Adipose Tissue Fatty Acid Research Articles

G protein-coupled receptor 120 in mediating the regulation effect of saturated and unsaturated long-chain fatty acid on human adipocytes

ObjectiveTo explore G protein-coupled receptor 120 (GPR120)'s role in mediating saturated and unsaturated long-chain fatty acid on adipocyte inflammation, ER stress and insulin signaling pathway. MethodsOmental adipose tissue from 5 patients undergoing elective gallstone removal surgery was collected and the primary adipocytes were isolated and cultured. In the first experiment, cells were divided into the following four groups: (1) Control group; (2): Docosahexaenoic acid (DHA) group; (3)DHA+10 μmol/L GW9508 group; and (4) DHA+20 μmol/L GW9508 group. In the second experiment, cells were divided into the following four groups:(1) Control group; (2) Palmic acid (PA) group; (3) PA+10 μmol/L GW9508 group; and (4) PA+20 μmol/L GW9508 group. Real time PCR and western blot were used to evaluate the gene and protein expression of GPR120, FABP4, inflammatory factors and ER stress markers. Results(1) Under the stimulation of DHA and PA, the expression of GPR and FABP4 were increased. But with inhibition of GPR120, the expression of GPR120and FABP4 decreased in both DHA and PA treatment groups.(2) DHA treatment could decrease TNF-alpha expression and inflammation factor mRNA levels in primary adipocytes. Production of these factors increased with inhibition of GPR120. PA treatment could increase TNF-alpha expression and inflammation factor mRNA levels in primary adipocytes. They were further increased by inhibition of GPR120. (3) DHA treatment could decrease ER stress in primary adipocytes. GPR120 inhibition could promote ER stress. PA treatment could increase ER stress in primary adipocytes. Again, GPR120 inhibition further increased ER stress. Conclusion GPR120 mediated long-chain fatty acid-related inflammation and ER stress regulation, and balanced the function of saturated and unsaturated long-chain fatty acid in adipose tissue.

Trans fatty acids in adipose tissue and risk of myocardial infarction: A case-cohort study.

BackgroundThe risk of coronary heart disease associated with intake of individual trans fatty acids (TFAs) is not clear. Adipose tissue content of TFAs is a biomarker of TFA intake and metabolism.ObjectiveWe investigated the rate of myocardial infarction (MI) associated with the adipose tissue content of total 18:1t, isomers of 18:1t (18:1 Δ6-10t and 18:1 Δ11t) and 18:2 Δ9c, 11t.MethodsA case-cohort study, nested within the Danish Diet, Cancer and Health cohort (n = 57,053), was conducted, which included a random sample (n = 3156) of the total cohort and all incident MI cases (n = 2148) during follow-up (14 years). Information on MI cases was obtained by linkage with nationwide registers and validated. Adipose tissue was taken from the participants buttocks and the fatty acid composition was determined by gas chromatography.ResultsWomen with higher adipose tissue content of total 18:1t had a 57% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.57; 95% confidence interval, 1.12–2.20; P-trend = 0.011) and women with higher content of 18:1 Δ6-10t had a 76% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.76; 95% confidence interval, 1.23–2.51; P-trend = 0.002). No association between 18:1 Δ11t content and MI rate was observed. In men, no associations between adipose tissue content of total 18:1t and 18:1 Δ6-10t and MI rate were observed. However, men with higher content of 18:1 Δ11t had a 48% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.48; 95% confidence interval, 1.17–1.86; P-trend = 0.003). Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men.ConclusionsAdipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men, whereas higher contents of isomers of 18:1t were associated with higher MI rates but the associations for individual 18:1t isomers differed, however, in women and men.

FADS1 genotype is distinguished by human subcutaneous adipose tissue fatty acids, but not inflammatory gene expression

Single nucleotide polymorphisms (SNPs) in FADS1/FADS2 genes are associated with changes in serum and tissue polyunsaturated fatty acid (PUFA) content. PUFA regulate inflammatory signaling pathways in adipose tissue; however, the effect of SNPs in FADS1/FADS2 on adipose tissue inflammation is equivocal. The present study examined if SNPs in FADS1/FADS2 modify human subcutaneous adipose tissue (SAT) fatty acid profiles and the expression of genes associated with inflammation/immune function, lipid metabolism, and cellular differentiation. SAT fatty acids and the expression of 117 genes were measured in 174 men and women from the DiOGenes Study using gas chromatography and qRT-PCR, respectively. Associations between fatty acids, gene expression, and SNPs in FADS1/FADS2 were investigated by linear regression and multivariate analysis. Four SNPs (rs174537, rs174546, rs174556, rs174601) in FADS1/FADS2 were significantly associated with SAT fatty acids. All SNPs were in high linkage disequilibrium with the commonly reported rs174537 SNP in FADS1. Minor allele carriers for rs174537 (GT+TT) had reduced 20:4n-6 (p = 1.74E-5), lower delta-5 desaturase enzyme activity (p = 2.09E-9), and lower FADS1 gene expression (p = 0.03) compared to major GG carriers. Multivariate analysis revealed that 20:4n-6 and 20:3n-6 explained ~19% of the variance between rs174537 genotypes, while gene expression explained <7%. Receiver operating characteristic (ROC) curves indicated that rs174537 genotype can be distinguished with SAT fatty acids (AUC = 0.842), but not gene expression (AUC = 0.627). No differences in SAT inflammatory gene expression were observed between rs174537 genotypes. SAT 20:3n-6 levels were positively correlated with the expression of several inflammatory genes, and inversely correlated with FADS1 expression. This study showed that FADS1 genotype is distinguished by SAT fatty acid profiles, but not inflammatory gene expression.

Relevance of human fat distribution on lipid and lipoprotein metabolism and cardiovascular disease risk.

Upper body abdominal and lower body gluteofemoral fat depot masses display opposing associations with plasma lipid and lipoprotein and cardiovascular disease (CVD) risk profiles. We review developments on adipose tissue fatty acid metabolism in the context of body fat distribution and how that might be related to adverse lipid and lipoprotein profiles and CVD risk. Recent data have confirmed the paradoxical relationship of upper abdominal and lower body gluteofemoral adiposity and CVD risk. Mechanistically, this is likely to reflect the different ways fat depots handle lipid storage and release, which impacts directly and indirectly on lipid and lipoprotein metabolism. The upper body enhances immediate fat storage pathway with rapid uptake of dietary-derived fatty acids, whereas the lower body fat depot has a reduced lipid turnover accommodating a slower fat redistribution. Body fat distribution and the fat depots' ability to undergo appropriate expansion when fat storage is required, rather than overall body fatness, appear as the important determinant of metabolic health. A focus on fat distribution in overweight people, preferably using precise imaging methods, rather than quantifying total body fatness, is likely to provide the medical community with better tools to stratify and treat patients with obesity-related complications.

Interorgan Metabolic Crosstalk in Human Insulin Resistance.

Excessive energy intake and reduced energy expenditure drive the development of insulin resistance and metabolic diseases such as obesity and type 2 diabetes mellitus. Metabolic signals derived from dietary intake or secreted from adipose tissue, gut, and liver contribute to energy homeostasis. Recent metabolomic studies identified novel metabolites and enlarged our knowledge on classic metabolites. This review summarizes the evidence of their roles as mediators of interorgan crosstalk and regulators of insulin sensitivity and energy metabolism. Circulating lipids such as free fatty acids, acetate, and palmitoleate from adipose tissue and short-chain fatty acids from the gut effectively act on liver and skeletal muscle. Intracellular lipids such as diacylglycerols and sphingolipids can serve as lipotoxins by directly inhibiting insulin action in muscle and liver. In contrast, fatty acid esters of hydroxy fatty acids have been recently shown to exert a series of beneficial effects. Also, ketoacids are gaining interest as potent modulators of insulin action and mitochondrial function. Finally, branched-chain amino acids not only predict metabolic diseases, but also inhibit insulin signaling. Here, we focus on the metabolic crosstalk in humans, which regulates insulin sensitivity and energy homeostasis in the main insulin-sensitive tissues, skeletal muscle, liver, and adipose tissue.

Adipocyte Insulin Resistance Index in Youth along the Span of Glycemia from Normal Glucose Tolerance (NGT) to Impaired Glucose Tolerance (IGT) to Type 2 Diabetes (T2D)

One of the pathophysiological components of T2D is adipocyte insulin resistance. We demonstrated diminished insulin suppression of lipolysis, using the hyperinsulinemic-euglycemic clamp combined with [2H5]glycerol tracer, in obese IGT vs. NGT youth (Diabetes 66: 2017). Herein we examined a surrogate index of adipose tissue insulin resistance (AT-IR= fasting insulin x FFA) to test the hypothesis that AT-IR increases from normal weight (NW) to obese NGT to IGT to T2D. A total of 2youth (70 M/135 F; Tanner IV-V) had body composition, visceral adipose tissue (VAT), fasting glucose, insulin and free fatty acids (FFA), and AT-IR evaluated. Despite hyperinsulinemia in obese IGT youth, fasting FFA was higher compared with NW and obese NGT peers (Table). AT-IR was 2.2 fold higher in obese NGT, 4.3 fold higher in IGT and 4.6 fold higher in T2D compared with NW before and after adjusting for sex, Tanner stage, BMI and VAT. In conclusion, the surrogate index of AT-IR reflects pathophysiological alterations in adipose tissue insulin sensitivity showing progressive increase in AT-IR in youth from normal weight to obese, and from NGT to IGT to T2D. This AT-IR, derived from fasting blood samples, could be used in epidemiological, observational and/or interventional studies investigating changes in adipocyte insulin sensitivity in obese youth with IGT and T2D. Variables, mean ± SEMNW (n=49)Obese-NGT (n=89)Obese-IGT (n=38)Obese-T2D (n=29)P, ANCOVAAge (years)14.4 ± 0.314.6 ± 0.214.9 ± 0.415.2 ± 0.3NSBMI (kg/m2)20.6 ± 0.333.9 ± 0.736.8 ± 1.036.8 ± 1.0&amp;lt;0.0001Visceral adipose tissue (cm2)24.4 ± 2.260.8 ± 4.185.1 ± 5.183.6 ± 7.7&amp;lt;0.0001Fasting glucose (mg/dL)95.1 ± 0.895.4 ± 0.696.8 ± 1.2121.5 ± 4.8&amp;lt;0.0001Fasting insulin (µU/mL)16.2 ± 0.831.3 ± 1.550.4 ± 4.957.6 ± 9.6&amp;lt;0.0001Fasting FFA (mmol/L)0.25 ± 0.020.28 ± 0.010.35 ± 0.020.32 ± 0.020.001AT-IR (µU/mL x mmol/L)4.± 0.388.98 ± 0.6917.51 ± 1.9918.59 ± 3.00&amp;lt;0.0001 Disclosure J. Kim: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. H. Tfayli: None. S. Michaliszyn: None. S.A. Arslanian: None.

Adipogenic/lipogenic gene expression and fatty acid composition in chuck, loin, and round muscles in response to grain feeding of Yanbian Yellow cattle.

We hypothesized that gene expression and fatty acid composition would differ among different muscle depots and over time on a grain-based finishing diet. Additionally, we hypothesized that the concentration of SFA would decrease and the concentration of MUFA would increase proportionately with increases in percent intramuscular lipid (%IML). Ten Yanbian Yellow cattle steers (approximately 8 mo of age) were fed a corn-based diet in which the proportion of corn in the ration was increased at 4-mo intervals. Muscle samples were taken by biopsy from the chuck (trapezius), loin (longissimus dorsi), and round (biceps femoris) muscles at 12, 16, 20, 24, and 28 mo of age. The %IML increased from 12 to 28 mo of age, especially between 24 and 28 mo of age, with loin > round > chuck (age × muscle interaction P < 0.001). The percentage (g/100 g total fatty acids) of oleic acid (18:1n-9), linoleic acid (18:2n-6), and α-linolenic acid (18:3n-3), and the MUFA:SFA ratio increased with age, whereas palmitic (16:0) and stearic acid (18:0) decreased with age in all muscles (age effect P < 0.001). The expression of sterol regulatory element binding protein (SREBP1), adipose tissue fatty acid- binding protein (FABP4), stearoyl-CoA desaturase (SCD), acetyl-CoA carboxylase (ACC1), and lipoprotein lipase (LPL) increased, whereas the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and fatty acid synthase (FASN) decreased with age. Expression of PPARγ, FABP4, SREBP1, SCD, FASN, ACC1, and LPL was greater in the loin than in the chuck or round (age × muscle interaction P < 0.001), although the MUFA:SFA ratio was greater in the chuck than in the loin or round (muscle effect P < 0.001). In conclusion, adipogenic gene expression was greater in the loin than in the chuck or round muscles, consistent with the greater %IML of the loin. However, the greater SCD gene expression in the loin did not result in a greater amount of MUFA in the loin, relative to the chuck and round.

Effects of full fat rice bran and defatted rice bran on growth performance and carcass characteristics of growing-finishing pigs.

The objective was to test the hypothesis that increasing inclusion levels of full fat rice bran (FFRB) or defatted rice bran (DFRB) are not detrimental to growth or carcass characteristics, longissimus muscle (LM) quality, or fat quality when fed to growing-finishing pigs. A total of 224 barrows and gilts were randomly allotted to 7 treatments, with 4 pigs per pen and 8 pen replicates per treatment. Pigs had an average initial BW of 28.2 ± 4.1 kg and a 3-phase feeding program was used. A basal diet containing corn and soybean meal, 3 diets containing corn, soybean meal, and 10, 20, or 30% FFRB, and 3 diets containing corn, soybean meal, and 10, 20, or 30% DFRB were formulated within each phase. Daily feed allotments and pig BW at the start of the experiment and at the conclusion of each phase were recorded. On the last day of the experiment, 1 pig per pen was harvested and carcass characteristics, LM quality, and fat quality were determined. For the overall experimental period, no effects of dietary treatments were observed for average daily gain. However, average daily feed intake (ADFI) decreased (linear, P < 0.05) and gain to feed ratio (G:F) increased (linear, P < 0.05) for pigs fed diets with increasing concentrations of FFRB. In contrast, ADFI increased linearly (P < 0.05) and G:F decreased (linear, P < 0.05) as DFRB was included in the diets. There were no effects of dietary treatments on LM quality. The length of the bellies decreased (linear and quadratic, P < 0.05) as the inclusion of FFRB or DFRB increased in the diets. The concentration of crude fat in the adipose tissue of pigs increased linearly (P < 0.05) as the concentration of FFRB or DFRB increased in the diets. The concentration of saturated fatty acids in the adipose tissue of pigs fed diets containing FFRB decreased (linear, P < 0.05), whereas the concentration of polyunsaturated fatty acids (PUFA) increased (linear, P < 0.05). In contrast, addition of DFRB did not affect the concentration of fatty acids in adipose tissues. In conclusion, 30% FFRB included in diets for growing-finishing pigs may improve G:F without affecting carcass characteristics or LM quality with the exception that PUFA in adipose tissues will increase. However, inclusion of DFRB in diets for growing-finishing pigs will reduce G:F without affecting the LM quality or composition of adipose tissues.

460 Effect of Different Fatty Acid Profiles in the Maternal and Finishing Diet on Subcutaneous Adipose Tissue Fatty Acid Profile and Gene Expression.

460 Effect of Different Fatty Acid Profiles in the Maternal and Finishing Diet on Subcutaneous Adipose Tissue Fatty Acid Profile and Gene Expression.

Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis.

Alterations in ectopic lipid deposition and circulating lipids are major risk factors for developing cardiometabolic diseases. Angiopoietin-like protein 4 (ANGPTL4), a protein that inhibits lipoprotein lipase (LPL), controls fatty acid (FA) uptake in adipose and oxidative tissues and regulates circulating triacylglycerol-rich (TAG-rich) lipoproteins. Unfortunately, global depletion of ANGPTL4 results in severe metabolic abnormalities, inflammation, and fibrosis when mice are fed a high-fat diet (HFD), limiting our understanding of the contribution of ANGPTL4 in metabolic disorders. Here, we demonstrate that genetic ablation of ANGPTL4 in adipose tissue (AT) results in enhanced LPL activity, rapid clearance of circulating TAGs, increased AT lipolysis and FA oxidation, and decreased FA synthesis in AT. Most importantly, we found that absence of ANGPTL4 in AT prevents excessive ectopic lipid deposition in the liver and muscle, reducing novel PKC (nPKC) membrane translocation and enhancing insulin signaling. As a result, we observed a remarkable improvement in glucose tolerance in short-term HFD-fed AT-specific Angptl4-KO mice. Finally, lack of ANGPTL4 in AT enhances the clearance of proatherogenic lipoproteins, attenuates inflammation, and reduces atherosclerosis. Together, these findings uncovered an essential role of AT ANGPTL4 in regulating peripheral lipid deposition, influencing whole-body lipid and glucose metabolism and the progression of atherosclerosis.

WITHDRAWN: G protein-coupled receptor 120 in mediating the regulation effect of saturated and unsaturated long-chain fatty acid on human adipocytes

Abstract Objective To explore G protein-coupled receptor 120 (GPR120)'s role in mediating saturated and unsaturated long-chain fatty acid on adipocyte inflammation, ER stress and insulin signaling pathway. Methods Omental adipose tissue from 5 patients undergoing elective gallstone removal surgery was collected and the primary adipocytes were isolated and cultured. In the first experiment, cells were divided into the following four groups: (1) Control group; (2): Docosahexaenoic acid (DHA) group; (3)DHA+10 μmol/L GW9508 group; and (4) DHA+20 μmol/L GW9508 group. In the second experiment, cells were divided into the following four groups:(1) Control group; (2) Palmic acid (PA) group; (3) PA+10 μmol/L GW9508 group; and (4) PA+20 μmol/L GW9508 group. Real time PCR and western blot were used to evaluate the gene and protein expression of GPR120, FABP4, inflammatory factors and ER stress markers. Results (1) Under the stimulation of DHA and PA, the expression of GPR and FABP4 were increased. But with inhibition of GPR120, the expression of GPR120and FABP4 decreased in both DHA and PA treatment groups.(2) DHA treatment could decrease TNF-alpha expression and inflammation factor mRNA levels in primary adipocytes. Production of these factors increased with inhibition of GPR120. PA treatment could increase TNF-alpha expression and inflammation factor mRNA levels in primary adipocytes. They were further increased by inhibition of GPR120. (3) DHA treatment could decrease ER stress in primary adipocytes. GPR120 inhibition could promote ER stress. PA treatment could increase ER stress in primary adipocytes. Again, GPR120 inhibition further increased ER stress. Conclusion GPR120 mediated long-chain fatty acid-related inflammation and ER stress regulation, and balanced the function of saturated and unsaturated long-chain fatty acid in adipose tissue.

Investigation of Adipose Tissue Fatty Acid Composition in Men with Uronephrolithiasis and Metabolic Syndrome.

BackgroundFatty acids (FA) and their metabolites are closely related to some mechanisms involved in the development of uronephrolithiasis. The aim of this study was to evaluate the relationship between FA composition and type of kidney stones.Material/MethodsAbdominal adipose tissue fatty acid methyl esters of 71 men with nephrolithiasis were identified by GC/MS, and the type of kidney stones was identified using FTIR infrared spectroscopy. Patients were divided into groups according to diagnosis of metabolic syndrome (MS) and type of kidney stone. The composition of FA was compared within different groups of patients with different types of kidney stones and between the patients and healthy individuals (control group) (n=100).ResultsIndividuals with nephrolithiasis had a significantly higher level of monounsaturated fatty acids (MUFA) and a lower level of polyunsaturated fatty acids (PUFA) versus healthy individuals. Patients with MS had a higher level of 18: 1ω9 and a lower level of 16: 1ω7 than patients without MS. Individuals with nephrolithiasis, but without MS, had a higher level of saturated fatty acids (SFA) compared to controls. The level of PUFA was higher in the control group (p<0.0001) compared to individuals with uronephrolithiasis, with or without MS. PUFA, ω – 6 PUFA, and 18: 2ω6 were higher in patients with calcium-based kidney stones without MS versus patients with uric acid kidney stones with MS.ConclusionsThe levels of MUFA were significantly higher and the levels of PUFA were significantly lower in patients with uronephrolithiasis compared to controls.

Substituting ground woody plants for cottonseed hulls in lamb feedlot diets: carcass characteristics, adipose tissue fatty acid composition, and sensory panel traits

Effects of using ground woody plants in Rambouillet wether lamb (n = 48) feedlot diets on carcass characteristics, adipose tissue fatty acid composition, and sensory panel traits were evaluated. In a randomized design study with two feeding periods (period 1 = fed a 70% concentrate diet from days 0 to 27; period 2 = fed an 86% concentrate diet from days 28 to 57), lambs were individually fed six diets that differed only by roughage source (n = 8 animals/treatment; initial BW = 32.9 ± 3.2 kg): cottonseed hulls (CSH; control) or ground wood consisting of either redberry (RED), blueberry (BLUE), one-seed (ONE), or eastern red cedar (ERC) Juniperus spp., or Prosopis glandulosa (MESQ). After 57 d, the lambs were humanely harvested and after chilling (2 ± 1 oC) 24 h, carcasses were evaluated for carcass traits. At 48 h postmortem, the longissimus thoracis (LT) was removed from the left side of the carcass, and after freezing for no more than 3 mo, were thawed for 24 h, cooked, and evaluated by a trained sensory panel. Additionally, volatile aroma chemicals on the LT were determined by gas chromatograph/mass spectrometer/olfactory (GC/MS/OF, respectively) analyses. Lamb HCW was greater (P = 0.01) for lambs fed CSH compared with all other diets, but lambs had similar (P > 0.08) LM area, back fat thickness, leg circumference, and body wall. Neither adipose tissue fatty acid composition (P > 0.08) nor trained sensory panel evaluation (P > 0.18) was affected by finishing diet roughage source. Of the 81 volatile aroma compounds found in the grilled lamb chops, only seven were affected (P < 0.05) by dietary roughage source and included 1-pentanol (a sweet, pleasant aroma), heptenal (a fishy aroma), pentanal (fermented, bready aroma description), 1-(1H-pyrol-2yl)-ethanone (caramel-like), 2-heptanone (cheesy, banana, fruity aromatic), 6,7-dodecanedione (unknown aroma), and butanoic acid (a sweaty, rancid aroma). The addition of any of four species of juniper or mesquite may be substituted for CSH without negatively affecting carcass fat and muscling, fatty acid, or sensory traits.

Adipose tissue fatty acids present in dairy fat and risk of stroke: the Danish Diet, Cancer and Health cohort.

The role of dairy fat for the risk of stroke is not yet clear. Adipose tissue reflects long-term fatty acid intake and metabolism. We, therefore, investigated associations for percentages of adipose tissue fatty acids, for which dairy products are a major source (12:0, 14:0, 14:1 cis-9, 15:0, 17:0, 18:1 trans-11 and 18:2 cis-9, trans-11), with incident total stroke and stroke subtypes. We conducted a case-cohort study within the Danish Diet, Cancer and Health cohort, including all incident stroke cases (n = 2108) and a random sample of the total cohort (n = 3186). The fatty acid composition of adipose tissue biopsies was determined by gas chromatography and specific fatty acids were expressed as percentage of total fatty acids. Stroke cases were identified in the Danish National Patient Registry and the diagnoses were individually verified. We recorded 2108 stroke cases of which 1745 were ischemic, 249 were intracerebral hemorrhages and 102 were subarachnoid hemorrhages. We observed a lower rate of ischemic stroke for a higher adipose tissue percentage of 12:0, 14:0, 15:0, 17:0, 18:1 trans-11 and 18:2 cis-9, trans-11. Adipose tissue percentages of 15:0 and 18:1 trans-11 were also inversely associated with intracerebral hemorrhage, whereas no associations between the adipose tissue fatty acids and subarachnoid hemorrhage were observed. No associations between 14:1 cis-9 and ischemic or hemorrhagic stroke were found. Our results suggest that a larger percentage in adipose tissue of fatty acids for which dairy products are a major source is associated with a lower rate of ischemic stroke.

Adipocyte ACLY Facilitates Dietary Carbohydrate Handling and Protects Against Insulin Resistance in Females

Sugars and refined carbohydrates are major components of the modern diet. ATP-citrate lyase (ACLY) is upregulated in adipocytes in response to carbohydrate consumption and generates acetyl-CoA for both lipid synthesis and acetylation reactions. Here we investigated the role of ACLY in the metabolic and transcriptional responses to carbohydrates in adipocytes, and unexpectedly uncovered a sexually dimorphic function in maintaining systemic metabolic homeostasis. When fed a high sucrose diet, AclyFAT-/- females exhibit a lipodystrophy-like phenotype, with minimal fat accumulation, insulin resistance, and hepatic lipid accumulation, while AclyFAT-/- males have only mild metabolic phenotypes. We find that ACLY is crucial for nutrientdependent ChREBP activation in adipocytes and plays a key role particularly in females in the storage of newly synthesized fatty acids in adipose tissue. The data indicate that adipocyte ACLY is important in females for the systemic handling of dietary carbohydrates and for the preservation of metabolic homeostasis.

Human hepatic lipase overexpression in mice induces hepatic steatosis and obesity through promoting hepatic lipogenesis and white adipose tissue lipolysis and fatty acid uptake.

Human hepatic lipase (hHL) is mainly localized on the hepatocyte cell surface where it hydrolyzes lipids from remnant lipoproteins and high density lipoproteins and promotes their hepatic selective uptake. Furthermore, hepatic lipase (HL) is closely associated with obesity in multiple studies. Therefore, HL may play a key role on lipid homeostasis in liver and white adipose tissue (WAT). In the present study, we aimed to evaluate the effects of hHL expression on hepatic and white adipose triglyceride metabolism in vivo. Experiments were carried out in hHL transgenic and wild-type mice fed a Western-type diet. Triglyceride metabolism studies included β-oxidation and de novo lipogenesis in liver and WAT, hepatic triglyceride secretion, and adipose lipoprotein lipase (LPL)-mediated free fatty acid (FFA) lipolysis and influx. The expression of hHL promoted hepatic triglyceride accumulation and de novo lipogenesis without affecting triglyceride secretion, and this was associated with an upregulation of Srebf1 as well as the main genes controlling the synthesis of fatty acids. Transgenic mice also exhibited more adiposity and an increased LPL-mediated FFA influx into the WAT without affecting glucose tolerance. Our results demonstrate that hHL promoted hepatic steatosis in mice mainly by upregulating de novo lipogenesis. HL also upregulated WAT LPL and promoted triglyceride-rich lipoprotein hydrolysis and adipose FFA uptake. These data support the important role of hHL in regulating hepatic lipid homeostasis and confirm the broad cardiometabolic role of HL.

Serum adiponectin and TNFα concentrations are closely associated with epicardial adipose tissue fatty acid profiles in patients undergoing cardiovascular surgery

BackgroundEpicardial adipose tissue (EAT) releases both adiponectin and TNFα, and these two adipokines play important roles in heart diseases such as coronary arterial disease. The aim of the present study was to clarify whether fatty acid (FA) profiles in EAT are linked to the serum concentration of these adipokines. The relationships between serum adipokine levels and FA profiles in patients undergoing cardiovascular surgery were analyzed. MethodsPatients (n=21) undergoing cardiovascular surgery (11 males, 70.4±9.0years, BMI 26.0±5.1kg/m2) were included. EAT samples were taken. We measured clinical biochemical data and FA profiles in venous blood and EAT samples using gas chromatography. Serum adiponectin and TNFα concentrations were also measured. ResultsThe adiponectin and TNFα levels were not correlated with any fatty acid concentration in serum lipids. In contrast, there was a positive correlation between the serum adiponectin level and epicardial level of nervonic acid (C24:1ω9, r=0.525, P=0.025). In multiple regression analysis, adiponectin showed a positive association with the epicardial C24:1ω9 concentration after controlling for age and BMI, or TG, non-HDL-C, and BNP. The serum TNFα concentration was negatively correlated with the epicardial C18:3ω3, C12:0 and C18:0 content. In multiple regression analysis, the serum TNFα concentration showed a positive association with the epicardial C18:3ω3 level (β=−0.575, P=0.015). ConclusionsThese results suggest that there is a close relationship between epicardial FA profiles and serum levels of adiponectin and TNFα. Dietary therapy to target FA profiles may be helpful to modulate inflammation.

Oleate ameliorates palmitate-induced reduction of NAMPT activity and NAD levels in primary human hepatocytes and hepatocarcinoma cells

BackgroundNicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide adenine dinucleotide (NAD) levels are crucial for liver function. The saturated fatty acid palmitate and the unsaturated fatty acid oleate are the main free fatty acids in adipose tissue and human diet. We asked how these fatty acids affect cell survival, NAMPT and NAD levels in HepG2 cells and primary human hepatocytes.MethodsHepG2 cells were stimulated with palmitate (0.5mM), oleate (1mM) or a combination of both (0.5mM/1mM) as well as nicotinamide mononucleotide (NMN) (0.5 mM) or the specific NAMPT inhibitor FK866 (10nM). Cell survival was measured by WST-1 assay and Annexin V/propidium iodide staining. NAD levels were determined by NAD/NADH Assay or HPLC. Protein and mRNA levels were analysed by Western blot analyses and qPCR, respectively. NAMPT enzyme activity was measured using radiolabelled 14C–nicotinamide. Lipids were stained by Oil red O staining.ResultsPalmitate significantly reduced cell survival and induced apoptosis at physiological doses. NAMPT activity and NAD levels significantly declined after 48h of palmitate. In addition, NAMPT mRNA expression was enhanced which was associated with increased NAMPT release into the supernatant, while intracellular NAMPT protein levels remained stable. Oleate alone did not influence cell viability and NAMPT activity but ameliorated the negative impact of palmitate on cell survival, NAMPT activity and NAD levels, as well as the increased NAMPT mRNA expression and secretion. NMN was able to normalize intracellular NAD levels but did not ameliorate cell viability after co-stimulation with palmitate. FK866, a specific NAMPT inhibitor did not influence lipid accumulation after oleate-treatment.ConclusionsPalmitate targets NAMPT activity with a consequent cellular depletion of NAD. Oleate protects from palmitate-induced apoptosis and variation of NAMPT and NAD levels. Palmitate-induced cell stress leads to an increase of NAMPT mRNA and accumulation in the supernatant. However, the proapoptotic action of palmitate seems not to be mediated by decreased NAD levels.

Alterations in fatty acid metabolism in response to obesity surgery combined with dietary counseling

Background:The effects of obesity surgery on serum and adipose tissue fatty acid (FA) profile and FA metabolism may modify the risk of obesity-related diseases.Methods:We measured serum (n=122) and adipose tissue (n=24) FA composition and adipose tissue mRNA expression of genes regulating FA metabolism (n=100) in participants of the Kuopio Obesity Surgery Study (KOBS, age 47.2±8.7 years, BMI 44.6±6.0, 40 men, 82 women) before and one year after obesity surgery. As part of the surgery protocol, all the subjects were instructed to add sources of unsaturated fatty acids, such as rapeseed oil and fatty fish, into their diet. The results were compared with changes in serum FA composition in 122 subjects from the Finnish Diabetes Prevention study (DPS) (age 54.3±7.1 years, BMI 32.2±4.6, 28 men, 94 women).Results:The proportion of saturated FAs decreased and the proportion of n-3 and n-6 FAs increased in serum triglycerides after obesity surgery (all P<0.002). Weight loss predicted changes in quantitative amounts of saturated FAs, monounsaturated FAs, n-3 and n-6 FAs in triglycerides (P<0.002 for all). Moreover, the changes in adipose tissue FAs reflected the changes in serum FAs, and some of the changes were associated with mRNA expression of elongases and desaturases in adipose tissue (all P<0.05). In line with this the estimated activity of elongase (18:1 n-7/16:1 n-7) increased significantly after obesity surgery in all lipid fractions (all P<4 × 10−7) and the increase in the estimated activity of D5D in triglycerides was associated with higher weight loss (r=0.415, P<2 × 10−6). Changes in serum FA profile were similar after obesity surgery and lifestyle intervention, except for the change in the absolute amounts of n-3 FAs between the two studies (P=0.044).Conclusions:Beneficial changes in serum and adipose tissue FAs after obesity surgery could be associated with changes in endogenous metabolism and diet.

Abstract P223: The ω-oxidation Pathway Underlies Hexadecanedioate Induced Blood Pressure Elevation

Background: A novel pathway for blood pressure (BP) regulation involving the dicarboxylic acid hexadecanedioate (HEXA) was identified in a study associating BP and mortality outcomes with fasting blood metabolites. The functional role of HEXA on BP elevation and vascular reactivity was confirmed by oral administration of hexadecanedioic acid to WKY rats. This study characterized the metabolic effects of hexadecanedioic acid administration in WKY rats, and assessed hemodynamic changes after modulation of endogenous HEXA levels by perturbing the ω-oxidation pathway in the SHRSP rat. Methods: WKY were treated orally with hexadecanedioic acid (250 mg/kg/day) or vehicle (n=5/group) for 3 weeks. Aorta, heart, brain, adipose, kidney, and liver were harvested and global metabolic profiles analysed by UPLC-MS/MS (Metabolon). The aldehyde dehydrogenase (ALDH) inhibitor disulfiram (25 mg/kg/day) or vehicle were administered to SHRSP rats for 14 days (n=7/group). BP was assessed by tail plethysmography and mesenteric arteries were used to assess vascular function by wire myography. Results: Treatment with hexadecanedioic acid increased HEXA levels in all tissues except brain in WKY rats. Metabolomic analysis identified increased fatty acid (FAs) metabolites (e.g. acylcarnitines) in heart, long-chain FAs and ketone body (β-hydroxybutyric acid) in kidney, and dicarboxylate FAs in adipose tissue from hexadecandioic acid treated rats indicating an impairment of FA β-oxidation and a shift towards ω-oxidation. SHRSP rats showed a significant reduction in BP after treatment with disulfiram (ΔSBP, 20.7±4.6 mmHg; P =2.4x10 -4 ). Mesenteric resistance arteries from disulfiram treated SHRSP demonstrated a shift to the right in the contractile response curve to noradrenaline, indicating reduced vascular sensitivity compared to control vessels. Conclusion: Administration of hexadecanedioic acid in addition to increasing BP impacts several metabolic readouts including changes in FA metabolism. Importantly, we demonstrate that inhibition of the ω-oxidation pathway enzyme, ALDH, results in a significant lowering of BP in the hypertensive SHRSP rat. The ω-oxidation pathway is a target for further research to elucidate mechanisms by which HEXA affects BP.