Search

Background and aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. Methods Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. Results Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. Conclusions These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.

In health, the liver is metabolically flexible over the course of the day, as it undertakes a multitude of physiological processes including the regulation of intrahepatic and systemic glucose and lipid levels. The liver is the first organ to receive insulin and through a cascade of complex metabolic processes, insulin not only plays a key role in the intrahepatic regulation of glucose and lipid metabolism, but also in the regulation of systemic glucose and lipid concentrations. Thus, when intrahepatic insulin signalling becomes aberrant then this may lead to perturbations in intrahepatic metabolic processes that have the potential to impact on metabolic health. For example, obesity is associated with intrahepatic fat accumulation (known as nonalcoholic liver disease (NAFLD)) and hyperinsulinaemia, the latter as a result of insulin hypersecretion or impaired hepatic insulin extraction. Although insulin signalling directly alters intra- and extrahepatic metabolism, the regulation of hepatic glucose and fatty acid metabolism is also indirectly driven by substrate availability. Here we discuss the direct and indirect effects of insulin on intrahepatic processes such as the synthesis of fatty acids and peripherally regulating the flux of fatty acids to the liver; processes that may play a role in the development of insulin resistance and/or intrahepatocellular triacylglycerol (IHTAG) accumulation in humans.

The prevalence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) is increasing. As a strong association between these two diseases exist, it is unsurprising that the number of patients with coexisting NAFLD and T2D is also increasing. These patients display a deleterious metabolic profile (e.g. hypertriglyceridemia), and increased mortality rates relative to those with only NAFLD or T2D in isolation, therefore effective treatment strategies are required. Here we review the available intervention studies that have investigated changes in lifestyle (diet and exercise/physical activity) on metabolic parameters in patients with both NAFLD and T2D. Based on the available evidence, it appears that the addition of any kind of exercise (i.e. resistance, aerobic, or high-intensity intermittent exercise) is beneficial for patients with both NAFLD and T2D. These effects appear to occur independently of changes in bodyweight. Hypocaloric diets leading to weight loss are also effective in improving metabolic parameters in patients with both NAFLD and T2D, with data indicating that ~7-10% weight loss is required in order to observe beneficial effects. It is unclear if multidisciplinary interventions incorporating changes in both diet and physical activity levels are a more effective treatment strategy in this population than diet or exercise interventions in isolation. In conclusion, it is clear that lifestyle interventions are an effective treatment strategy in patients with both NAFLD and T2D, although further research is required to optimise these interventions and determine their scalability.

Background/Objective Although assumed, it remains unclear that fatty acid (FA) biomarkers of n-3 long-chain PUFA reflect wide ranges of intake. However, to be utilised as biomarkers, to predict dietary intake, dose-response curves that cover a spectrum of intakes are required. The aim of the study was to investigate whether the FA composition of plasma phosphatidylcholine (PC) is a sensitive biomarker of n-3 FAs from fish oil, across a range of supplementation doses, and alpha-linolenic acid (ALA) supplementation, in young, healthy women. Subjects/Methods A total of 303 young women were randomized to intakes ranging between 0.33 and 4.50 g EPA+DHA/day from fish oil (not all doses used in each year) or flaxseed oil (5.90–6.60 g/day) daily for 14 days in a series of trials, over five years. Fasting blood was collected at baseline (Day 0) and day 14 and plasma PC FA composition, total and HDL-cholesterol and triacylglycerol concentrations measured. Results Fourteen days supplementation with fish oil significantly (P Conclusion Our data demonstrate plasma PC is a sensitive biomarker of n-3 FA intake and reflects changes within 14 days across a range of intakes.

Intramyocellular lipid (IMCL) is of particular metabolic interest, but despite many proton magnetic resonance spectroscopy (1H MRS) studies reporting IMCL content measured by the methylene (CH2) resonance signal, little is known about its composition. Here we validated IMCL CH3:CH2 ratio as a compositional marker using 1H MRS at short echo time, and investigated IMCL content and composition during a 28-hour fast in 24 healthy males. Increases in IMCL CH2 relative to the creatine and phosphocreatine resonance (Cr) at 3.0 ppm (an internal standard) correlated with circulating free fatty acid (FA) concentrations, supporting the concept of increased FA influx into IMCL. Significant decreases in IMCL CH3:CH2 ratio indicated a less unsaturated IMCL pool after fasting, and this compositional change related inversely to IMCL baseline composition, suggesting a selective efflux of unsaturated shorter-chain FA from the IMCL pool. This novel in vivo evidence reveals IMCL turnover during extended fasting, consistent with the concept of a flexible, responsive myocellular lipid store. There were also differences between soleus and tibialis anterior in basal IMCL composition and in response to fasting. We discuss the potential of this marker for providing insights into normal physiology and mechanisms of disease.

Context The effects of energy-balanced bed rest on metabolic flexibility have not been thoroughly examined. Objective We investigated the effects of 21 days of bed rest, with and without whey protein supplementation, on metabolic flexibility while maintaining energy balance. We hypothesized that protein supplementation mitigates metabolic inflexibility by preventing muscle atrophy. Design and Setting Randomized crossover longitudinal study conducted at the German Aerospace Center, Cologne, Germany. Participants and Interventions Ten healthy men were randomly assigned to dietary countermeasure or isocaloric control diet during a 21-day bed rest. Outcome Measures Before and at the end of the bed rest, metabolic flexibility was assessed during a meal test. Secondary outcomes were glucose tolerance by oral glucose tolerance test, body composition by dual energy X-ray absorptiometry, ectopic fat storage by magnetic resonance imaging, and inflammation and oxidative stress markers. Results Bed rest decreased the ability to switch from fat to carbohydrate oxidation when transitioning from fasted to fed states (i.e., metabolic inflexibility), antioxidant capacity, fat-free mass (FFM), and muscle insulin sensitivity along with greater fat deposition in muscle (P < 0.05 for all). Changes in fasting insulin and inflammation were not observed. However, glucose tolerance was reduced during acute overfeeding. Protein supplementation did not prevent FFM loss and metabolic alterations. Conclusions Physical inactivity triggers metabolic inflexibility, even when energy balance is maintained. Although reduced insulin sensitivity and increased fat deposition were observed at the muscle level, systemic glucose intolerance was detected only in response to a moderately high-fat meal. This finding supports the role of physical inactivity in metabolic inflexibility and suggests that metabolic inflexibility precedes systemic glucose intolerance., Bed-rest–induced physical inactivity triggers metabolic inflexibility, which can be used as an early marker of metabolic disturbances developed in response to the adoption of sedentary behaviors.

Upper-body adiposity is associated with increased metabolic disease risk, whilst lower-body adiposity is paradoxically protective. Efforts to understand the underlying mechanisms require appropriate and reproducible in vitro culture models. We have therefore generated immortalised (im) human preadipocyte (PAD) cell lines derived from paired subcutaneous abdominal and gluteal adipose tissue. These cell lines, denoted imAPAD and imGPAD display enhanced proliferation and robust adipogenic capacities. Differentiated imAPAD and imGPAD adipocytes synthesise triglycerides de novo and respond lipolytically to catecholamine-stimulation. Importantly the cells retain their depot-of-origin ‘memory’ as reflected by inherent differences in fatty acid metabolism and expression of depot-specific developmental genes. These features make these cell lines an invaluable tool for the in vitro investigation of depot-specific human adipocyte biology.

BACKGROUND AND AIM: Replacing saturated fat with polyunsaturated fat reduces plasma cholesterol concentrations; however, it has not been well documented how rapidly the decline occurs nor how long is required to reach the maximum cholesterol-lowering effect. The aim of the present study was to determine the time course of change in plasma cholesterol concentrations when participants adopt a lipid-lowering diet. METHODS AND RESULTS: Participants (n = 19) were asked to follow for 19 days a diet high in saturated fat and then crossed over--without washout--for 19 days to a diet high in n-6 polyunsaturated fat. Participants were asked to maintain a total fat intake of 30-33% of total energy on both diets. Energy and nutrient intakes were assessed by self-reported food records covering 3 days. Plasma total cholesterol concentrations were measured on days 0, 1, 2, 5, 8, 12, and 19 of the n-6 polyunsaturated fat rich diet. Mean (95% CI) plasma total cholesterol concentration declined from 5.10 mmol/L (4.77, 5.46) at day 0 to 4.25 mmol/L (3.83, 4.67) on day 12 and remained unchanged at 4.23 mmol/L (3.85, 4.61) on day 19. A statistically significant decrease in plasma cholesterol concentration was achieved on day 2 of the intervention; by day 5, 59% (0.51 mmol/L) of the maximum reduction (0.87 mmol/L) had been reached. CONCLUSIONS: Adopting a lipid lowering diet initiates an immediate decline in plasma cholesterol concentration, the full effect of which is achieved within two weeks.

Context:\ud 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified.\ud Objective:\ud Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism.\ud Design:\ud We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry.\ud Setting:\ud The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom.\ud Main Outcome Measure:\ud Incorporation of hepatic lipid was measured with MRS.\ud Results:\ud Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism.\ud Conclusions:\ud Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.\ud - See more at: http://press.endocrine.org/doi/10.1210/jc.2015-2928#sthash.KmmY91Iw.dpuf

OBJECTIVE: We aimed to determine differences in the postprandial contributions of different fatty acid sources to VLDL triglycerides (TGs) in healthy men and women with varying degrees of insulin resistance. RESEARCH DESIGN AND METHODS: Insulin-resistant (n = 11) and insulin-sensitive (n = 11) men and women (n = 6) were given an intravenous infusion of [(2)H(2)]palmitic acid to investigate systemic nonesterified fatty acid (NEFA) incorporation into VLDL TGs. Participants were also fed a mixed meal containing [U-(13)C]palmitic acid to investigate the contribution of dietary fatty acids to VLDL TG production. Blood samples were taken over the following 6 h. Separation of VLDL was performed by density gradient ultracentrifugation and immunoaffinity techniques specific to apolipoprotein B-100. RESULTS: Insulin-resistant and insulin-sensitive men had similar postprandial chylomicron and chylomicron remnant TG concentrations, but insulin-resistant men had higher postprandial VLDL TG concentrations (median [range]; area under the curve 485 micromol/l [123-992] vs. 287 micromol/l [162-510]; P < 0.05). At 360 min, most of the difference in VLDL TGs was accounted for by an additional contribution from splanchnic fat (means +/- SE; 331 +/- 76 micromol/l vs. 89 +/- 25 micromol/l; P < 0.01). The contribution of fatty acids from endogenous systemic NEFAs was similar across the groups, as were dietary fatty acids. There was no difference in the VLDL TG concentration or the contribution of different fatty acid sources between insulin-sensitive men and women. CONCLUSIONS: In the postprandial period, the only sources of fatty acids for VLDL TG production to differ in the insulin-resistant compared with the insulin-sensitive men are those derived from splanchnic sources.