Fatty Acid Flux Research Articles

Acyl-CoA Thioesterase 1 (ACOT1) Regulates PPARα to Couple Fatty Acid Flux With Oxidative Capacity During Fasting.

Hepatic acyl-CoA thioesterase 1 (ACOT1) catalyzes the conversion of acyl-CoAs to fatty acids (FAs) and CoA. We sought to determine the role of ACOT1 in hepatic lipid metabolism in C57Bl/6J male mice 1 week after adenovirus-mediated Acot1 knockdown. Acot1 knockdown reduced liver triglyceride (TG) as a result of enhanced TG hydrolysis and subsequent FA oxidation. In vitro experiments demonstrated that Acot1 knockdown led to greater TG turnover and FA oxidation, suggesting that ACOT1 is important for controlling the rate of FA oxidation. Despite increased FA oxidation, Acot1 knockdown reduced the expression of peroxisome proliferator–activated receptor α (PPARα) target genes, whereas overexpression increased PPARα reporter activity, suggesting ACOT1 regulates PPARα by producing FA ligands. Moreover, ACOT1 exhibited partial nuclear localization during fasting and cAMP/cAMP-dependent protein kinase signaling, suggesting local regulation of PPARα. As a consequence of increased FA oxidation and reduced PPARα activity, Acot1 knockdown enhanced hepatic oxidative stress and inflammation. The effects of Acot1 knockdown on PPARα activity, oxidative stress, and inflammation were rescued by supplementation with Wy-14643, a synthetic PPARα ligand. We demonstrate through these results that ACOT1 regulates fasting hepatic FA metabolism by balancing oxidative flux and capacity.

Advances in the pathogenesis of non alcoholic fatty liver disease

Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen-associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894.

Dyslipidemia and associated factors among diabetic patients attending Durame General Hospital in Southern Nations, Nationalities, and People's Region.

BackgroundDiabetes mellitus is a group of metabolic disorders that are caused by deficiency in insulin secretion or the decreased ability of insulin to act effectively on target tissues, particularly muscle, liver, and fat. As a result of insulin resistance in the target tissues, particularly in the adipocytes, free fatty acid flux is increased, leading to increased lipid synthesis in hepatocytes, which is responsible for diabetic dyslipidemia.ObjectiveThe objective of this study was to determine the prevalence and associated factors of dyslipidemia among diabetic patients in Durame General Hospital in Kembata Tembaro zone.MethodsA cross-sectional study was conducted from September 2015 to April 2016. In total, 224 subjects were involved in the study by using convenient sampling techniques. Face-to-face interview–administered questionnaire was used to collect sociodemographic data and other possible clinical data associated with the prevalence of dyslipidemia. Fasting venous blood specimens were collected to assess serum lipid profiles. Blood pressure (BP), weight, height, and waist circumference were measured.ResultsThe prevalence of dyslipidemia was 65.6%. Individual lipid abnormality of elevated LDL-C, TC, TG, and reduced HDL-C were identified in 43.8%, 23.7%, 40.6%, and 41.9% of study subjects, respectively. The prevalence of dyslipidemia was significantly associated with high BP, high body mass index, aging, and longer duration of diabetes mellitus.ConclusionHigh prevalence of dyslipidemia was found among diabetic patients in the study area. Therefore, a compressive mechanism is required to screen, treat, and prevent dyslipidemia.

Decoupled reciprocal subsidies of biomass and fatty acids in fluxes of invertebrates between a temperate river and the adjacent land

Streams and riparian areas are tightly coupled through reciprocal trophic subsidies, and there is evidence that these subsidies affect consumers in connected ecosystems. Most studies of subsidies consider only their quantity and not their quality. We determined the bidirectional exchange of organisms between the Kowie River and its riparian zone in South Africa using floating pyramidal traps (to measure insect emergence) and pan traps (to capture infalling invertebrates). The exchanges of biomass were variable spatially (three sites) and temporally (four seasons), with emergence declining about two orders of magnitude between summer (169–1402 mg m−2 day−1) and winter (3–28 mg m−2 day−1) across all sites, while invertebrate infall declined by a much smaller range from summer (413–679 mg m−2 day−1) to winter (11–220 mg m−2 day−1). Conversely, the absolute flux of physiologically important highly unsaturated fatty acids contained in the emergent and infalling arthropods peaked at comparable values in summer (emergence = 0.3–18 mg m−2 day−1 and infall = 0.3–3 mg m−2 day−1) and declined less in winter (emergence = 0.01–0.51 mg m−2 day−1 and infall = 0.01–0.03 mg m−2 day−1). During some seasons, there was no net flux of essential fatty acids, but there was generally a net flow of highly unsaturated fatty acids from river to land, even when land-to-river inputs dominated by biomass. Thus, quantitative net fluxes of biomass were decoupled from net fluxes of qualitatively key nutrients, establishing the importance of considering both the quality and the quantity of trophic subsidies.

Lipids: A Suitable Therapeutic Target in Diabetic Neuropathy?

Diabetic polyneuropathy (DPN) encompasses multiple syndromes with a common pathogenesis. Glycemic control shows a limited correlation with DPN, arguing in favor of major involvement of other factors, one of which is alterations of lipid and lipoprotein metabolism. Consistent associations have been found between plasma triglycerides/remnant lipoproteins and the risk of DPN. Studies in cultured nerve tissue or in murine models of diabetes have unveiled mechanisms linking lipid metabolism to DPN. Deficient insulin action increases fatty acids flux to nerve cells, inducing mitochondrial dysfunction, anomalous protein kinase C signaling, and perturbations in the physicochemical properties of the plasma membrane. Oxidized low-density lipoproteins bind to cellular receptors and promote generation of reactive oxygen species, worsening mitochondrial function and altering the electrical properties of neurons. Supplementation with specific fatty acids has led to prevention or reversal of different modalities of DPN in animal models. Post hoc and secondary analyses of clinical trials have found benefits of cholesterol reducing (statins and ezetimibe), triglyceride-reducing (fibrates), or lipid antioxidant (thioctic acid) therapies over the progression and severity of DPN. However, these findings are mostly hypothesis-generating. Randomized trials are warranted in which the impact of intensive plasma lipids normalization on DPN outcomes is specifically evaluated.

What is the influence of complement factor C3 and lipid metabolism of adipose tissue on hepatic steatosis in mice?

NALFD (non-alcoholic fatty liver disease) represents a fatty liver whereby lipid accumulation (steatosis) occurs. In recent decades, the prevalence of NAFLD has dramatically increased. Activation of the complement system, which is an important subset of the immune system, and especially complement factor C3, may have a significant role in the progression of NAFLD. In this study is examined if there are, next to alterations in hepatic lipid metabolism, also alterations present in the lipid metabolism of adipose tissue. It appears that acylation stimulating protein (ASP) has an important role in linking the activation of complement and lipid metabolism of adipose tissue in NAFLD. In this study the following research question is stated: What is the influence of complement factor C3 and the lipid metabolism of adipose tissue on hepatic steatosis in mice? It is expected that wild type mice on a HFD diet will show the highest hepatic lipid accumulation. Furthermore the expression of some enzymes involved in lipid metabolism will be altered. Liver and adipose tissue from C3+/+ (n=17) and C3-/- (n=17) mice is used. The control group (n=12) received a chow diet and the experimental group (n=22) a high fat diet (HFD). The hepatic lipid accumulation and the expression of some enzymes, involved in the lipid metabolism of adipose tissue, are determined in these mice. The results, showed no significant differences in lipid accumulation between both mouse groups. The expression levels of the enzymes FASN, SCD1, PPARγ and DGAT1 were significantly different between the diets in one or both mouse groups. The expression of the enzymes HSL and DGAT1 were significantly higher in the C3+/+ mice compared to the C3-/- mice. It can be concluded from histological stainings and preliminary scoring results that hepatic lipid accumulation occurs the most in C3+/+ mice on a HFD. However it seems that lipids do not only accumulate by C3 activation, but also other mechanisms seems to play a role. It is assumed that in C3-/- mice the ASP pathway is disturbed, which will lead to an increased flux of fatty acids to the liver. In C3+/+ mice there is a higher adipose tissue lipolysis and lipogenesis present since the expression of HSL and DGAT were increased.

Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart

The mammalian heart is a major consumer of ATP and requires a constant supply of energy substrates for contraction. Not surprisingly, alterations of myocardial metabolism have been linked to the development of contractile dysfunction and heart failure. Therefore, unraveling the link between metabolism and contraction should shed light on some of the mechanisms governing cardiac adaptation or maladaptation in disease states. The isolated working rat heart preparation can be used to follow, simultaneously and in real time, cardiac contractile function and flux of energy providing substrates into oxidative metabolic pathways. The present protocol aims to provide a detailed description of the methods used in the preparation and utilization of buffers for the quantitative measurement of the rates of oxidation for glucose and fatty acids, the main energy providing substrates of the heart. The methods used for sample analysis and data interpretation are also discussed. In brief, the technique is based on the supply of 14C- radiolabeled glucose and a 3H- radiolabeled long-chain fatty acid to an ex vivo beating heart via normothermic crystalloid perfusion. 14CO2 and 3H2O, end byproducts of the enzymatic reactions involved in the utilization of these energy providing substrates, are then quantitatively recovered from the coronary effluent. With knowledge of the specific activity of the radiolabeled substrates used, it is then possible to individually quantitate the flux of glucose and fatty acid in the oxidation pathways. Contractile function of the isolated heart can be determined in parallel with the appropriate recording equipment and directly correlated to metabolic flux values. The technique is extremely useful to study the metabolism/contraction relationship in response to various stress conditions such as alterations in pre and after load and ischemia, a drug or a circulating factor, or following the alteration in the expression of a gene product.

Methods for the Determination of Rates of Glucose and Fatty Acid Oxidation in the Isolated Working Rat Heart.

The mammalian heart is a major consumer of ATP and requires a constant supply of energy substrates for contraction. Not surprisingly, alterations of myocardial metabolism have been linked to the development of contractile dysfunction and heart failure. Therefore, unraveling the link between metabolism and contraction should shed light on some of the mechanisms governing cardiac adaptation or maladaptation in disease states. The isolated working rat heart preparation can be used to follow, simultaneously and in real time, cardiac contractile function and flux of energy providing substrates into oxidative metabolic pathways. The present protocol aims to provide a detailed description of the methods used in the preparation and utilization of buffers for the quantitative measurement of the rates of oxidation for glucose and fatty acids, the main energy providing substrates of the heart. The methods used for sample analysis and data interpretation are also discussed. In brief, the technique is based on the supply of 14C- radiolabeled glucose and a 3H- radiolabeled long-chain fatty acid to an ex vivo beating heart via normothermic crystalloid perfusion. 14CO2 and 3H2O, end byproducts of the enzymatic reactions involved in the utilization of these energy providing substrates, are then quantitatively recovered from the coronary effluent. With knowledge of the specific activity of the radiolabeled substrates used, it is then possible to individually quantitate the flux of glucose and fatty acid in the oxidation pathways. Contractile function of the isolated heart can be determined in parallel with the appropriate recording equipment and directly correlated to metabolic flux values. The technique is extremely useful to study the metabolism/contraction relationship in response to various stress conditions such as alterations in pre and after load and ischemia, a drug or a circulating factor, or following the alteration in the expression of a gene product.

Hepatic adaptations to maintain metabolic homeostasis in response to fasting and refeeding in mice.

BackgroundThe increased incidence of obesity and associated metabolic diseases has driven research focused on genetically or pharmacologically alleviating metabolic dysfunction. These studies employ a range of fasting-refeeding models including 4–24 h fasts, “overnight” fasts, or meal feeding. Still, we lack literature that describes the physiologically relevant adaptations that accompany changes in the duration of fasting and re-feeding. Since the liver is central to whole body metabolic homeostasis, we investigated the timing of the fast-induced shift toward glycogenolysis, gluconeogenesis, and ketogenesis and the meal-induced switch toward glycogenesis and away from ketogenesis.MethodsTwelve to fourteen week old male C57BL/6J mice were fasted for 0, 4, 8, 12, or 16 h and sacrificed 4 h after lights on. In a second study, designed to understand the response to a meal, we gave fasted mice access to feed for 1 or 2 h before sacrifice. We analyzed the data using mixed model analysis of variance.ResultsFasting initiated robust metabolic shifts, evidenced by changes in serum glucose, non-esterified fatty acids (NEFAs), triacylglycerol, and β-OH butyrate, as well as, liver triacylglycerol, non-esterified fatty acid, and glycogen content. Glycogenolysis is the primary source to maintain serum glucose during the first 8 h of fasting, while de novo gluconeogenesis is the primary source thereafter. The increase in serum β-OH butyrate results from increased enzymatic capacity for fatty acid flux through β-oxidation and shunting of acetyl-CoA toward ketone body synthesis (increased CPT1 (Carnitine Palmitoyltransferase 1) and HMGCS2 (3-Hydroxy-3-Methylglutaryl-CoA Synthase 2) expression, respectively). In opposition to the relatively slow metabolic adaptation to fasting, feeding of a meal results in rapid metabolic changes including full depression of serum β-OH butyrate and NEFAs within an hour.ConclusionsHerein, we provide a detailed description of timing of the metabolic adaptations in response to fasting and re-feeding to inform study design in experiments of metabolic homeostasis. Since fasting and obesity are both characterized by elevated adipose tissue lipolysis, hepatic lipid accumulation, ketogenesis, and gluconeogenesis, understanding the drivers behind the metabolic shift from the fasted to the fed state may provide targets to limit aberrant gluconeogenesis and ketogenesis in obesity.

Palmitoyl-carnitine production by blood cells associates with the concentration of circulating acyl-carnitines in healthy overweight women

Circulating acyl-carnitines (acyl-CNTs) are associated with insulin resistance (IR) and type 2 diabetes (T2D) in both rodents and humans. However, the mechanisms whereby circulating acyl-CNTs are increased in these conditions and their role in whole-body metabolism remains unknown. The purpose of this study was to determine if, in humans, blood cells contribute in production of circulating acyl-CNTs and associate with whole-body fat metabolism. Eight non-diabetic healthy women (age: 47±19y; BMI: 26±1kg·m-2) underwent stable isotope tracer infusion and hyperinsulinemic-euglycemic clamp study to determine invivo whole-body fatty acid flux and insulin sensitivity. Blood samples collected at baseline (0min) and after 3h of clamp were used to determine the synthesis rate of palmitoyl-carnitine (palmitoyl-CNT) invitro. The fractional synthesis rate of palmitoyl-CNT was significantly higher during hyperinsulinemia (0.788±0.084 vs. 0.318±0.012%·hr-1, p=0.001); however, the absolute synthesis rate (ASR) did not differ between the periods (p=0.809) due to ∼30% decrease in blood palmitoyl-CNT concentration (p=0.189) during hyperinsulinemia. The ASR of palmitoyl-CNT significantly correlated with the concentration of acyl-CNTs in basal (r=0.992, p<0.001) and insulin (r=0.919, p=0.001) periods; and the basal ASR significantly correlated with plasma palmitate oxidation (r=0.764, p=0.027). In women, blood cells contribute to plasma acyl-CNT levels and the acyl-CNT production is linked to plasma palmitate oxidation, a marker of whole-body fat metabolism. Future studies are needed to confirm the role of blood cells in acyl-CNT and lipid metabolism under different physiological (i.e., in response to meal) and pathological (i.e., hyperlipidemia, IR and T2D) conditions.

Effects of subacute ruminal acidosis and low feed intake on short-chain fatty acid transporters and flux pathways in Holstein steers.

The objective of this study was to investigate the role of protein-mediated transport pathways for short-chain fatty acid flux across the ruminal epithelium, using subacute ruminal acidosis (SARA) and feed restriction as models. Twenty-one Holstein steers (216.8 ± 31.4 kg BW) were individually housed and fed a total mixed ration (TMR) with a 50:50 forage:concentrate ad libitum for 5 d. After the 5 d diet adjustment period, calves were assigned 1 of 3 treatments: control (CTRL) calves were fed the TMR ad libitum on d 1, subacute ruminal acidosis calves were given 25% of their ad libitum DMI on d 1 and then given a barley grain challenge at 30% of ad libitum DMI on d2 (ACID) calves were given 25% of their ad libitum DMI on d 1 and then given a barley grain challenge at 30% of ad libitum DMI on d 2, and feed restriction (FR) calves were given 25% of their ad libitum DMI for 5 d. Reticuloruminal pH was continuously measured during the entire study. At the end of the study, rumen tissue was harvested and acetate and butyrate flux were measured. Selective inhibitors were used to differentiate total flux (TOTAL), protein-mediated flux (PMF), and passive diffusion flux (PDF). The duration that rumen pH was <5.6 was greater in ACID calves compared with CTRL and FR calves (57 ± 90 vs. 519.71 ± 90 vs. 30 ± 90 min/d for CTRL, ACID, and FR, respectively; < 0.01). Total acetate flux was greater in FR than in CTRL (630.6 ± 38.9 vs. 421.1 ± 41.4 nmol/cm × h, respectively; < 0.01), but no difference was observed between CTRL and ACID (421.1 ± 41.4 vs. 455.4 ± 38.9 nmol/cm × h, respectively). Also, total butyrate flux was greater in FR than in CTRL (1,241.9 ± 94.8 vs. 625.5 ± 86.3 nmol/cm × h, respectively; < 0.01), but no difference was detected between CTRL and ACID (625.5 ± 86.3 vs. 716.7 ± 81.0 nmol/cm × h, respectively). For butyrate flux, PMF was greater for FR than for CTRL (479.21 ± 103.9 vs. 99.9 ± 86.3 nmol/cm × h, respectively; < 0.01), but no difference was observed between the CTRL and ACID treatments (99.9 ± 86.3 vs. 90.2 ± 81.0 nmol/cm × h, respectively). Immunofluorescence analysis showed an increase in monocarboxylate cotransporter isoform 1 abundance in the FR treatment compared with the ACID treatment (9,250 ± 1,648 vs. 4,187 ± 1,537 arbitrary units, respectively; = 0.03) but not compared with the CTRL treatment (9,250 ± 1,648 vs. 7,241 ± 1,648 arbitrary units, respectively; = 0.15). These data identify a short-term adaptive response of the ruminal epithelium to dietary changes that involves PMF and PDF.

Techno-environmental assessment of integrating polyhydroxyalkanoate (PHA) production with services of municipal wastewater treatment

In this paper, the potential impacts in the techno-environmental performance of a municipal wastewater treatment plant with integrated mixed-microbial-culture polyhydroxyalkanoate (PHA) production are presented for the first time. A life cycle assessment was conducted based on mass and energy balances. The techno-environmental performance was evaluated for five wastewater treatment configurations: a reference case and four alternative processes producing PHA-rich biomass using influent municipal wastewater as the only organic carbon source. The integration of PHA-rich biomass production into a municipal wastewater treatment plant with sludge digestion sustains the overall conversion yield for total products of biogas and PHA-rich biomass (around 0.26 gCOD products per influent gCOD treated). PHA production integration has the potential to improve the overall environmental performance with respect to the reference case. Even when no benefits were accounted for substitutions related to the biogas and PHA-rich biomass, similar or improved environmental performances were estimated for all four alternatives for global warming potential, acidification potential, terrestrial eutrophication potential, and photo-oxidant formation potential. When benefits were accounted from substitutions of electricity and heat co-generated from biogas and of PHA-rich biomass by pure-culture PHA-rich biomass from sugar fermentation, gains were even higher due to the diversion of carbon from biogas to PHA-rich biomass. Freshwater and marine eutrophication potentials were dependent on effluent specifications. Case-by-case process configurations influence the mass and energy balance and trade-offs of process integration. The production and export of PHA-rich biomass decreased the aeration requirements for COD and nitrogen removal; however, increased demands for heat, power and chemicals were incurred for the generation of volatile fatty acids from primary solids fermentation. The choice of nitrogen-removal approach (nitrification-denitrification vs. anammox) also impacted energy consumption. Using influent wastewater as the sole carbon supply, the energy balance and PHA production were sensitive to the efficiency of primary treatment and available flux of volatile fatty acids into PHA production. Other regional inputs of organic residuals may improve carbon recovery in the treatment facility. The improved environmental performance of the treatment configurations motivates the idea that individual municipal wastewater treatment plants may become suppliers of renewable raw materials of higher value than that of biogas and/or energy and heat today.

Fluxes of biomass and essential polyunsaturated fatty acids from water to land via chironomid emergence from a mountain lake

The taxonomic composition, seasonal dynamics, and emergence intensity of chironomid adults (the Chironomidae family) emerging from Oiskoe mountain oligotrophic lake (Western Sayan, Southern Siberia) have been established. The value of the annual emergence of chironomid adults averages 0.42 g wet weight m-2 in the lake area and approaches the value of potential emergence, which is calculated based on the estimate of zoobenthos secondary production. For the first time the fatty-acid composition and contents of essential omega-3 polyunsaturated fatty acids (PUFAs) are compared between the larvae and adult stages of chironomids. The PUFA content per wet weight unit in adults is more than 7 times higher than that in larvae. The PUFA flux per lake area unit resulting from the chironomid emergence amounted to 1.752 mg m-2 y-1, which is over 10 times lower than the global estimate for the emergence of amphibiotic insects. Calculations show that the PUFA flux brought with the chironomid emergence per land unit of the studied mountain territory is very low when compared to that for other landscapes, with the exception of the shoreline part of the territory with a width of 15 m, in which the PUFA flux is comparable to that in productive landscapes.

Direct effect of p,p'- DDT on mice liver

ABSTRACT Contact with the pesticide dichlorodiphenyltrichloroethane (p,p′-DDT) can be the cause of various harmful effects in humans, wildlife, and the environment. This pesticide is known to be persistent, lipophilic, resistant to degradation, and bioaccumulive in the environment and to be slowly released into bloodstream. Growing evidence shows that exposure to DDT is linked to type 2 diabetes mellitus. Individuals exposed to elevated levels of DDT and its metabolite have an increased prevalence of diabetes and insulin resistance. To evaluate these possible relationships, experiments were performed on eight-week-old female mice, divided into three groups (n = 10 per group): Group 1 received a vehicle-control intraperitoneal (i.p.) injection of sesame oil; Groups 2 and 3 received an i.p. dose of 50 and 100 µg/g p,p′-DDT respectively, dissolved in sesame oil. All groups were treated once daily for four days. Real-time PCR analysis of several genes was undertaken. Additionally, biochemical parameters and histopathological changes were measured. NQO1, HMOX1, NR1I3 and NR3C1 were up-regulated in DDT-exposed animals compared to the vehicle control group, while only SREBP1 was down-regulated in the 100 µg/g group. MTTP and FABP5, not previously reported for DDT exposure, but involved in regulation of fatty acid fluxes, could also function as biomarkers cross-talking between these signaling pathways. These results suggest that beyond epidemiological data, there is increasing molecular evidence that DDT may mimic different processes involved in diabetes and insulin resistance pathways.

Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes.

The clinical correlations linking diabetes mellitus with accelerated atherosclerosis, cardiomyopathy, and increased post-myocardial infarction fatality rates are increasingly understood in mechanistic terms. The multiple mechanisms discussed in this review seem to share a common element: prolonged increases in reactive oxygen species (ROS) production in diabetic cardiovascular cells. Intracellular hyperglycemia causes excessive ROS production. This activates nuclear poly(ADP-ribose) polymerase, which inhibits GAPDH, shunting early glycolytic intermediates into pathogenic signaling pathways. ROS and poly(ADP-ribose) polymerase also reduce sirtuin, PGC-1α, and AMP-activated protein kinase activity. These changes cause decreased mitochondrial biogenesis, increased ROS production, and disturbed circadian clock synchronization of glucose and lipid metabolism. Excessive ROS production also facilitates nuclear transport of proatherogenic transcription factors, increases transcription of the neutrophil enzyme initiating NETosis, peptidylarginine deiminase 4, and activates the NOD-like receptor family, pyrin domain-containing 3 inflammasome. Insulin resistance causes excessive cardiomyocyte ROS production by increasing fatty acid flux and oxidation. This stimulates overexpression of the nuclear receptor PPARα and nuclear translocation of forkhead box O 1, which cause cardiomyopathy. ROS also shift the balance between mitochondrial fusion and fission in favor of increased fission, reducing the metabolic capacity and efficiency of the mitochondrial electron transport chain and ATP synthesis. Mitochondrial oxidative stress also plays a central role in angiotensin II-induced gap junction remodeling and arrhythmogenesis. ROS contribute to sudden death in diabetics after myocardial infarction by increasing post-translational protein modifications, which cause increased ryanodine receptor phosphorylation and downregulation of sarco-endoplasmic reticulum Ca(++)-ATPase transcription. Increased ROS also depress autonomic ganglion synaptic transmission by oxidizing the nAch receptor α3 subunit, potentially contributing to the increased risk of fatal cardiac arrhythmias associated with diabetic cardiac autonomic neuropathy.

Antiobesity efficacy of GLP-1 receptor agonist liraglutide is associated with peripheral tissue-specific modulation of lipid metabolic regulators.

To investigate the role of glucagon-like-peptide-1 receptor (GLP-1R) in peripheral lipid metabolism. Both lean and high-fat diet (HFD)-induced obesity (DIO) rats were used to compare the peripheral effects of the subcutaneous and repeated administration of the GLP-1R agonist liraglutide on the expression of key regulators involved in lipid metabolism, β-oxidation and thermogenesis in liver, abdominal muscle, and epididymal white adipose tissue (eWAT). We observed that liraglutide reduced caloric intake, body weight, and plasma levels of triglycerides and VLDL in a diet-independent manner. However, changes in liver fat content and the expression of lipid metabolism regulators were produced in a diet and tissue-dependent manner. In lean rats, liraglutide increased the gene/protein expression of elements involved in lipogenesis (ChREBP, Acaca/ACC, Fasn/FAS, Scd1/SCD1, PPARα/γ), β-oxidation (CPT1b), and thermogenesis (Cox4i1, Ucp1/UCP1) in eWAT and muscle, which suggest an increase in fatty-acid flux and utilization to activate energy expenditure. Regarding DIO rats, the specific reduction of liver lipid content by liraglutide was associated with a decreased expression of main elements involved in lipogenesis (phospho-ACC), peroxisomal β-oxidation (ACOX1), and lipid flux/storage (Pparγ/PPARγ) in liver, which suggest a recovery of lipid homeostasis. Interestingly, the muscle of DIO rats treated with liraglutide showed a decreased expression of PPARγ and the thermogenic factor UCP1. These results help us to better understand the peripheral mechanisms regulating lipid metabolism that underlay the effectiveness of GLP-1 analogues for the treatment of diabetes and obesity. © 2016 BioFactors, 42(6):600-611, 2016.

Living with lipids: Reflections of a fat physiologist

Living with lipids: Reflections of a fat physiologist

Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders

The adipose tissue is a central metabolic organ in the regulation of whole-body energy homeostasis. The white adipose tissue functions as a key energy reservoir for other organs, whereas the brown adipose tissue accumulates lipids for cold-induced adaptive thermogenesis. Adipose tissues secrete various hormones, cytokines, and metabolites (termed as adipokines) that control systemic energy balance by regulating appetitive signals from the central nerve system as well as metabolic activity in peripheral tissues. In response to changes in the nutritional status, the adipose tissue undergoes dynamic remodeling, including quantitative and qualitative alterations in adipose tissue-resident cells. A growing body of evidence indicates that adipose tissue remodeling in obesity is closely associated with adipose tissue function. Changes in the number and size of the adipocytes affect the microenvironment of expanded fat tissues, accompanied by alterations in adipokine secretion, adipocyte death, local hypoxia, and fatty acid fluxes. Concurrently, stromal vascular cells in the adipose tissue, including immune cells, are involved in numerous adaptive processes, such as dead adipocyte clearance, adipogenesis, and angiogenesis, all of which are dysregulated in obese adipose tissue remodeling. Chronic overnutrition triggers uncontrolled inflammatory responses, leading to systemic low-grade inflammation and metabolic disorders, such as insulin resistance. This review will discuss current mechanistic understandings of adipose tissue remodeling processes in adaptive energy homeostasis and pathological remodeling of adipose tissue in connection with immune response.

Narrow time window of metabolic changes associated with transition to overt heart failure in Tgaq*44 mice.

The timing and consequences of alternations in substrate utilization in heart failure (HF) and their relationship with structural changes remain unclear. This study aimed to analyze metabolic changes associated with transition to overt heart failure in transgenic mouse model of HF resulting from cardiac-specific overexpression of constitutively active Gαq*. Structural changes quantified by morphometry, relative cardiac mRNA and protein expression of PPARα, FAT/CD36, CPT-1, GLUT-4 and glycolytic efficiency following administration of 1-(13)C glucose were investigated in 4-14-month-old Tgαq*44 mice (TG), compared with age-matched FVB wild type mice (WT). Initial hypertrophy in TG (4-10-month of age) was featured by an accelerated glycolytic pathway that was not accompanied by structural changes in cardiomyocytes. In 10-month-old TG, cardiomyocyte elongation and hypertrophic remodeling and increased glycolytic flux was accompanied by relatively low expression of FAT/CD36, CPT-1 and PPARα. During the transition phase (12-month-old TG), a pronounced increase in PPARα with an increase in relative fatty acid (FA) flux was associated with anomalies of cardiomyocytes with accumulation of lipid droplets and glycogen as well as cell death. At the stage of overt heart failure (14-month-old TG), an accelerated glycolytic pathway with a decline in FA oxidation was accompanied by further structural changes. Tgαq*44 mice display three distinct phases of metabolic/structural changes during hypertrophy and progression to HF, with relatively short period of increase in FA metabolism, highlighting a narrow metabolic changes associated with transition to overt heart failure in Tgaq*44 mice that have therapeutic significance.

Understanding the control of acyl flux through the lipid metabolic network of plant oil biosynthesis

Plant oil biosynthesis involves a complex metabolic network with multiple subcellular compartments, parallel pathways, cycles, and pathways that have a dual function to produce essential membrane lipids and triacylglycerol. Modern molecular biology techniques provide tools to alter plant oil compositions through bioengineering, however with few exceptions the final composition of triacylglycerol cannot be predicted. One reason for limited success in oilseed bioengineering is the inadequate understanding of how to control the flux of fatty acids through various fatty acid modification, and triacylglycerol assembly pathways of the lipid metabolic network. This review focuses on the mechanisms of acyl flux through the lipid metabolic network, and highlights where uncertainty resides in our understanding of seed oil biosynthesis. This article is part of a Special Issue entitled: Plant Lipid Biology edited by Kent D. Chapman and Ivo Feussner.