Lower Plasma Triacylglycerol Research Articles

Metformin Lowers Plasma Triacylglycerol Levels in Mice with Impaired Carnitine Biosynthesis and Fatty Liver

The antidiabetic drug metformin has a wide range of metabolic effects and may also reduce the risk of obesity-related diseases. The aim of the current study was to investigate if metformin could counteract meldonium-induced fatty liver. Four groups of male C57BL/6J mice were fed a low-fat control diet, or low-fat diets supplemented with metformin, meldonium, or metformin and meldonium for three weeks. Meldonium treatment led to 5.2-fold higher hepatic triacylglycerol (TAG) levels compared to control, and metformin lowered the meldonium-induced lipid accumulation insignificantly by 21%. Mice treated with metformin and meldonium demonstrated significantly lower weight gain, visceral adipose tissue weight and plasma levels of TAG compared to meldonium alone. The hepatic mRNA level of carnitine palmitoyl transferase 1 was increased 2-fold with combined meldonium and metformin treatment compared to meldonium treatment (p < 0.001). Increased hepatic expression of genes involved in fatty acid oxidation and lipid transport was observed in the combination group compared to control, and increased gene expression of the mitochondrial uncoupling protein UCP2 was observed compared to the meldonium group. In addition, the product of fatty acid oxidation, acetylcarnitine, increased in plasma in metformin-treated mice. Altogether, metformin treatment influenced hepatic lipid metabolism and lowered plasma TAG in meldonium-induced fatty liver in mice.

Microbial oil, alone or paired with β-glucans, can control hypercholesterolemia in a zebrafish model

Dyslipidemia is often associated with unhealthy dietary habits, and many mammalian studies have explored the mode of action of certain bioactive compounds such as β-glucans and n-3 PUFAs to understand their potential to normalize the lipid metabolism. There are only a few investigations that adopted omic approaches to unveil their combined effect on hypercholesterolemia. Zebrafish (Danio rerio) was used as a model organism to reveal the efficacy of Schizochytrium oil and β-glucans (from Euglena gracilis and Phaeodactylum tricornutum) against cholesterol-rich diet induced dyslipidemia. One of the folowing four diets was fed to a particular group of fish: a control high-cholesterol diet, a Schizochytrium oil diet or one of the two diets containing the oil and β-glucan. The plasma HDL, expression of hepatic genes linked to, among others, ferric ion binding and plasma phosphatidylcholines were higher and plasma cholesterol esters and triacylglycerols were lower in the microbial oil-fed fish compared to the fish fed high cholesterol diet. While the fish fed a mix of microbial oil and Euglena β-glucan had lower plasma triacylglycerols and expression of hepatic genes linked to PPAR signaling pathway and enriched biosynthesis of plasma unsaturated fatty acids, the fish fed microbial oil-Phaeodactylum β-glucan combination had lower abundance of triacylglycerols rich in saturated and mono-unsaturated fatty acids and cholesterol esters in the plasma.

Detection of typical indigenous gut bacteria related to turmeric (Curcuma longa) powder in mouse caecum and human faecal cultures.

Turmeric (Curcuma longa; TM) is widely used as a spice and possesses anti-inflammatory, antioxidant, and antibacterial properties. The relationship between TM functions and gut microbiota is still unclear. To investigate the effect of TM on gut microbiota and to identify indigenous gut bacteria that are responsive to TM, we fed Institute of Cancer Research mice a diet containing either no fibre (NF, n = 6) or 5% (w/w) TM (n = 6) for 14days. Moreover, we obtained human stool samples from four healthy volunteers and incubated the samples without (control) or with 2% (w/v) TM at 37°C for 24h. Subsequently, microbiota analysis in murine caecal samples and human faecal cultures was performed using 16S rRNA (V4) amplicon sequencing. Higher faecal weights (p < 0.01) and lower plasma triacylglycerol levels (p < 0.05) were measured in the TM-fed mice than in the NF-fed mice. Furthermore, TM feeding increased the abundance of butyrate-producing and other short-chain fatty acid (SCFA)-producing bacteria in mice as well as in human faecal cultures, and Roseburia bacteria were detected as TM-responsive indigenous gut bacteria (TM-RIB) both in mice and in human faecal cultures. Lastly, in the case of human faecal cultures, SCFA contents and antioxidant properties were higher in TM cultures than in control cultures (p < 0.05). TM appears to hold the potential to positively affect the host by altering the gut microbiota. Further studies are required to clarify the synergistic effects of TM and TM-RIB.

Effect of temperature manipulation during incubation on body weight, plasma parameters, muscle histology, and expression of myogenic genes in breast muscle of embryos and broiler chickens from two commercial strains

ABSTRACT 1. This study evaluated the effect of a higher incubation temperature on body weight, plasma profile, histology and expression of myogenin (MYOG), insulin-like growth factor-I (IGF-I) and vascular endothelial growth factor A (VEGFA) genes in breast muscle of embryos and broilers from two commercial strains. 2. A total of 784 eggs from Ross 308 and Cobb 500 broiler breeder flocks were used. Half of the eggs per strain were incubated at control temperature (37.8°C), whereas the other half were exposed to heat treatment (HT) of 38.8°C between embryonic day (ED) 10 and 14, for 6 h/day. Embryos and chicks were sampled on ED 19 and at hatch. A total of 480, one-day-old chicks per strain and incubation temperature were reared up to 42 d post-hatch. 3. The HT increased hatch weight of Ross chicks and 42-d body weight of broilers from both strains. Lower plasma triacylglycerol levels were measured for HT embryos and broilers on ED 19 and 42 d post-hatch, respectively. HT reduced plasma T3 levels in Ross embryos and broilers for the same periods. Hepatic TBARS concentrations were elevated by HT compared to the control incubation. 4. The HT reduced breast muscle VEGFA gene expression of Cobb embryos on ED 19, whereas expression was stimulated in day-old chicks. At 42 d post-hatch, fibre area was increased by HT regardless of strain. Compared to the control incubation, HT increased the breast yield of Ross broilers and leg yield of Cobb. Ross-HT broilers had a higher pH at 24 h after slaughter and better water holding capacity than Cobb-HT broilers. 5. These results suggested that HT increased body weight, fibre area, IGF-I gene expression and lowered plasma triacylglycerol levels of broiler chickens from both strains at 42 d. However, HT influenced the expression of VEGF-A and MYOG genes and meat quality differently between the broiler strains.

Effect of 6,9,12,15-Hexadecatetraenoic Acid (C16:4n-1)-Ethyl Ester on Lipid Content and Fatty Acid Composition in the Blood and Organs of Mice.

The effects of 6,9,12,15-hexadecatetraenoic acid (C16:4n-1, HDTA), an n-1 polyunsaturated fatty acid (FA), on plasma and liver lipid content and distribution in blood and tissues were investigated. Mice were fed experimental diets containing 10% HDTA or eicosapentaenoic acid in ethyl ester form based on corn oil for four weeks. Dietary HDTA intake lowered plasma triacylglycerol content without affecting plasma total cholesterol content. HDTA barely accumulated in the epididymal white adipose tissue (eWAT), while C18:4n-1, an HDTA metabolite, was detected in small amounts (< 1% of total FAs) in the plasma, liver, and eWAT.

Lactation Versus Formula Feeding: Insulin, Glucose, and Fatty Acid Metabolism During the Postpartum Period.

Milk production may involve a transient development of insulin resistance in nonmammary tissues to support redistribution of maternal macronutrients to match the requirements of the lactating mammary gland. In the current study, adipose and liver metabolic responses were measured in the fasting state and during a two-step (10 and 20 mU/m2/min) hyperinsulinemic-euglycemic clamp with stable isotopes, in 6-week postpartum women who were lactating (n = 12) or formula-feeding (n = 6) their infants and who were closely matched for baseline characteristics (e.g., parity, body composition, and intrahepatic lipid). When controlling for the low insulin concentrations of both groups, the lactating women exhibited a fasting rate of endogenous glucose production (EGP) that was 2.6-fold greater and a lipolysis rate that was 2.3-fold greater than the formula-feeding group. During the clamp, the groups exhibited similar suppression rates of EGP and lipolysis. In the lactating women only, higher prolactin concentrations were associated with greater suppression rates of lipolysis and lower intrahepatic lipid and plasma triacylglycerol concentrations. These data suggest that whole-body alterations in glucose transport may be organ specific and facilitate nutrient partitioning during lactation. Recapitulating a shift toward noninsulin-mediated glucose uptake could be an early postpartum strategy to enhance lactation success in women at risk for delayed onset of milk production.

Theracurmin (Highly Bioavailable Curcumin) Prevents High Fat Diet-Induced Hepatic Steatosis Development in Mice

Curcumin, a hydrophobic polyphenol isolated from the Curcuma longa L. plant, has many pharmacological properties, including antioxidant, anti-inflammatory, and chemo-preventive activities. Curcumin has been shown to have potential in preventing nonalcoholic fatty liver disease (NAFLD). However, the low bioavailability of curcumin has proven to be a major limiting factor in its clinical adoption. Theracurmin, a highly bioavailable curcumin that utilizes micronized technology showed improved biological absorbability in vivo. The aim of this study was to investigate the role of theracurmin in modulating hepatic lipid metabolism in vivo. A fatty liver mouse model was produced by feeding mice a high fat diet (HFD; 60% fat) for 12 weeks. We found that treatment for 12 weeks with theracurmin significantly lowered plasma triacylglycerol (TG) levels and reduced HFD-induced liver fat accumulation. Theracurmin treatment lowered hepatic TG and total cholesterol (T-CHO) levels in HFD-fed mice compared to controls. In addition, theracurmin administration significantly reduced lipid peroxidation and cellular damage caused by reactive oxygen species in HFD-fed mice. Overall, these results suggest that theracurmin has the ability to control lipid metabolism and can potentially serve as an effective therapeutic remedy for the prevention of fatty liver.

The proposed systemic thermogenic metabolites succinate and 12,13-diHOME are inversely associated with adiposity and related metabolic traits: evidence from a large human cross-sectional study

Aims/hypothesisCirculating succinate and 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were recently shown to promote brown adipocyte thermogenesis and protect against metabolic disorders in rodents. This study aimed to evaluate the associations between plasma levels of these metabolites and adiposity and metabolic profile in humans.MethodsFasting plasma succinate and 12,13-diHOME levels were quantified using ultra HPLC-tandem MS in 2248 individuals (50% female, mean age 41.3 ± 5.9 years, mean BMI 26.1 ± 4.6 kg/m2) in addition to fasting plasma biochemistry. Total and regional adiposity were assessed with dual-energy x-ray absorptiometry. An age- and sex-adjusted linear regression model was used to determine the associations between succinate and 12,13-diHOME levels and body composition and metabolic profile. Two-sample Mendelian randomisation was used to assess the associations between genetically determined BMI and metabolic traits with circulating plasma succinate and 12,13-diHOME.ResultsA one-SD higher plasma succinate and 12,13-diHOME concentration was associated with a 0.15 SD (95% CI 0.28, 0.03) and 0.08 SD (0.15, 0.01) lower total fat mass respectively. Additionally, a one-SD higher plasma 12,13-diHOME level was associated with a 0.09 SD (0.16, 0.02) lower fasting plasma insulin and 0.10 SD (0.17, 0.04) lower plasma triacylglycerol. In Mendelian randomisation analyses, genetically determined higher BMI, fasting hyperinsulinaemia and elevated lipid levels were not associated with changes in either plasma succinate or plasma 12,13-diHOME concentrations. No indications of bias due to directional pleiotropy were detected in the Mendelian randomisation analyses.Conclusions/interpretationOur findings tentatively suggest that plasma succinate and 12,13-diHOME may play a role in the regulation of energy metabolism and brown adipose tissue activation in humans. Further studies encompassing direct assessment of brown adipose tissue activity and dietary supplementation are necessary to investigate the potential beneficial effects of these metabolites on systemic metabolism.

A Two-Week Treatment with Plant Extracts Changes Gut Microbiota, Caecum Metabolome, and Markers of Lipid Metabolism in ob/ob Mice.

ScopeTargeting gut microbiota dysbiosis by prebiotics is effective, though side effects such as abdominal bloating and flatulence may arise following high prebiotic consumption over weeks. The aim is therefore to optimize the current protocol for prebiotic use.Methods and resultsTo examine the prebiotic properties of plant extracts, two independent studies are conducted in ob/ob mice, over two weeks. In the first study, Porphyra umbilicalis and Melissa officinalis L. extracts are evaluated; in the second study, a high vs low dose of an Emblica officinalis Gaertn extract is assessed. These plant extracts affect gut microbiota, caecum metabolome, and induce a significant lower plasma triacylglycerols (TG) following treatment with P. umbilicalis and significantly higher plasma free fatty acids (FFA) following treatment with the low‐dose of E. officinalis Gaertn. Glucose‐ and insulin‐tolerance are not affected but white adipose tissue and liver gene expression are modified. In the first study, IL‐6 hepatic gene expression is significantly (adjusted p = 0.0015) and positively (r = 0.80) correlated with the bacterial order Clostridiales in all mice.ConclusionThe data show that a two‐week treatment with plant extracts affects the dysbiotic gut microbiota and changes both caecum metabolome and markers of lipid metabolism in ob/ob mice.

Effect of Acute Ingestion of Green Tea Extract and Lemon Juice on Oxidative Stress and Lipid Profile in Pigs Fed a High-Fat Diet.

Green tea and its catechins have been shown to ameliorate high fat diet-induced oxidative stress and hyperlipidemia. However, low bioavailability of catechins limits their therapeutic potential. Lemon juice (LJ) has been suggested to enhance the bioavailability of catechins in vitro. This study investigated the antioxidative and hypolipidemic efficacy of a single dose of green tea extract (GTE) or GTE plus LJ (GTE + LJ) in high-fat diet fed pigs. Sixteen pigs ingested a single dose of GTE (190 mg/kg/day) or GTE + LJ (0.75 mL/kg/day) mixed with low-fat (LF; 5% fat) or high-fat (HF; 22% fat) diets and blood samples were collected for 24 h. Plasma catechin level peaked at two hours, and gradually returned to baseline after six hours following the intake. The addition of LJ significantly increased plasma catechin level. The diet containing GTE did not lower plasma cholesterol and triacylglycerol (TG) concentrations, superoxide dismutase (SOD) and catalase activity, or malondialdehyde concentration in 24 h in HF-fed pigs. Addition of a single dose of LJ, however, significantly decreased plasma TG level in LF groups but did not cause further changes on any other markers compared to the GTE alone. Our findings indicate limited effect of a single meal containing GTE on plasma antioxidant enzymes, lipid profile, and lipid peroxidation in pigs and no significant synergistic/additive action of adding LJ to GTE within 24 h in pigs. A study with a longer treatment period is warranted to further understand the potential role of GTE in reducing HF diet-induced oxidative stress and the possible synergistic role of LJ.

Methyl donor supplementation suppresses the progression of liver lipid accumulation while modifying the plasma triacylglycerol lipidome in periparturient Holstein dairy cows

Co-supplementation of methyl donors may lower hepatic lipid content in transition cows. To define the ability of methyl donor supplementation (MDS) to reduce hepatic lipid content and modify the plasma lipidome, 30 multiparous Holstein cows (2.04 ± 0.69 lactations; 689 ± 58 kg of body weight; 3.48 ± 0.10 units of body condition score) were fed a ration with or without rumen-protected methyl donors (22 g/d of Met, 10 g/d of choline chloride, 3 g/d of betaine, 96 mg/d of riboflavin, and 1.4 mg/d of vitamin B12) from d -28 before expected calving through d 14 postpartum. Cows were randomly enrolled based on predefined selection criteria (body condition score and parity). Base diets without MDS were formulated for gestation (15.4% crude protein with a predicted Lys-to-Met ratio of 3.25; 1.44 Mcal of net energy for lactation/kg of dry matter) and lactation (16.6% crude protein with a predicted Lys-to-Met ratio of 3.36; 1.64 Mcal of net energy for lactation/kg of dry matter). Blood sampling occurred from d -28 relative to expected calving through d 14 postpartum. Liver tissue was biopsied at d -28 relative to expected calving and on d 5 and 14 postpartum. In addition to routine analyses, serum AA concentrations on d 10 and 12 were quantified using mass spectrometry. Plasma triacylglycerol (TAG) and cholesteryl esters (CE) were qualitatively measured using time-of-flight mass spectrometry. Data were analyzed using a mixed model with repeated measures. Dry matter intake and milk yield were not modified by MDS. The transition from d -28 relative to expected parturition to d 14 postpartum was characterized by increased plasma fatty acid (0.15 to 0.71 mmol/L) and β-hydroxybutyrate (0.34 to 0.43 mmol/L) levels and liver lipid content (3.91 to 9.16%). Methyl donor supplementation increased the serum Met level by 26% and decreased the serum Lys-to-Met ratio by 21% on d 10 and 12, respectively. Moreover, the increase in hepatic lipid content from d 5 through 14 postpartum was suppressed with MDS relative to control (3.57 vs. -0.29%). Dietary MDS modified the TAG and CE lipidome. For example, MDS increased plasma TAG 46:3 (carbon number:double bond) by 116% relative to control cows on d 5 postpartum. Moreover, MDS tended to increase plasma CE 34:6. In contrast, MDS lowered plasma TAG 54:8 by 39% relative to control cows on d 5 postpartum. We concluded that in the absence of gains in dry matter intake and milk and milk protein yields, dietary MDS slows the progression of hepatic lipid accumulation and modifies the plasma TAG lipidome in transition cows.

ARB treatment ameliorates triacylglycerol accumulation during insulin‐resistant conditions in the liver of OLETF rats

Non‐alcoholic fatty liver disease (NAFLD) is a growing concern globally, and is associated with obesity, hyperlipemia, hypertension, insulin resistance, and diabetes; all traits linked to metabolic syndrome, which affects 20% of the US population. While angiotensin receptor blockers (ARB) effectively ameliorate the hypertension associated with metabolic disorders, its potential benefits on other aspects of metabolism during such conditions are not fully appreciated. ARB treatment may reduce overproduction and accumulation of hepatic triacylglycerols (TG), but it remains unknown whether ARB treatment has favorable effects in fatty livers associated with insulin resistance. To evaluate the benefits of the ARB treatment on lipid‐related genes, three groups (n=4–6) of 25‐week‐old rats were used: (1) LETO (lean strain‐control), (2) insulin resistant OLETF, and 3) OLETF + ARB (10 mg olmesartan/kg/d × 8 wks). An oral glucose tolerance test (oGTT) was performed to mimic a high glucose challenge. Liver and plasma were collected at T0, T30, and T60 min of the oGTT. We measured gene expression of hepatic PPARα, SREBP1c, FASN, and CPT1 along with TG and cholesterol levels in liver and plasma. PPARα expression was 1.6‐fold lower at T0 in OLETF+ARB compared with OLETF, but no changes were detected for other genes evaluated. Hepatic TG content was 1.5‐, 3.4‐ and 1.5‐fold lower at T0, T30, and T60, respectively, in OLETF+ARB compared to OLETF, along with 1.2‐fold lower plasma TG at T30. These changes suggest that AT1 signaling contributes to stabilizing lipid metabolism especially during a glucose challenge, and contributes to maintaining lower hepatic TG content that translates to reduced plasma TG during a glucose challenge.Support or Funding InformationM. Thorwald was supported by NIH NCMHD9T37MD001480. R.M. Ortiz was partially supported by NIH NHLBIK02HL103787. Research was partially funded by NIH NHLBIR01HL091767.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Investigation of Lipid Metabolism by a New Structured Lipid with Medium- and Long-Chain Triacylglycerols from Cinnamomum camphora Seed Oil in Healthy C57BL/6J Mice.

In the present study, a new structured lipid with medium- and long-chain triacylglycerols (MLCTs) was synthesized from camellia oil (CO) and Cinnamomum camphora seed oil (CCSO) by enzymatic interesterification. Meanwhile, the antiobesity effects of structured lipid were investigated through observing the changes of enzymes related to lipid mobilization in healthy C57BL/6J mice. Results showed that after synthesis, the major triacylgeride (TAG) species of intesterificated product changed to LaCC/CLaC (12.6 ± 0.46%), LaCO/LCL (21.7 ± 0.76%), CCO/LaCL (14.2 ± 0.55%), COO/OCO (10.8 ± 0.43%), and OOO (18.6 ± 0.64%). Through second-stage molecular distillation, the purity of interesterified product (MLCT) achieved 95.6%. Later, male C57BL/6J mice were applied to study whether the new structured lipid with MLCT has the efficacy of preventing the formation of obesity or not. After feeding with different diets for 6 weeks, MLCTs could reduce body weight and fat deposition in adipose tissue, lower plasma triacylglycerols (TG) (0.89 ± 0.16 mmol/L), plasma total cholesterol (TC) (4.03 ± 0.08 mmol/L), and hepatic lipids (382 ± 34.2 mg/mice) by 28.8%, 16.0%, and 30.5%, respectively, when compared to the control 2 group. This was also accompanied by increasing fecal lipids (113%) and the level of enzymes including cyclic adenosine monophosphate (cAMP), protein kinase A (PKA), hormone-sensitive lipase (HSL), and adipose triglyceride lipase (ATGL) related to lipid mobilization in MLCT group. From the results, it can be concluded that MLCT reduced body fat deposition probably by modulating enzymes related to lipid mobilization in C57BL/6J mice.

Parental and early-feeding effects of dietary methionine in rainbow trout (Oncorhynchus mykiss)

We studied the effect of changes in dietary methionine (Met) supply in broodstock and first-feeding rainbow trout fry (offspring). Three plant-based diets differing in Met level (deficient, adequate or in excess of the established requirement) were fed to the broodstock (male and female) for 6months prior to spawning (diets BD, BA and BE, respectively). The offspring from the parental Met-groups was then challenged in turn with the different Met fry-diets (FD, FA and FE, respectively) for 3weeks from first-feeding. At spawning, females fed diet BD had significantly higher plasma total and LDL-cholesterol and slightly lower plasma triacylglycerol. Diet BD reduced female (but not male) growth, weight of spawn and egg size, but had no effect on relative fecundity. The free amino acid profile of oocytes was modified, with levels of Met and Cys correlating positively with the Met-levels of broodstock diets. SAM and SAH levels in oocytes followed the same pattern, as opposed to SAM/SAH ratio. At the swim-up stage, no significant effect of parental diet on fry weight was noted, whereas survival was the highest in fry from BE-broodstock. The subsequent 21-day fry feeding with different Met levels highly affected the daily growth index with a significant interaction between the parental-diet and fry-diet effects. The expression of a number of genes regulating sulfur amino acid metabolism was modified either directly by the dietary Met supply in both broodstock liver and in whole fry (e.g. BHMT1, GR, GSTπ, MsrA1) or indirectly by the parental Met intakes as seen in the swim-up fry (e.g. BHMT1, MTR, GSTπ, MsrA1). Importantly, long-lasting parental effects linked to broodstock Met-intake were seen in the fry, 21-days after first-feeding and irrespective of the fry diet (CTH, MsrA1, MsrB2, SOD2). Similarly, parental effects were noted on the gene expression of both NPY and POMC feeding peptides in fry prior to exogenous feeding which persisted for POMC in the 21-day fry. Parental effects were also demonstrated on the key myogenic gene Myog, on fMHC and GDH in swim-up fry, which persisted for GDH in 21-day fry. In summary, our results demonstrate that dietary Met levels of rainbow trout broodstock affect various traits in the offspring, some of which persisted during the first weeks of exogenous feeding. Further studies need to evaluate the long-term persistence of the parental effects over time and to elucidate the mechanisms, whether epigenetic or not. Statement of relevanceDetermining the multiple effects of dietary methionine levels on reproductive, growth performance and metabolism in offspring will help improve formulations of low fish meal feeds for rainbow trout at sensitive life cycle stages.

Central GLP-1 receptor signalling accelerates plasma clearance of triacylglycerol and glucose by activating brown adipose tissue in mice.

Aims/hypothesisGlucagon-like peptide 1 (GLP-1) receptor (GLP-1R) agonism, used in the treatment of type 2 diabetes, has recently been shown to increase thermogenesis via the brain. As brown adipose tissue (BAT) produces heat by burning triacylglycerol (TG) and takes up glucose for de novo lipogenesis, the aim of this study was to evaluate the potential of chronic central GLP-1R activation by exendin-4 to facilitate clearance of lipids and glucose from the circulation by activating BAT.MethodsLean and diet-induced obese (DIO) C57Bl/6J mice were used to explore the effect of a 5 day intracerebroventricular infusion of the GLP-1 analogue exendin-4 or vehicle on lipid and glucose uptake by BAT in both insulin-sensitive and insulin-resistant conditions.ResultsCentral administration of exendin-4 in lean mice increased sympathetic outflow towards BAT and white adipose tissue (WAT), resulting in increased thermogenesis as evidenced by increased uncoupling protein 1 (UCP-1) protein levels and decreased lipid content, while the uptake of TG-derived fatty acids was increased in both BAT and WAT. Interestingly, in DIO mice, the effects on WAT were blunted, while exendin-4 still increased sympathetic outflow towards BAT and increased the uptake of plasma TG-derived fatty acids and glucose by BAT. These effects were accompanied by increased fat oxidation, lower plasma TG and glucose concentrations, and reduced body weight.Conclusions/interpretationCollectively, our results suggest that BAT activation may be a major contributor to the glucose- and TG-lowering effects of GLP-1R agonism.

Plasma triacylglycerol‐lowering activity of citrus polymethoxylated flavones is mediated by modulating the genes involved in lipid metabolism in hamsters

The present study investigated the underlying mechanism by which citrus polymethoxylated flavones (PMF) reduced plasma triacylglycerols (TG) in hamsters. Four groups of male hamsters were given a non‐cholesterol diet (NCD), a high cholesterol diet (HCD), a high cholesterol diet with supplementation of 0.5% PMF (L‐PMF), and a high cholesterol diet with supplementation of 1.0% PMF (H‐PMF), respectively, for 8 weeks. Results showed PMF could lower plasma TG by 32–46%, but it had no effect on plasma cholesterol. This was accompanied by down‐regulation of mRNA of liver sterol regulatory element binding protein‐1c (SREBP1c), fatty acid synthase (FAS), and peroxisome proliferator activated receptor alpha (PPARα) while up‐regulation of liver lipoprotein lipase (LPL). In addition, dietary PMF increased cholesterol by 5–15% and total lipids by 34–43% in the liver. PMF supplementation also reduced the body weight gain and the relative weights of white adipose tissue pads by 23–39%, possibly by decreasing the gene expression of FAS and LPL in the epididymal fat pad. It was concluded that plasma TG‐lowering activity of dietary PMF was mediated by modulating genes involved in lipid metabolism in hamsters.Practical applications: Hyperlipidemia is one of the risk factors for coronary heart diseases. The present study found that polymethoxylated flavones (PMF) were effective in reducing plasma triacylglycerols and adipose tissue weight. PMF may be developed as a nutraceutical to prevent hyperlipidemia and obesity.Citrus polymethoxylated flavones are able to reduce plasma triacylglycerols via two mechanisms of inhibition of lipogenesis and enhancement of lipid uptake by the liver, most likely mediated by down‐regulation of SREBP1c and FAS along with up‐regulation of LPL in the liver.

Corn oil versus lard: Metabolic effects of omega-3 fatty acids in mice fed obesogenic diets with different fatty acid composition.

Mixed results have been obtained regarding the level of insulin resistance induced by high-fat diets rich in saturated fatty acids (SFA) when compared to those enriched by polyunsaturated fatty acids (PUFA), and how metabolic effects of marine PUFA of n-3 series, i.e. docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), depend on dietary lipid background. Here we compared two high-fat diets, in which the major lipid constituent was based either on SFA in the form of pork lard (LHF diet) or PUFA of n-6 series (Omega-6) as corn oil (cHF diet). Both cHF and LHF parental diets were also supplemented with EPA+DHA (∼30g/kg diet) to produce cHF+F and LHF+F diet, respectively. Male C57BL/6N mice were fed the experimental diets for 8 weeks. Insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamps in mice fed LHF and cHF diets, and then metabolic effects of cHF+F and LHF+F diets were assessed focusing on the liver and epididymal white adipose tissue (eWAT). Both LHF and cHF induced comparable weight gain and the level of insulin resistance, however LHF-fed mice showed increased hepatic steatosis associated with elevated activity of stearoyl-CoA desaturase-1 (SCD1), and lower plasma triacylglycerol levels when compared to cHF. Despite lowering hepatic SCD1 activity, which was concomitant with reduced hepatic steatosis reaching the level observed in cHF+F mice, LHF+F did not decrease adiposity and the weight of eWAT, and rather further impaired insulin sensitivity relative to cHF+F, that tended to improve it. In conclusion, high-fat diets containing as much as ∼35 weight% as lipids induce similar weight gain and impairment of insulin sensitivity irrespective whether they are based on SFA or Omega-6. Although the SFA-rich diet containing EPA+DHA efficiently reduced hepatic steatosis, it did so without a corresponding improvement in insulin sensitivity and in the absence of effect on adiposity.

New Nordic Diet-Induced Weight Loss Is Accompanied by Changes in Metabolism and AMPK Signaling in Adipose Tissue.

The molecular mechanisms behind diet-induced metabolic improvements remain to be studied. This study sought to investigate whether expression of proteins in skeletal muscle or adipose tissue could explain improvements in glucose and lipid homeostasis after weight loss. Volunteers consumed a New Nordic Diet (NND) or an Average Danish Diet for 26 weeks in a controlled, free-living setting. Sixty four moderately obese women and men (44 ± 2 y; body mass index, 31 ± 1 kg/m(2)). Fasting blood samples and biopsies from the vastus lateralis muscle and subcutaneous abdominal adipose tissue (SCAT) were obtained at week 0 and 26. Gene and protein expressions were analyzed by real-time PCR and Western blotting. Improved homeostasis homeostatic model of assessment-insulin resistance index and lowered plasma triacylglycerol concentration after NND coincided with molecular adaptations in SCAT but not in skeletal muscle. NND induced greater reduction in fat mass than ADD (-6 ± 1 kg and -2 ± 1 kg; P < .01). In SCAT this was associated with increased AMPK and acetyl-CoA carboxylase phosphorylation (P < .05). Concomitantly, NND induced up-regulation of Akt2 and Akt substrate of 160 kDa (P < .05) as well as fatty acid transport protein 4 and membrane associated fatty acid binding protein (P < .05). Indices of increased oxidative capacity were observed, as carnitine palmitoyl transferase 1 mRNA (P = .08) as well as citrate synthase (P = .1) and cytochrome c (P = .05) protein tended to increase. NND-induced metabolic improvements were accompanied by increased AMPK signaling in SCAT, suggesting a role of AMPK in these adaptations. The concomitant up-regulation of key glucose and lipid-handling proteins suggests an improved metabolic capacity in adipose tissue after weight loss.

Choline deficiency impairs intestinal lipid metabolism in the lactating rat

Choline is a precursor to phosphatidylcholine (PC), a structural molecule in cellular membranes that is crucial for cell growth and function. PC is also required for the secretion of lipoprotein particles from liver and intestine. Choline requirements are increased during lactation when maternal choline is supplied to the offspring through breast milk. To investigate the effect of dietary choline on intestinal lipid metabolism during lactation, choline-supplemented (CS), phosphatidylcholine-supplemented (PCS) or choline-deficient (CD) diets were fed to dams during the suckling period. CD dams had lower plasma triacylglycerol, cholesterol and apoB in the fasted state and following a fat-challenge (P<.05). There was a higher content of neutral lipids and lower content of PC in the intestine of CD dams, compared with CS and PCS fed animals (P<.05). In addition, there was lower (P<.05) villus height in CD dams, which indicated a reduced absorptive surface area in the intestine. Choline is critical for the absorption of fat in lactating rats and choline deficiency alters intestinal morphology and impairs chylomicron secretion by limiting the supply of PC.

Toona sinensis leaf extract inhibits lipid accumulation through up-regulation of genes involved in lipolysis and fatty acid oxidation in adipocytes.

Toona sinensis leaf (TSL) has been shown to lower plasma triacylglycerol levels and diminish the size of visceral fat cells in vivo. The molecular mechanism of TSL ethanol extract (TSL-E) on lipid metabolism in 3T3-L1 adipocytes was investigated in this study. Oil Red O staining as well as immunoblotting, real-time PCR, and dual-Luciferase reporter system were performed to investigate the effect of TSL-E on lipid accumulation and the regulation of lipid metabolism, respectively. In addition, active compounds in the TSL-E were analyzed by HPLC. TSL-E significantly decreased lipid accumulation, stimulated free fatty acid (FFA) release, and up-regulated peroxisome proliferator-activated receptor-α (PPARα) and genes involved in peroxisomal (acyl-CoA oxidase) and mitochondrial (uncouple protein 3) fatty acid oxidation. TSL-E also up-regulated cytoplasmic triacylglycerol hydrolysis gene (adipose triglyceride lipase) and genes related to fatty acid oxidation (AMP-activated protein kinase, acetyl-CoA carboxylase, carnitine palmitoyltransferase I, PPARγ, and adiponectin). The major constituents directly inducing PPARα transactivity in TSL-E are gallic acid, rutin, palmitic acid, linoleic acid, and α-linolenic acid. These results indicate that the inhibitory effect of TSL-E on lipid accumulation was through PPARα activation and further up-regulation of PPARα-mediated genes plus up-regulation of cytoplasmic genes involved in lipid catabolism.