Visual and oculomotor outcomes in children with prenatal opioid exposure.

PURPOSE OF REVIEW: To summarize the visual and oculomotor outcomes in children with prenatal opioid exposure and review the effects of opioids on the developing central nervous system. RECENT FINDINGS: Animal models and imaging studies in children suggest that prenatal opioid exposure may affect neuronal survival and result in delayed maturation of white matter tracts and decreased volumes in certain brain areas. Visual evoked potential testing in children demonstrates delayed maturation of the afferent visual system in opioid-exposed groups compared with controls, though 'catch-up' development is seen with longitudinal follow-up. Strabismus and nystagmus are also more common in exposed children, and these findings appear to persist. SUMMARY: As rates of opioid dependence and prenatal opioid exposure continue to increase, it is important to evaluate the short-term and long-term effects of opioids on the developing visual system. An understanding of these risks is important when counseling the parents or guardians of opioid-exposed children, though larger studies with more long-term follow-up will improve our prognostic abilities.

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.

Gut microbiota manipulation with prebiotics in patients with non-alcoholic fatty liver disease: a randomized controlled trial protocol.

BACKGROUND: Evidence for the role of the gut microbiome in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is emerging. Strategies to manipulate the gut microbiota towards a healthier community structure are actively being investigated. Based on their ability to favorably modulate the gut microbiota, prebiotics may provide an inexpensive yet effective dietary treatment for NAFLD. Additionally, prebiotics have established benefits for glucose control and potentially weight control, both advantageous in managing fatty liver disease. Our objective is to evaluate the effects of prebiotic supplementation, adjunct to those achieved with diet-induced weight loss, on heptic injury and liver fat, the gut microbiota, inflammation, glucose tolerance, and satiety in patients with NAFLD. METHODS/DESIGN: In a double blind, placebo controlled, parallel group study, adults (BMI ≥25) with confirmed NAFLD will be randomized to either a 16 g/d prebiotic supplemented group or isocaloric placebo group for 24 weeks (n = 30/group). All participants will receive individualized dietary counseling sessions with a registered dietitian to achieve 10 % weight loss. Primary outcome measures include change in hepatic injury (fibrosis and inflammation) and liver fat. Secondary outcomes include change in body composition, appetite and dietary adherence, glycemic and insulinemic responses and inflammatory cytokines. Mechanisms related to prebiotic-induced changes in gut microbiota (shot-gun sequencing) and their metabolic by-products (volatile organic compounds) and de novo lipogenesis (using deuterium incorporation) will also be investigated. DISCUSSION: There are currently no medications or surgical procedures approved for the treatment of NAFLD and weight loss via lifestyle modification remains the cornerstone of current care recommendations. Given that prebiotics target multiple metabolic impairments associated with NAFLD, investigating their ability to modulate the gut microbiota and hepatic health in patients with NAFLD is warranted. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02568605) Registered 30 September 2015.

Elevated lipogenesis and diminished cholesterol synthesis in patients with hepatitis C viral infection compared to healthy humans.

UNLABELLED: Hepatitis C virus (HCV) exerts a profound influence on host lipid metabolism. It has been suggested that the synthesis of both fatty acids (FA) and cholesterol is dysregulated in HCV but this has not been directly quantified in humans. The purpose of this study was to measure lipogenesis and cholesterol synthesis using stable isotopes in patients with HCV (n = 5) and healthy control (n = 9) subjects recruited from the University of Alberta hospital. Blood samples were taken at fasting (0 and 24 hours) and after meals over the day to mimic typical food consumption and postprandial metabolism. Isolation of free cholesterol (FC), cholesteryl ester (CE), and triglyceride (TG) from plasma and very low-density lipoproteins (VLDL) was used to measure FA and cholesterol synthesis using deuterium uptake and isotope ratio mass spectrometry. FA composition was analyzed by gas chromatography. VLDL-TG levels of polyunsaturated fatty acids (PUFA), including linoleic and linolenic acid, were lower in HCV compared to control (P < 0.05 for both). Fasting hepatic lipogenesis was significantly higher in HCV (2.80 ± 0.55%) compared to control (1.19 ± 0.27%; P = 0.03). Conversely, fasting whole-body synthesis of FC (HCV 1.64 ± 0.28% versus control 8.78 ± 1.59%) and CE (HCV 0.26 ± 0.08% versus control 1.92 ± 0.25%), as well as hepatic FC synthesis (HCV 1.68 ± 0.26% versus control 8.12 ± 0.77%) was lower in HCV (P < 0.001 for all). CONCLUSION: These data provide evidence that lipogenesis is elevated while cholesterol synthesis is impaired in HCV, supporting previous findings from cellular and animal models. Low PUFA levels combined with elevated lipogenesis suggests a role for dietary PUFA supplementation in HCV patients.

Evaluation of yellow pea fibre supplementation on weight loss and the gut microbiota: a randomized controlled trial.

BACKGROUND: Fibre intake among North Americans is currently less than half the recommended amount. Consumers are interested in food products that could promote weight loss and improve health. Consequently, evaluation of unique fibre sources with potential gut-mediated benefits for metabolic health warrants investigation. Our objective is to assess the effects of yellow pea fibre supplementation on weight loss and gut microbiota in an overweight and obese adult population. METHODS/DESIGN: In a double blind, placebo controlled, parallel group study, overweight and obese (BMI = 25-38) adults will be randomized to either a 15 g/d yellow pea fibre supplemented group or isocaloric placebo group for 12 weeks (n = 30/group). The primary outcome measure is a change in body fat from baseline to 12 weeks. Secondary outcomes include glucose tolerance, appetite regulation, serum lipids and inflammatory markers. Anthropometric data (height, weight, BMI, and waist circumference) and food intake (by 3-day weighed food records) will be measured at baseline and every 4 weeks thereafter. Subjective ratings of appetite will be recorded by participants at home on a weekly basis using validated visual analogue scales. At week 0 and at the end of the study (week 12), an ad libitum lunch buffet protocol for objective food intake measures and dual-energy X-ray absorptiometry (DXA) scan for body composition will be completed. Participants will be instructed not to change their exercise habits during the 12 week study. Glucose and insulin will be measured during an oral glucose tolerance test at weeks 0 and 12. Levels of lipids and CRP will be measured and inflammatory markers (adiponectin, leptin, TNF-α, IL-6 and IL-8) in the serum will be quantified using Milliplex kits. Mechanisms related to changes in gut microbiota, serum and fecal water metabolomics will be assessed. DISCUSSION: Globally the development of functional foods and functional food ingredients are critically needed to curb the rise in metabolic disease. This project will assess the potential of yellow pea fibre to improve weight control via gut-mediated changes in metabolic health in overweight and obese adults. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01719900) Registered October 23, 2012.

Postprandial metabolism of meal triglyceride in humans.

The intake of dietary fat above energy needs has contributed to the growing rates of obesity worldwide. The concept of disease development occurring in the fed state now has much support and dysregulation of substrate flux may occur due to poor handling of dietary fat in the immediate postprandial period. The present paper will review recent observations implicating cephalic phase events in the control of enterocyte lipid transport, the impact of varying the composition of meals on subsequent fat metabolism, and the means by which dietary lipid carried in chylomicrons can lead to elevated postprandial non-esterified fatty acid concentrations. This discussion is followed by an evaluation of the data on quantitative meal fat oxidation at the whole body level and an examination of dietary fat clearance to peripheral tissues - with particular attention paid to skeletal muscle and liver given the role of ectopic lipid deposition in insulin resistance. Estimates derived from data of dietary-TG clearance show good agreement with clearance to the liver equaling 8-12% of meal fat in lean subjects and this number appears higher (10-16%) in subjects with diabetes and fatty liver disease. Finally, we discuss new methods with which to study dietary fatty acid partitioning in vivo. Future research is needed to include a more comprehensive understanding of 1) the potential for differential oxidation of saturated versus unsaturated fatty acids which might lead to meaningful energy deficit and whether this parameter varies based on insulin sensitivity, 2) whether compartmentalization exists for diet-derived fatty acids within tissues vs. intracellular pools, and 3) the role of reduced peripheral fatty acid clearance in the development of fatty liver disease. Further advancements in the quantitation of dietary fat absorption and disposal will be central to the development of therapies designed to treat diet-induced obesity. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.

Don't Miss This! Red Flags in the Pediatric Eye Exam: Pupils.

The pupillary exam in the pediatric population is a vital part of any clinician's workup. In the right clinical setting, pupillary abnormalities such as anisocoria, light-near dissociation, an afferent pupillary defect, and paradoxic pupillary constriction in the dark can be red flags that trigger further examination and workup. Through both careful physical examination and detailed history-taking and observation, potentially vision- and life-threatening conditions can be detected.

Impact of dietary fiber supplementation on modulating microbiota-host-metabolic axes in obesity.

Low dietary fiber intake is associated with higher rates of microbiota-associated chronic diseases such as obesity. Low-fiber diets alter not only microbial composition but also the availability of metabolic end products derived from fermentation of fiber. Our objective was to examine the effects of dietary fiber supplementation on gut microbiota and associated fecal and serum metabolites in relation to metabolic markers of obesity. We conducted a 12-week, single-center, double-blind, placebo-controlled trial with 53 adults with overweight or obesity. They were randomly assigned to a pea fiber (PF, 15 g/d in wafer form; n=29) or control (CO, isocaloric amount of wafers; n=24) group. Blood and fecal samples were collected at baseline and 12 weeks. Serum metabolomics, gut microbiota and fecal short-chain fatty acids (SCFAs) and bile acids (BAs) were examined. Within-group but not between-group analysis showed a significant effect of treatment on serum metabolites at 12 weeks compared to baseline. Fiber significantly altered fecal SCFAs and BAs with higher acetate and reduced isovalerate, cholate, deoxycholate and total BAs content in the PF group compared to baseline. Microbiota was differentially modulated in the two groups, including an increase in the SCFA producer Lachnospira in the PF group and decrease in the CO group. The change in body weight of participants showed a negative correlation with their change in Lachnospira (r=-0.463, P=.006) abundance. The current study provides insight into the actions of pea fiber and its impact on modulating microbiota-host-metabolic axes in obesity.

Consuming yellow pea fiber reduces voluntary energy intake and body fat in overweight/obese adults in a 12-week randomized controlled trial.

BACKGROUND & AIMS: The purpose of this randomized, double-blind, placebo-controlled study was to assess the effects of yellow pea fiber intake on body composition and metabolic markers in overweight/obese adults. METHODS: Participants (9 M/41 F; age 44 ± 15 y, BMI 32.9 ± 5.9 kg/m2) received isocaloric doses of placebo (PL) or pea fiber (PF; 15 g/d) wafers for 12 weeks. Outcome measures included changes in anthropometrics, body composition (DXA), oral glucose tolerance test (OGTT), food intake (ad libitum lunch buffet), and biochemical indices. RESULTS: The PF group lost 0.87 ± 0.37 kg of body weight, primarily due to body fat (-0.74 ± 0.26 kg), whereas PL subjects gained 0.40 ± 0.39 kg of weight over the 12 weeks (P = 0.022). The PF group consumed 16% less energy at the follow-up lunch buffet (P = 0.026), whereas the PL group did not change. During the OGTT, glucose area under the curve (AUC) was lower in PF subjects at follow-up (P = 0.029); insulin increased in both groups over time (P = 0.008), but more so in the PL group (38% higher AUC vs. 10% higher in the PF group). There were no differences in gut microbiota between groups. CONCLUSIONS: In the absence of other lifestyle changes, incorporating 15 g/day yellow pea fiber may yield small but significant metabolic benefits and aid in obesity management. Clinical Trial Registry: ClinicalTrials.gov NCT01719900.

An LC-MRM method for measuring intestinal triglyceride assembly using an oral stable isotope-labeled fat challenge.

AIM: A traditional oral fatty acid challenge assesses absorption of triacylglycerol (TG) into the periphery through the intestines, but cannot distinguish the composition or source of fatty acid in the TG. Stable isotope-labeled tracers combined with LC-MRM can be used to identify and distinguish TG synthesized with dietary and stored fatty acids. RESULTS: Concentrations of three abundant TGs (52:2, 54:3 and 54:4) were monitored for incorporation of one or two (2)H11-oleate molecules per TG. This method was subjected to routine assay validation and meets typical requirements for an assay to be used to support clinical studies. CONCLUSION: Calculations for the fractional appearance rate of TG in plasma are presented along with the intracellular enterocyte precursor pool for 12 study participants.

Palmitoleic acid is elevated in fatty liver disease and reflects hepatic lipogenesis.

BACKGROUND: Biochemical evidence has linked the coordinate control of fatty acid (FA) synthesis with the activity of stearoyl-CoA desaturase-1 (SCD1). The ratio of 16:1n-7 to 16:0 [SCD116] in plasma triacylglycerol FA has been used as an index to reflect liver SCD116 activity and has been proposed as a biomarker of FA synthesis, although this use has not been validated by comparison with isotopically measured de novo lipogenesis (DNL(Meas)). OBJECTIVE: We investigated plasma lipid 16:1n-7 and FA indexes of elongation and desaturation in relation to lipogenesis. DESIGN: In this cross-sectional investigation of metabolism, 24 overweight adults, who were likely to have elevated DNL, consumed D2O for 10 d and had liver fat (LF) measured by magnetic resonance spectroscopy. Very-low-density lipoprotein (VLDL)-triacylglycerols and plasma free FA [nonesterified fatty acids (NEFAs)] were analyzed by using gas chromatography for the FA composition (molar percentage) and gas chromatography-mass spectrometry and gas chromatography-combustion isotope ratio mass spectrometry for deuterium enrichment. RESULTS: In all subjects, VLDL-triacylglycerol 16:1n-7 was significantly (P < 0.01) related to DNL(Meas) (r = 0.56), liver fat (r = 0.53), and adipose insulin resistance (r = 0.56); similar positive relations were shown with the SCD116 index, and the pattern in NEFAs echoed that of VLDL-triacylglycerols. Compared with subjects with low LF (3.1 ± 2.7%; n = 11), subjects with high LF (18.4 ± 3.6%; n = 13) exhibited a 45% higher VLDL-triacylglycerol 16:1n-7 molar percentage (P < 0.01), 16% of subjects had lower 18:2n-6 (P = 0.01), and 27% of subjects had higher DNL as assessed by using a published DNL index (ratio of 16:0 to 18:2n-6; P = 0.03), which was isotopically confirmed by DNL(Meas) (increased 2.5-fold; P < 0.01). Compared with 16:0 in the diet, the low amount of dietary 16:1n-7 in VLDL-triacylglycerols corresponded to a stronger signal of elevated DNL. CONCLUSION: The current data provide support for the use of the VLDL-triacylglycerol 16:1n-7 molar percentage as a biomarker for elevated liver fat when isotope use is not feasible; however, larger-scale confirmatory studies are needed.

Exercise training modifies gut microbiota in normal and diabetic mice.

Cecal microbiota from type 2 diabetic (db/db) and control (db/(+)) mice was obtained following 6 weeks of sedentary or exercise activity. qPCR analysis revealed a main effect of exercise, with greater abundance of select Firmicutes species and lower Bacteroides/Prevotella spp. in both normal and diabetic exercised mice compared with sedentary counterparts. Conversely, Bifidobacterium spp. was greater in exercised normal but not diabetic mice (exercise × diabetes interaction). How exercise influences gut microbiota requires further investigation.

De novo lipogenesis and cholesterol synthesis in humans with long-standing type 1 diabetes are comparable to non-diabetic individuals.

BACKGROUND: Synthesis of lipid species, including fatty acids (FA) and cholesterol, can contribute to pathological disease. The purpose of this study was to investigate FA and cholesterol synthesis in individuals with type 1 diabetes, a group at elevated risk for vascular disease, using stable isotope analysis. METHODS: Individuals with type 1 diabetes (n = 9) and age-, sex-, and BMI-matched non-diabetic subjects (n = 9) were recruited. On testing day, meals were provided to standardize food intake and elicit typical feeding responses. Blood samples were analyzed at fasting (0 and 24 h) and postprandial (2, 4, 6, and 8 hours after breakfast) time points. FA was isolated from VLDL to estimate hepatic FA synthesis, whereas free cholesterol (FC) and cholesteryl ester (CE) was isolated from plasma and VLDL to estimate whole-body and hepatic cholesterol synthesis, respectively. Lipid synthesis was measured using deuterium incorporation and isotope ratio mass spectrometry. RESULTS: Fasting total hepatic lipogenesis (3.91 ± 0.90% vs. 5.30 ± 1.22%; P = 0.41) was not significantly different between diabetic and control groups, respectively, nor was synthesis of myristic (28.60 ± 4.90% vs. 26.66 ± 4.57%; P = 0.76), palmitic (12.52 ± 2.75% vs. 13.71 ± 2.64%; P = 0.65), palmitoleic (3.86 ± 0.91% vs. 4.80 ± 1.22%; P = 0.65), stearic (5.55 ± 1.04% vs. 6.96 ± 0.97%; P = 0.29), and oleic acid (1.45 ± 0.28% vs. 2.10 ± 0.51%; P = 0.21). Postprandial lipogenesis was also not different between groups (P = 0.38). Similarly, fasting synthesis of whole-body FC (8.2 ± 1.3% vs. 7.3 ± 0.8%/day; P = 0.88) and CE (1.9 ± 0.4% vs. 2.0 ± 0.3%/day; P = 0.96) and hepatic FC (8.2 ± 2.0% vs. 8.1 ± 0.8%/day; P = 0.72) was not significantly different between diabetic and control subjects. CONCLUSIONS: Despite long-standing disease, lipogenesis and cholesterol synthesis was not different in individuals with type 1 diabetes compared to healthy non-diabetic humans.