Lipid Meal Research Articles

Dietary lacto-sacc stimulates the immune response of gravid mud crab (Scylla olivacea)

Mud crabs have a functioning innate immune system. Probiotics have a considerable effect in improving immune responses in gravid mud crab. The current study investigated the influence of three lacto-sacc concentrations (T1=0 %, T2=1 %, and T3=1.5 %) in a 45 % protein and 12 % lipid meal on the immune response of gravid mud crabs. Three groups of wild gravid mud crabs (average weight: 122.33±1.53 g) were raised individually in bamboo spawning boxes at mangrove pens for 12 weeks. Wild gravid mud crabs (T4) were also caught from the river during the breeding season and tested to offer a more exact assessment of the effect of lacto-sacc. After a 12-week feeding study, T3 therapy resulted in the highest total hemocyte count levels (P < 0.05), followed by T2 and T1. The T3 treatment results in somewhat faster hemolymph clotting, although there is no significant difference among the treatments (P < 0.05). T3 treatments significantly improved immunological parameters (PO, proPO, and SOD enzyme) and survival (61.67±2.89 %) when challenged with Vibrio parahaemolyticus. In the challenge test, the immunological markers THC, PO, and proPO correlated positively, but hemolymph clotting time and mortality linked negatively. Furthermore, T1 was compared to an untreated wild gravid female mud crab (T4), and the results were almost identical. Thus, 1.5 % lacto-sacc is recommended for gravid mud crabs.

Inclusion of Oat Polar Lipids in a Solid Breakfast Improves Glucose Tolerance, Triglyceridemia, and Gut Hormone Responses Postprandially and after a Standardized Second Meal: A Randomized Crossover Study in Healthy Subjects.

Previously, it has been indicated that oat polar lipids included in a liquid meal may have the potential to beneficially modulate various cardiometabolic variables. The purpose of this study was to evaluate the effects of oat polar lipids in a solid food matrix on acute and second meal glucose tolerance, blood lipids, and concentrations of gut-derived hormones. The oat polar lipids were consumed at breakfast and effects on the biomarkers were investigated in the postprandial period and following a standardized lunch. Twenty young, healthy subjects consumed in total four different breakfast meals in a crossover study design. The breakfasts consisted of 1. White wheat bread (WWB) with an added 7.5 g of oat polar lipids (PLL); 2. WWB with an added 15 g of oat polar lipids (PLH); 3. WWB with and added 16.6 g of rapeseed oil (RSO) as a representative of commonly consumed oils; and 4. WWB consumed alone, included as a reference. All products with added lipids contained equivalent amounts of fat (16.6 g) and available carbohydrates (50 g). Rapeseed oil was added to the oat polar lipid meals to equal 16.6 g of total fat. The standardized lunch was composed of WWB and meatballs and was served 3.5 h after the breakfast. Test variables (blood glucose, serum insulin, triglyceride (TG), free fatty acids (FFA), ghrelin, GLP-1, PYY, and GIP) were measured at fasting and repeatedly during the 5.5 h after ingestion of the breakfast. After breakfast, PLH substantially lowered postprandial glucose and insulin responses (iAUC 0-120 min) compared with RSO and WWB (p < 0.05). Furthermore, a reduced glycaemic response to lunch (210-330 min) was observed following the PLH breakfast compared to all of the other breakfasts served (p < 0.05). Oat polar lipids (PLH) significantly reduced TG and ghrelin and increased circulating gut hormones GLP-1 and PYY compared to RSO (p < 0.05). The results show that exchanging part of the dietary lipids with oat polar lipids has the potential to improve postprandial blood glucose regulation and gut hormones and thus may have a preventive effect against type 2 diabetes.

THU-415 - Glucose and lipid metabolism alterations after an oral lipid meal in patients with non-alcoholic fatty liver disease carrying the PNPLA3 rs738409 polymorphism

THU-415 - Glucose and lipid metabolism alterations after an oral lipid meal in patients with non-alcoholic fatty liver disease carrying the PNPLA3 rs738409 polymorphism

Impact of Sequential Lipid Meals on Lymphatic Lipid Absorption and Transport in Rats.

The sequential meal pattern has recently received more attention because it reflects a phycological diet style for human beings. The present study investigated the effects of the second lipid meal on lymphatic lipid absorption and transport in adult rats following a previous lipid meal. Using the well-established lymph fistula model, we found that the second lipid meal significantly increased the lymphatic output of triglycerides, cholesterol, phospholipids, and non-esterified fatty acids compared with a single lipid meal. Besides that, the time reaching the peak of each lipid output was significantly faster compared with the first lipid meal. Additionally, the second lipid meal significantly increased the lymphatic output of apolipoprotein A-IV (ApoA-IV), but not apolipoprotein B-48 (ApoB-48) or apolipoprotein A-I (ApoA-I). Interestingly, the triglyceride/apoB-48 ratio was significantly increased after the second lipid meal, indicating the increased chylomicron size in the lymph. Finally, the second lipid meal increased the lymphatic output of rat mucosal mast cell protease II (RMCPII). No change was found in the expression of genes related to the permeability of lymphatic lacteals, including vascular endothelial growth factor-A (Vegfa), vascular endothelial growth factor receptor 1 (Flt1), and Neuropilin1 (Nrp1). Collectively, the second lipid meal led to the rapid appearance of bigger-sized chylomicrons in the lymph. It also increased the lymphatic output of various lipids and apoA-IV, and mucosal mast cell activity in the intestine.

Dietary palmitate and oleate differently modulate insulin sensitivity in human skeletal muscle

Aims/hypothesisEnergy-dense nutrition generally induces insulin resistance, but dietary composition may differently affect glucose metabolism. This study investigated initial effects of monounsaturated vs saturated lipid meals on basal and insulin-stimulated myocellular glucose metabolism and insulin signalling.MethodsIn a randomised crossover study, 16 lean metabolically healthy volunteers received single meals containing safflower oil (SAF), palm oil (PAL) or vehicle (VCL). Whole-body glucose metabolism was assessed from glucose disposal (Rd) before and during hyperinsulinaemic–euglycaemic clamps with d-[6,6-2H2]glucose. In serial skeletal muscle biopsies, subcellular lipid metabolites and insulin signalling were measured before and after meals.ResultsSAF and PAL raised plasma oleate, but only PAL significantly increased plasma palmitate concentrations. SAF and PAL increased myocellular diacylglycerol and activated protein kinase C (PKC) isoform θ (p < 0.05) but only PAL activated PKCɛ. Moreover, PAL led to increased myocellular ceramides along with stimulated PKCζ translocation (p < 0.05 vs SAF). During clamp, SAF and PAL both decreased insulin-stimulated Rd (p < 0.05 vs VCL), but non-oxidative glucose disposal was lower after PAL compared with SAF (p < 0.05). Muscle serine1101-phosphorylation of IRS-1 was increased upon SAF and PAL consumption (p < 0.05), whereas PAL decreased serine473-phosphorylation of Akt more than SAF (p < 0.05).Conclusions/interpretationLipid-induced myocellular insulin resistance is likely more pronounced with palmitate than with oleate and is associated with PKC isoforms activation and inhibitory insulin signalling.Trial registrationClinicalTrials.gov.NCT01736202.FundingGerman Federal Ministry of Health, Ministry of Culture and Science of the State North Rhine-Westphalia, German Federal Ministry of Education and Research, European Regional Development Fund, German Research Foundation, German Center for Diabetes Research.Graphical abstract

Dietary Lipid Modulation of Intestinal Serotonin in Ballan Wrasse (Labrus bergylta)-In Vitro Analyses.

Serotonin (5-HT) is pivotal in the complex regulation of gut motility and consequent digestion of nutrients via multiple receptors. We investigated the serotonergic system in an agastric fish species, the ballan wrasse (Labrus bergylta) as it represents a unique model for intestinal function. Here we present evidence of the presence of enterochromaffin cells (EC cells) in the gut of ballan wrasse comprising transcriptomic data on EC markers like adra2a, trpa1, adgrg4, lmxa1, spack1, serpina10, as well as the localization of 5-HT and mRNA of the rate limiting enzyme; tryptophan hydroxylase (tph1) in the gut epithelium. Second, we examined the effects of dietary marine lipids on the enteric serotonergic system in this stomach-less teleost by administrating a hydrolyzed lipid bolus in ex vivo guts in an organ bath system. Modulation of the mRNA expression from the tryptophan hydroxylase tph1 (EC cells isoform), tph2 (neural isoform), and other genes involved in the serotonergic machinery were tracked. Our results showed no evidence to confirm that the dietary lipid meal did boost the production of 5-HT within the EC cells as mRNA tph1 was weakly regulated postprandially. However, dietary lipid seemed to upregulate the post-prandial expression of tph2 found in the serotonergic neurons. 5-HT in the intestinal tissue increased 3 hours after “exposure” of lipids, as was observed in the mRNA expression of tph2. This suggest that serotonergic neurons and not EC cells are responsible for the substantial increment of 5-HT after a lipid-reach “meal” in ballan wrasse. Cells expressing tph1 were identified in the gut epithelium, characteristic for EC cells. However, Tph1 positive cells were also present in the lamina propria. Characterization of these cells together with their implications in the serotonergic system will contribute to broad the scarce knowledge of the serotonergic system across teleosts.

1981-P: The Regulation of Incretin Secretion in Baby Rats in Response to a Lipid Meal

Background: Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that augment glucose-stimulated insulin secretion, promote pancreatic β-cell proliferation, neogenesis and inhibit β-cell apoptosis. Thus, they are excellent therapeutic targets against type 2 diabetes. Using a lymph fistula rat model, we studied the secretion of incretins into lymph. In adult rats, we found that GIP and GLP-1 concentrations in the fasting lymph were 132 ± 19 pg/ml and 31 ± 8 pM, respectively. After intraduodenal lipid infusion, their concentrations rose to 441 ± 144 pg/ml and 154 ± 23 pM, respectively. Rationale: However, little is known about nutrient-stimulated secretion of GIP and GLP-1 in baby rats, whose gastrointestinal system and pancreatic β-cells are immature compared to adult rats. Methods: Using our well-established lymph fistula model with conscious baby rats, just weaned (21 day after birth) and weighing 50-65 g, we assessed the secretion of GIP and GLP-1 in lymph after an intraduodenal challenge of lipid meal. Results: Fasting GIP and GLP-1 levels were 295.4 ± 48.1 pg/ml and 59.6 ± 16.2 pM, respectively. After lipid infusion, GIP and GLP-1 levels increased to 1052 ± 90.1 pg/ml and 192.0 ± 19.7 pM respectively. Elevated incretin levels in baby rats (relative to adult animals) indicate possible involvement in the maturation of the enteroendocrine system and β-cells. This increase may be also important to ensure the adequate secretion of insulin to regulate blood glucose as the animals shift from a high-fat mother’s milk diet to a chow diet. Further studies are needed to determine the physiological role of the higher incretin levels in baby rats. Conclusions: Lymph fistula baby rats can serve as an excellent model to study regulation of gut hormones by nutrient absorption at their early developmental stage. This model can also be used to study the influence of mother’s milk on the secretion of gut hormones and their impact on glucose and lipid metabolism in the newborn. Disclosure J. Qu: None. Q. Yang: None. C. Ko: None. M. Liu: None. D.D. Black: Advisory Panel; Self; Intercept Pharmaceuticals, Inc. P. Tso: None. Funding National Institutes of Health (DK59630)

Erratum: Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism.

Objective Fructose is partly metabolized in small bowel enterocytes, where it can be converted into glucose or fatty acids. It was therefore hypothesized that Roux-en-Y gastric bypass (RYGB) may significantly alter fructose metabolism. Methods We performed a randomized clinical study in eight patients 12-17 months after RYGB and eight control (Ctrl) subjects. Each participant was studied after ingestion of a protein and lipid meal (PL) and after ingestion of a protein+lipid+fructose+glucose meal labeled with 13C-fructose (PLFG). Postprandial blood glucose, fructose, lactate, apolipoprotein B48 (apoB48), and triglyceride (TG) concentrations, 13C-palmitate concentrations in chylomicron-TG and VLDL-TG, fructose oxidation (13CO2 production), and gluconeogenesis from fructose (GNGf) were measured over 6 hours. Results After ingestion of PLFG, postprandial plasma fructose, glucose, insulin, and lactate concentrations increased earlier and reached higher peak values in RYGB than in Ctrl. GNGf was 33% lower in RYGB than Ctrl (P = 0.041), while fructose oxidation was unchanged. Postprandial incremental areas under the curves for total TG and chylomicrons-TG were 72% and 91% lower in RYGB than Ctrl (P = 0.064 and P = 0.024, respectively). ApoB48 and 13C-palmitate concentrations were not significantly different. Conclusions Postprandial fructose metabolism was not grossly altered, but postprandial lipid concentrations were markedly decreased in subjects having had RYGB surgery.

Resistant starch suppresses postprandial hypertriglyceridemia in rats

Postprandial increase in blood triglyceride levels is an independent risk factor for coronary artery disease, and dietary resistant starch (RS) is increasingly being considered for its contribution to disease prevention. Specifically, RS has beneficial effects on of the glycemic index, diabetes, cholesterol levels, and weight management. However, the effects of once-daily intake of RS on postprandial hypertriglyceridemia remain poorly characterized. In this study, the effects of a single administration of cornstarch-derived RS on postprandial increases in blood triglyceride levels were investigated in rats using oral fat tolerance/loading tests. Following the administration of lipid meals, increases in serum triglycerides levels were significantly reduced in rats fed corn oil containing 500mg/mL RS. Moreover, fecal lipid volumes and wet weights following lipid meals were significantly greater in rats fed corn oil containing 500mg/mL RS than in the corn oil only group, confirming the inhibition of dietary fat absorption. Finally, a significant positive correlation was observed between fecal lipid contents and wet weights in rats administered RS. These results suggest that RS intake with dietary fats induces defecation and confirm results of recent reports on the health-promoting potential of once-daily RS intake.

Postprandial lymphatic pump function after a high-fat meal: a characterization of contractility, flow, and viscosity.

Dietary lipids are transported from the intestine through contractile lymphatics. Chronic lipid loads can adversely affect lymphatic function. However, the acute lymphatic pump response in the mesentery to a postprandial lipid meal has gone unexplored. In this study, we used the rat mesenteric collecting vessel as an in vivo model to quantify the effect of lipoproteins on vessel function. Lipid load was continuously monitored by using the intensity of a fluorescent fatty-acid analog, which we infused along with a fat emulsion through a duodenal cannula. The vessel contractility was simultaneously quantified. We demonstrated for the first time that collecting lymphatic vessels respond to an acute lipid load by reducing pump function. High lipid levels decreased contraction frequency and amplitude. We also showed a strong tonic response through a reduction in the end-diastolic and systolic diameters. We further characterized the changes in flow rate and viscosity and showed that both increase postprandially. In addition, shear-mediated Ca(2+) signaling in lymphatic endothelial cells differed when cultured with lipoproteins. Together these results show that the in vivo response could be both shear and lipid mediated and provide the first evidence that high postprandial lipid has an immediate negative effect on lymphatic function even in the acute setting.

A Food Effect Study of an Oral Thrombin Inhibitor and Prodrug Approach To Mitigate It.

LB30870, a new direct thrombin inhibitor, showed 80% reduction in oral bioavailability in fed state. The present study aims to propose trypsin binding as a mechanism for such negative food effect and demonstrate a prodrug approach to mitigate food effect. Effect of food composition on fed state oral bioavailability of LB30870 was studied in dogs. Various prodrugs were synthesized, and their solubility, permeability, and trypsin binding affinity were measured. LB30870 and prodrugs were subject to cocrystallization with trypsin, and the X-ray structures of cocrystals were determined. Food effect was studied in dogs for selected prodrugs. Protein or lipid meal appeared to affect oral bioavailability of LB30870 in dogs more than carbohydrate meal. Blocking both carboxyl and amidine groups of LB30870 resulted in trypsin Ki values orders of magnitude higher than that of LB30870. Prodrugs belonged to either Biopharmaceutical Classification System I, II, or III. X-ray crystallography revealed that prodrugs did not bind to trypsin, but instead their hydrolysis product at the amidine blocking group formed cocrystal with trypsin. A prodrug with significantly less food effect than LB30870 was identified. Binding of prodrugs to food components such as dietary fiber appeared to counteract the positive effect brought with the prodrug approach. Further formulation research is warranted to enhance the oral bioavailability of prodrugs. In conclusion, this study is the first to demonstrate that the negative food effect of LB30870 can be attributed to trypsin binding. Trypsin binding study is proposed as a screening tool during lead optimization to minimize food effect.

Effects of roux-en-Y gastric bypass surgery on postprandial fructose metabolism.

Fructose is partly metabolized in small bowel enterocytes, where it can be converted into glucose or fatty acids. It was therefore hypothesized that Roux-en-Y gastric bypass (RYGB) may significantly alter fructose metabolism. We performed a randomized clinical study in eight patients 12-17 months after RYGB and eight control (Ctrl) subjects. Each participant was studied after ingestion of a protein and lipid meal (PL) and after ingestion of a protein+lipid+fructose+glucose meal labeled with (13) C-fructose (PLFG). Postprandial blood glucose, fructose, lactate, apolipoprotein B48 (apoB48), and triglyceride (TG) concentrations, (13) C-palmitate concentrations in chylomicron-TG and VLDL-TG, fructose oxidation ((13) CO2 production), and gluconeogenesis from fructose (GNGf) were measured over 6 hours. After ingestion of PLFG, postprandial plasma fructose, glucose, insulin, and lactate concentrations increased earlier and reached higher peak values in RYGB than in Ctrl. GNGf was 33% lower in RYGB than Ctrl (P = 0.041), while fructose oxidation was unchanged. Postprandial incremental areas under the curves for total TG and chylomicrons-TG were 72% and 91% lower in RYGB than Ctrl (P = 0.064 and P = 0.024, respectively). ApoB48 and (13) C-palmitate concentrations were not significantly different. Postprandial fructose metabolism was not grossly altered, but postprandial lipid concentrations were markedly decreased in subjects having had RYGB surgery.

Effects of Roux‐en‐Y gastric bypass on sugar‐induced hypertriglyceridemia

Oral fructose increases postprandial blood triglyceride (TG) concentrations, possibly by stimulating intestinal de novo lipogenesis (iDNL) and decreasing extrasplanchnic TG clearance. We hypothesized that these effects of fructose may be abolished by Roux‐en‐Y‐gastric bypass (RYGB) due to bypass of the proximal small bowel. To evaluate this hypothesis, we studied 8 patients 12‐18 months after RYGB, and 8 age‐, weight‐ and gender‐matched controls (C). Each participant was studied on two occasions, over 6‐hours after ingestion of 1) a protein/ lipid meal (PL), and 2) a protein/ lipid/ glucose/ fructose meal (PLGF). Chylomicrons‐triglyceride secretion and clearance were assessed from postprandial incremental areas under the curve for TG and apoB48. Sugar‐related hyperlipemia was assessed from the difference between chylomicron‐TG iAUC after PLGF and after PL.Postprandial chylomicrons‐TG iAUCs were, in RYGB: 16.8 ± 7.0 mmol/L*360min after PL vs 6.4 ± 5.7 mmol/L*360min after PLGF (NS), and in C: 28.4 ± 12.7 mmol/L*360min after PL vs 67.9 ± 23.0 mmol/L*360min after PLGF (p = 0.025). Sugar‐related hypertriglyceridemia was 2.1 ± 10.6 mmol/L*360min in RYGB vs 46.7 ± 15.0 mmol/L*360min in C (p = 0.03). ApoB48 peaked earlier in RYGB than in C, but post‐prandial iAUCs for apoB48 were not different in the two groups.These results indicate that sugar induced hypertriglyceridemia was abolished after RYGB. A lower iDNL may possibly account for this effect of RYGB. An increased extrasplanchnic clearance of chylomicrons‐TG (as suggested by lower TG iAUCs together with unchanged apoB48 iAUCs) may also be involved.This work was supported by the Swiss National Science Foundation

Food composition influences metabolism, heart rate and organ growth during digestion in Python regius

Digestion in pythons is associated with a large increase in oxygen consumption (SDA), increased cardiac output and growth in visceral organs assisting in digestion. The processes leading to the large postprandial rise in metabolism in snakes is subject to opposing views. Gastric work, protein synthesis and organ growth have each been speculated to be major contributors to the SDA. To investigate the role of food composition on SDA, heart rate (HR) and organ growth, 48 ball pythons (Python regius) were fed meals of either fat, glucose, protein or protein combined with carbonate. Our study shows that protein, in the absence or presence of carbonate causes a large SDA response, while glucose caused a significantly smaller SDA response and digestion of fat failed to affect metabolism. Addition of carbonate to the diet to stimulate gastric acid secretion did not increase the SDA response. These results support protein synthesis as a major contributor to the SDA response and show that increased gastric acid secretion occurs at a low metabolic cost. The increase in metabolism was supported by tachycardia caused by altered autonomic regulation as well as an increased non-adrenergic, non-cholinergic (NANC) tone in response to all diets, except for the lipid meal. Organ growth only occurred in the small intestine and liver in snakes fed on a high protein diet.

A study of pathophysiological factors associated with gastro‐esophageal reflux disease in twins discordant for gastro‐esophageal reflux symptoms

Differences in lower esophageal sphincter (LES) and peristaltic function and in transient LES relaxations (TLESR) have been described in patients with gastro-esophageal reflux disease (GERD). However, some of these differences may be the result of chronic GERD rather than being an underlying contributory factor. Twins discordant for GERD symptoms, i.e., only one twin had GERD symptoms, underwent standard LES and esophageal body manometry, and then using a sleeve sensor prolonged LES and pH monitoring, 30 min before and 60 min after a 250 mL 1200 kcal lipid meal. Eight monozygotic and 24 dizygotic female twins were studied. Although there was no difference in preprandial LES pressure (symptomatic 13.2 ± 7.1 mmHg vs asymptomatic 15.1 ± 6.2 mmHg, P = 0.4), LES pressure fell further postprandially in symptomatic twins (LES pressure area under the curve 465 ± 126 vs 331 ± 141 mmHg h, P < 0.01). 12/37 (32%) of acid reflux episodes in symptomatic twins occurred due to low LES pressure or deep inspiration/strain and 0/17 in asymptomatic twins (P = 0.01). There was no difference between symptomatic and asymptomatic twins in: peristaltic amplitude, ineffective esophageal body motility, hiatus hernia prevalence, or LES length. There was also no difference in TLESR frequency preprandially (symptomatic median 1(range 0-2) vs asymptomatic 0(0-2), P = 0.08) or postprandially (2.5(1-8) vs 3(1-6), P = 0.81). Twins with GERD symptoms had lower postprandial LES pressure and given the close genetic link between the twins, it is possible that such differences are caused by GERD. Acid reflux episodes associated with a hypotensive LES were seen in symptomatic, but not in asymptomatic twins.

Abstract 388: Apolipoprotein A-V Deficiency in Mice Results In Increased Triglyceride and Cholesterol Absorption

Elevated plasma triglycerides constitute an independent risk factor for coronary heart disease. Discovered in 2001, apolipoprotein A-V (apoA-V) was found inversely proportional to plasma triglycerides (TG). Synthesized only in the liver, apoA-V exists in very low concentrations in the plasma (~10,000 fold lower than apoA-I). While apoA-V is proposed to enhance hydrolysis and reduce hepatic production of TG-rich lipoproteins, the role of apoA-V on intestinal lipid absorption has not been investigated. The aim of this study is to examine the effects of apoA-V deficiency on intestinal lipid absorption in chow-fed mice. Since mice lacking functional apoA-V have drastically elevated plasma TG, we hypothesize that apoA-V deficiency in mice elevates the lymphatic output of TG after a lipid meal. Using apoA-V knockout (n=8) and wildtype (n=8) control mice, we employed the conscious lymph fistula model to examine the transport of dietary TG and cholesterol into the lymph during a continuous lipid infusion. Interestingly, apoA-V knockout mice displayed a 2-fold elevation in dietary TG (P&lt;0.001) and a 3-fold elevation in dietary cholesterol (P&lt;0.001) transport into the lymph compared to wildtype mice, suggesting that a loss of apoA-V enhances transport across the enterocyte. However, apoA-V knockout mice displayed a 2-fold reduction (P&lt;0.05) in dietary TG accumulated in the intestinal mucosa while there was no difference in the mucosal accumulation of dietary cholesterol between apoA-V knockout and wildtype mice, suggesting that apoA-V affected TG and cholesterol transport in the enterocyte differently. We conclude apoA-V deficiency results in increased TG and cholesterol absorption in mice, and therefore plays a previously unknown role in intestinal lipid absorption.

Effect of peripheral administration of cholecystokinin on food intake in apolipoprotein AIV knockout mice

Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 μg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 μg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.

Sleeve Gastrectomy in Rats Improves Postprandial Lipid Clearance by Reducing Intestinal Triglyceride Secretion

Postprandial hyperlipidemia is a risk factor for atherosclerotic heart disease and is associated with the consumption of high-fat diets and obesity. Bariatric surgeries result in superior and more durable weight loss than dieting. These surgeries are also associated with multiple metabolic improvements, including reduced plasma lipid levels. We investigated whether the beneficial effects of vertical sleeve gastrectomy (VSG) on plasma lipid levels are weight independent. VSG was performed on Long-Evans rats with diet-induced obesity. Controls were sham-operated animals who were either pair-fed or ad libitum-fed. We measured fasting and postprandial levels of plasma lipid. To determine hepatic and intestinal triglyceride secretion, we injected the lipase inhibitor poloxamer 407 alone or before oral lipid gavage. (13)C-Triolein was used to estimate postprandial uptake of lipid in the intestine. Rats that received VSG and high-fat diets had markedly lower fasting levels of plasma triglyceride, cholesterol, and phospholipid than obese and lean (pair-fed) controls that were fed high-fat diets. Rats that received VSG had a marked, weight-independent reduction in secretion of intestinal triglycerides. VSG did not alter total intestinal triglyceride levels or size of the cholesterol storage pool nor did it affect the expression of genes in the intestine that control triglyceride metabolism and synthesis. VSG did not affect fasting secretion of triglyceride, liver weight, hepatic lipid storage, or transcription of genes that regulate hepatic lipid processing. VSG reduced postprandial levels of plasma lipid, independently of body weight. This resulted from reduced intestinal secretion of triglycerides following ingestion of a lipid meal and indicates that VSG has important effects on metabolism.

Effect of a fatty meal on inflammatory markers in healthy volunteers with a family history of type 2 diabetes

A family history of type 2 diabetes (T2D) confers a high risk of developing the disease, independent of that due to other common risk factors. Postprandial state is a pro-inflammatory condition associated with a transiently impaired endothelial function; an increased oxidative stress is considered as a mediator of such effects in T2D. We evaluated the short-term effect of a lipid meal on markers of early vascular damage in subjects at risk of developing T2D. A total of thirty-two healthy volunteers, divided according to the presence (FHD+) or absence (FHD-) of a family history of T2D, underwent a fatty meal test. We measured the monocyte mRNA expressions of IL-6, IL-8 and IL-1β, and IL-6, soluble CD40 ligand (sCD40L), vascular cellular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1) and nitrotyrosine plasma concentrations at baseline and in the post-meal phase, relating them to the lipid profile and other biochemical parameters. The basal expression of the cytokines did not differ in FHD- and FHD+ subjects; neither was it modified by the meal ingestion. IL-6 and sCD40L plasma levels, similar in the two groups in the fasting state, did not vary after the meal. VCAM-1 and ICAM-1 increased in FHD+ subjects but not in FHD- subjects. Nitrotyrosine, similar between the FHD- and FHD+ subjects at baseline, increased more in FHD+ subjects than in FHD- subjects after the meal. In conclusion, the presence of a familial history of T2D confers an abnormal endothelial activation after an oral lipid meal, coupled with an increased oxidative stress, supporting the hypothesis of an early endothelial dysfunction already present in healthy individuals prone to develop T2D.

Genetic Ablation of Apolipoprotein A-IV Accelerates Alzheimer's Disease Pathogenesis in a Mouse Model

The link between lipoprotein metabolism and Alzheimer's disease (AD) has been established. Apolipoprotein A-IV (apoA-IV), a component of lipoprotein particles similar to apolipoprotein E, has been suggested to play an important role in brain metabolism. Although there are clinical debates on the function of its polymorphism in AD, the pathologic role of apoA-IV in AD is still unknown. Here, we report that genetic ablation of apoA-IV is able to accelerate AD pathogenesis in mice. In a mouse model that overexpresses human amyloid precursor protein (APP) and presenilin 1, genetic reduction of apoA-IV augments extracellular amyloid-β peptide (Aβ) burden and aggravates neuron loss in the brain. In addition, genetic ablation of apoA-IV also accelerates spatial learning deficits and increases the mortality of mice. We have found that apoA-IV colocalizes within Aβ plaques in APP/presenilin 1 transgenic mice and binds to Aβ in vitro. Subsequent studies show that apoA-IV in this model facilitates Aβ uptake in the Aβ clearance pathway mediated by astrocytes rather than the amyloidogenic pathway of APP processing. Taken together, we conclude that apoA-IV deficiency increases Aβ deposition and results in cognitive damage in the mouse model. Enhancing levels of apoA-IV may have therapeutic potential in AD treatment.