of how lifestyle factors improve FA flux will aid in the development of improved treatments for the devastating condition of NAFLD.