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Objective:Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance.Design:We used radioactively labeled triglycerides to measure blood-brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints.Results:Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels.Conclusions:Triglycerides cross the blood-brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.

Bacterial interspecies interactions play clinically important roles in shaping microbial community composition. We observed that Corynebacterium spp. are overrepresented in children free of Streptococcus pneumoniae (pneumococcus), a common pediatric nasal colonizer and an important infectious agent. Corynebacterium accolens , a benign lipid-requiring species, inhibits pneumococcal growth during in vitro cocultivation on medium supplemented with human skin surface triacylglycerols (TAGs) that are likely present in the nostrils. This inhibition depends on LipS1, a TAG lipase necessary for C. accolens growth on TAGs such as triolein. We determined that C. accolens hydrolysis of triolein releases oleic acid, which inhibits pneumococcus, as do other free fatty acids (FFAs) that might be released by LipS1 from human skin surface TAGs. Our results support a model in which C. accolens hydrolyzes skin surface TAGS in vivo releasing antipneumococcal FFAs. These data indicate that C. accolens may play a beneficial role in sculpting the human microbiome. IMPORTANCE Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites . We show that Corynebacterium accolens , a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium . This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization. Little is known about how harmless Corynebacterium species that colonize the human nose and skin might impact pathogen colonization and proliferation at these sites . We show that Corynebacterium accolens , a common benign nasal bacterium, modifies its local habitat in vitro as it inhibits growth of Streptococcus pneumoniae by releasing antibacterial free fatty acids from host skin surface triacylglycerols. We further identify the primary C. accolens lipase required for this activity. We postulate a model in which higher numbers of C. accolens cells deter/limit S. pneumoniae nostril colonization, which might partly explain why children without S. pneumoniae colonization have higher levels of nasal Corynebacterium . This work narrows the gap between descriptive studies and the needed in-depth understanding of the molecular mechanisms of microbe-microbe interactions that help shape the human microbiome. It also lays the foundation for future in vivo studies to determine whether habitat modification by C. accolens could be promoted to control pathogen colonization.

Supramolecular polymerization within living cells has emerged as a promising strategy for controlling cellular functions. Lipid droplets, intracellular organelles mainly composed of neutral lipids, provide low-polarity environments, yet their role in regulating supramolecular assembly pathways remains unclear. Here we show that triolein, a representative triacylglycerol featuring three ester groups and cis-9-octadecenyl chains, acts as an effective medium for kinetically controlled supramolecular polymerization. An alanine-based diamide-functionalized fluorophore forms supramolecular polymers in triolein through a nucleation-elongation mechanism, in which an initial nucleus triggers subsequent growth. Although the thermodynamic stability is comparable to that in di- n -butyl ether, a commonly used organic solvent, triolein suppresses spontaneous nucleation and inter-fiber bundling, creating a lag phase during which seeded polymerization guides monomers along a defined assembly pathway. Kinetic studies with ethyl oleate, a structural analogue of triolein, indicate that transient solute-solvent interactions contribute to the suppression of both nucleation and bundling events. This kinetic control enables stepwise seeded growth of multiblock nanostructures and establishes neutral lipids as functional media for the precision-controlled construction of supramolecular polymers. Lipid droplets provide low-polarity environments, yet their role in regulating supramolecular assembly pathways remains unclear. Here the authors demonstrate that triolein suppresses spontaneous nucleation and inter-fiber bundling in nucleation–elongation supramolecular polymerization of diamide-functionalized fluorophores, enabling stepwise seeded growth of multiblock nanostructures.

The process of lipid droplet (LD) formation is an evolutionarily conserved process among all eukaryotes and plays an important role in both cellular physiology and disease. Recently, fat storage-inducing transmembrane proteins 1 and 2 (FIT1/FITM1 and FIT2/FITM2) were discovered as an evolutionarily conserved family of proteins involved in fat storage. In mammals, FIT1 is expressed primarily in skeletal muscle and FIT2 is expressed primarily in adipose, raising the possibility that FIT1 and FIT2 have unique functions. These proteins are exclusively localized to the endoplasmic reticulum (ER) and mediate triglyceride-rich LD accumulation when overexpressed in cells, mouse liver, or muscle. Unlike the ER-resident diacylglycerol O-acyltransferase family of triglyceride-synthesizing enzymes, FITs do not synthesize triglyceride, but rather partition triglyceride into LDs. The mechanism by which FIT proteins mediate this process has not been determined. A simple hypothesis was tested that FIT proteins bind to triglyceride to mediate LD formation. Here, it is shown that FIT proteins purified in detergent micelles directly bind triolein with specificity and saturation-binding kinetics. A FIT2 gain-of-function mutant that formed larger LDs, FLL(157–9)AAA, showed increased binding to triolein relative to wild-type FIT2, whereas FIT1 and a FIT2 partial loss-of-function mutant, N80A, had significantly lower triolein binding and produced smaller LDs. In summary, FIT proteins are transmembrane domain-containing proteins shown to bind triglyceride. These findings indicate that FITs have a unique biochemical mechanism in mediating LD formation and implicates triglyceride binding as important for FIT-mediated LD formation.

Background/objectives: Effects of high-protein diets that are rich in saturated fats on cell adhesion molecules, thrombogenicity and other nonlipid markers of atherosclerosis in humans have not been firmly established. We aim to investigate the effects of high-protein Malaysian diets prepared separately with virgin olive oil (OO), palm olein (PO) and coconut oil (CO) on cell adhesion molecules, lipid inflammatory mediators and thromobogenicity indices in healthy adults. Methods: A randomized cross-over intervention with three dietary sequences, using virgin OO, PO and CO as test fats, was carried out for 5 weeks on each group consisting of 45 men and women. These test fats were incorporated separately at two-thirds of 30% fat calories into high-protein Malaysian diets. Results: For fasting and nonfasting blood samples, no significant differences were observed on the effects of the three test-fat diets on thrombaxane B 2 (TXB 2 ), TXB 2 /PGF 1α ratios and soluble intracellular and vascular cell adhesion molecules. The OO diet induced significantly lower ( P <0.05) plasma leukotriene B 4 (LTB 4 ) compared with the other two test diets, whereas PGF 1α concentrations were significantly higher ( P <0.05) at the end of the PO diet compared with the OO diet. Conclusion: Diets rich in saturated fatty acids from either PO or CO and high in monounsaturated oleic acid from virgin OO do not alter the thrombogenicity indices—cellular adhesion molecules, thromboxane B 2 (TXB 2 ) and TXB 2 /prostacyclin (PGF 1α ) ratios. However, the OO diet lowered plasma proinflammatory LTB 4 , whereas the PO diet raised the antiaggregatory plasma PGF 1α in healthy Malaysian adults. This trial was registered at clinicaltrials.gov as NCT 00941837 .

Abdominal aortic aneurysm (AAA) is a vascular disease involving the gradual dilation of the abdominal aorta. It has been reported that development of AAA is associated with inflammation of the vascular wall; however, the mechanism of AAA rupture is not fully understood. In this study, we investigated the mechanism underlying AAA rupture using a hypoperfusion-induced animal model. We found that the administration of triolein increased the AAA rupture rate in the animal model and that the number of adipocytes was increased in ruptured vascular walls compared to non-ruptured walls. In the ruptured group, macrophage infiltration and the protein levels of matrix metalloproteinases 2 and 9 were increased in the areas around adipocytes, while collagen-positive areas were decreased in the areas with adipocytes compared to those without adipocytes. The administration of fish oil, which suppresses adipocyte hypertrophy, decreased the number and size of adipocytes, as well as decreased the risk of AAA rupture ratio by 0.23 compared to the triolein administered group. In human AAA samples, the amount of triglyceride in the adventitia was correlated with the diameter of the AAA. These results suggest that AAA rupture is related to the abnormal appearance of adipocytes in the vascular wall.

Abstract BACKGROUND: Triolein emulsion infusion into the carotid artery has been reported to induce temporary and reversible opening of the blood-brain barrier by increasing vascular permeability. OBJECTIVE: To evaluate the effect of triolein emulsion infusion on brain permeance by anticancer agents. METHODS: In the doxorubicin study. 2.4 mg/kg doxorubicin was injected immediately after triolein emulsion (1%, 1.5%, and 2%) infusion into rabbit carotid arteries. Two hours later, bilateral hemispheres and eyeballs were harvested, and doxorubicin concentrations were measured fluorometrically. Doxorubicin ratios of ipsilateral/contralateral hemispheres were compared with those of doxorubicin controls by use of the Kruskal-Wallis test followed by the Dunn test. In the cisplatin study, 10 mg/kg cisplatin was injected immediately after 2% triolein emulsion infusion into rat carotid arteries. Ipsilateral hemispheres were harvested 2, 6, 12, 24, and 36 hours after treatment. Time-dependent cisplatin concentrations were determined by liquid chromatography/electrospray ionization–tandem mass spectrometry/mass spectrometry. RESULTS: Doxorubicin concentrations were significantly higher in ipsilateral hemispheres and eyeballs in all 3 triolein treatment groups than in doxorubicin controls. In the cisplatin study, cisplatin concentrations in the ipsilateral hemispheres peaked at 6 hours after infusion of cisplatin. CONCLUSION: Brain permeance to anticancer agents was increased by triolein emulsion infusion, which suggests that triolein infusion might be a useful adjuvant treatment for brain tumors.

Low testosterone (T) levels in men have been shown to predict development of the metabolic syndrome, but the effects of T on lipid metabolism are incompletely understood. In a randomized, double-blind, placebo-controlled, crossover study, 12 healthy, young males received gonadotropin-releasing hormone agonist treatment 1 month prior to 3 of 4 trial days to induce castrate levels of T. On trial days, T gel was applied to the body containing either high or low physiological T dose or placebo. On the 4th trial day, participants constituted their own eugonadal controls. Each study comprised a 5-h basal period and a 3-h hyperinsulinemic-euglycemic clamp. Short-term hypogonadism did not affect VLDL triglyceride (TG) secretion, nor did it affect VLDL-TG concentrations. It was, however, characterized by lower total lipid oxidation. In addition, acute rescue with high physiological T increased VLDL-TG secretion during both basal and clamp conditions. These data show that T can act through fast nongenomic pathways in the liver. In addition, the early hypogonadal state is characterized by decreased total lipid oxidation, but whether these changes represent early hypogonadal metabolic dysfunction warrants further investigations. T is not a major determinant of resting VLDL-TG kinetics in men.

Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished the kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous but not ingested origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

A membrane of triolein-embedded cellulose acetate membrane (TECAM), as an integrative passive sampler, was applied to adsorb 28 polychlorinated biphenyls (PCBs) from pure water and sea water in order to probe into the influence of concentration fluctuation and water matrix. The results demonstrated the temporal variations of PCBs concentrations in TECAM followed the first-order kinetics model. The periodic refreshment of solution and matrix effects of sea water significantly prolonged the time that PCBs reached equilibrium stage. The refreshment facilitated the uptake mass in TECAM. On the contrary, the matrix effects of sea water and dissolved organic matter (DOM) declined the PCBs absorption to TECAM. The average log K P values of PCBs in pure water were about 1.2 log unit higher than those in sea water in the experiments that the solution was not refreshed, while the difference of average log K P values narrowed to 0.3 log unit if the PCBs solutions were periodically refreshed. The correlation between log K P and log K OW values fitted the quadratic curve well, which was similar to semi-permeable membrane device (SPMD). The appropriate sampling times ( t 94% ) ranged from 98.8 to 819 h (mean 500 h) for pure water with refreshment, much longer than those in sea water with refreshment (80.1~410 h, mean 189 h). The t 94% values in the solution with high DOM content increased significantly, up to 409 h. Furthermore,  comparing the two experiments that the spiked pure water and sea water solution were refreshed frequently, the estimated sampling rates ( R s ) in pure water (0.154~2.06 L/day with a mean value of 0.605 L/day) were slightly lower than those in sea water (0.292~3.84 L/day with a mean value of 1.69 L/day). However, the R s values in sea water with DOM declined sharply to 0.042 L/day. Therefore, concentration fluctuation, matrix effect, and DOM contents of sea water evidently posed significant influence on dynamic parameters of TECAM absorption, which would be screened and probed detailed in future. Graphical abstract