Release of Lipids Stored in the Intestine by Glucagon-Like Peptide-2 Involves a Gut-Brain Neural Pathway.

BACKGROUND: The gut hormone GLP-2 (glucagon-like peptide-2) plays important roles in lipid handling in the intestine. During postabsorptive stage, it releases preformed chylomicrons stored in the intestine, the underlying mechanisms of which are not well understood. Previous studies implicate the involvement of neural pathways in GLP-2's actions on lipid absorption in the intestine, but the role of such mechanisms in releasing postabsorptive lipid storage has not been established. METHODS: Here, in mesenteric lymph duct cannulated rats, we directly tested whether gut-brain neural communication mediates GLP-2's effects on postabsorptive lipid mobilization in the intestine. We performed total subdiaphragmatic vagotomy to disrupt the gut-brain neural communication and analyzed lipid output 5 hours after a lipid load in response to intraperitoneal GLP-2 or saline. RESULTS: Peripheral GLP-2 administration led to increased lymph lipid output and activation of proopiomelanocortin neurons in the arcuate nucleus of hypothalamus. Disruption of gut-brain neural communication via vagotomy blunted GLP-2's effects on promoting lipid release in the intestine. CONCLUSIONS: These results, for the first time, demonstrate a novel mechanism in which postabsorptive mobilization of intestinal lipid storage by GLP-2 enlists a gut-brain neural pathway.

Lymphatics - not just a chylomicron conduit.

PURPOSE OF REVIEW: Lymphatics are known to have active, regulated pumping by smooth muscle cells that enhance lymph flow, but whether active regulation of lymphatic pumping contributes significantly to the rate of appearance of chylomicrons (CMs) in the blood circulation (i.e., CM production rate) is not currently known. In this review, we highlight some of the potential mechanisms by which lymphatics may regulate CM production. RECENT FINDINGS: Recent data from our lab and others are beginning to provide clues that suggest a more active role of lymphatics in regulating CM appearance in the circulation through various mechanisms. Potential contributors include apolipoproteins, glucose, glucagon-like peptide-2, and vascular endothelial growth factor-C, but there are likely to be many more. SUMMARY: The digested products of dietary fats absorbed by the small intestine are re-esterified and packaged by enterocytes into large, triglyceride-rich CM particles or stored temporarily in intracellular cytoplasmic lipid droplets. Secreted CMs traverse the lamina propria and are transported via lymphatics and then the blood circulation to liver and extrahepatic tissues, where they are stored or metabolized as a rich energy source. Although indirect data suggest a relationship between lymphatic pumping and CM production, this concept requires more experimental evidence before we can be sure that lymphatic pumping contributes significantly to the rate of CM appearance in the blood circulation.

The Roles of Cytoplasmic Lipid Droplets in Modulating Intestinal Uptake of Dietary Fat.

Dietary fat absorption is required for health but also contributes to hyperlipidemia and metabolic disease when dysregulated. One step in the process of dietary fat absorption is the formation of cytoplasmic lipid droplets (CLDs) in small intestinal enterocytes; these CLDs serve as dynamic triacylglycerol storage organelles that influence the rate at which dietary fat is absorbed. Recent studies have uncovered novel factors regulating enterocyte CLD metabolism that in turn influence the absorption of dietary fat. These include peroxisome proliferator-activated receptor α activation, compartmentalization of different lipid pools, the gut microbiome, liver X receptor and farnesoid X receptor activation, obesity, and physiological factors stimulating CLD mobilization. Understanding how enterocyte CLD metabolism is regulated is key in modulating the absorption of dietary fat in the prevention of hyperlipidemia and its associated metabolic disorders.

GLP-1 (Glucagon-Like Peptide-1) Is Physiologically Relevant for Chylomicron Secretion Beyond Its Known Pharmacological Role.

[Figure: see text].

Glucose and GLP-2 (Glucagon-Like Peptide-2) Mobilize Intestinal Triglyceride by Distinct Mechanisms.

OBJECTIVE: Dietary triglycerides are partially retained in the intestine within intracellular or extracellular compartments, which can be rapidly mobilized in response to several stimuli, including glucose and GLP-2 (glucagon-like peptide-2). To elucidate the mechanism of intestinal lipid mobilization, this study examined the patterns and time course of lymph flow and triglycerides after glucose and GLP-2 treatment in rats. Approach and Results: Lymph flow, triglyceride concentration, and triglyceride output were assessed in mesenteric lymph duct-cannulated rats in response to an intraduodenal (i.d.) lipid bolus followed 5 hours later by either (1) i.d. saline+intraperitoneal (i.p.) saline (placebo), (2) i.d. glucose plus i.p. saline, (3) i.d. saline+i.p. GLP-2, or (4) i.d. glucose+i.p. GLP-2. GLP-2 and glucose administered alone or in combination stimulated total triglyceride output to a similar extent, but the timing and pattern of stimulation differed markedly. Whereas GLP-2 rapidly increased lymph flow with no effect on lymph triglyceride concentration or triglyceride:apoB48 (apolipoprotein B48) ratio (a surrogate marker of chylomicron size) compared with placebo, glucose transiently decreased lymph flow followed by delayed stimulation of lymph flow and increased lymph triglyceride concentration and triglyceride:apoB48 ratio. CONCLUSIONS: Glucose and GLP-2 robustly enhanced intestinal triglyceride output in rats but with different effects on lymph flow, lymph triglyceride concentration, and chylomicron size. GLP-2 stimulated triglyceride output primarily by enhancing lymph flow with no effect on chylomicron size, whereas glucose mobilized intestinal triglycerides, stimulating secretion of larger chylomicrons. This suggests that these 2 stimuli mobilize intestinal lipid by different mechanisms.

Glucagon-like peptide-2 mobilizes lipids from the intestine by a systemic nitric oxide-independent mechanism.

AIM: To test the hypothesis that gut hormone glucagon-like peptide-2 (GLP-2) mobilizes intestinal triglyceride (TG) stores and stimulates chylomicron secretion by a nitric oxide (NO)-dependent mechanism in humans. METHODS: In a randomized, single-blind, cross-over study, 10 healthy male volunteers ingested a high-fat formula followed, 7 hours later, by one of three treatments: NO synthase inhibitor L-NG -monomethyl arginine acetate (L-NMMA) + GLP-2 analogue teduglutide, normal saline + teduglutide, or L-NMMA + placebo. TG in plasma and lipoprotein fractions were measured, along with measurement of blood flow in superior mesenteric and coeliac arteries using Doppler ultrasound in six participants. RESULTS: Teduglutide rapidly increased mesenteric blood flow and TG concentrations in plasma, in TG-rich lipoproteins, and most robustly in chylomicrons. L-NMMA significantly attenuated teduglutide-induced enhancement of mesenteric blood flow but not TG mobilization and chylomicron secretion. CONCLUSIONS: GLP-2 mobilization of TG stores and stimulation of chylomicron secretion from the small intestine appears to be independent of systemic NO in humans.

Control of intestinal lipoprotein secretion by dietary carbohydrates.

PURPOSE OF REVIEW: Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (CVD). Lipoproteins secreted by the intestine can contribute to dyslipidemia and may increase risk for CVD. This review focuses on how dietary carbohydrates can impact the production of chylomicrons, thereby influencing plasma concentrations of triglycerides and lipoproteins. RECENT FINDINGS: Hypercaloric diets high in monosaccharides can exacerbate postprandial triglyceride concentration. In contrast, isocaloric substitution of monosaccharides into mixed meals has no clear stimulatory or inhibitory effect on postprandial triglycerides. Mechanistic studies with oral ingestion of carbohydrates or elevation of plasma glucose have demonstrated enhanced secretion of chylomicrons. The mechanisms underlying this modulation remain largely unknown but may include enhanced intestinal de novo lipogenesis and mobilization of intestinally stored lipids. SUMMARY: The studies reviewed here have implications for dietary recommendations regarding refined carbohydrate intake and prevention of CVD.

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP.

Evaluation of the specific effects of intranasal glucagon on glucose production and lipid concentration in healthy men during a pancreatic clamp.

AIM: To investigate the specific effects of intranasal glucagon (ING) on plasma glucose, endogenous glucose production (EGP) and lipid concentration. METHODS: We conducted a single-blind, randomized, crossover study at our academic investigation unit. Under pancreatic clamp conditions with tracer infusion, 1 mg ING or intranasal placebo (INP) was administered to 10 healthy men. As pilot studies showed that ING transiently increased plasma glucagon, we infused intravenous glucagon for 30 minutes along with INP to ensure similar plasma glucagon concentrations between interventions. The main outcome measures were plasma glucose, EGP, free fatty acid (FFA) and triglyceride (TG) concentrations. RESULTS: In the presence of similar plasma glucagon concentrations, the increase in plasma glucose under these experimental conditions was attenuated with ING (mean plasma glucose analysis of variance P < .001) with reduction in EGP (P = .027). No significant differences were seen in plasma FFA and TG concentrations. CONCLUSION: ING raises plasma glucose but this route of administration attenuates the gluco-stimulatory effect of glucagon by reducing EGP. This observation invites speculation about a potential central nervous system effect of glucagon, which requires further investigation. If ING is developed as a treatment for hypoglycaemia, this attenuated effect on plasma glucose should be taken into account.

Effects of Intranasal Insulin on Triglyceride-Rich Lipoprotein Particle Production in Healthy Men.

OBJECTIVE: Insulin administered directly into the brain acutely suppresses hepatic glucose production and triglyceride-rich lipoprotein (TRL) secretion in rodents. In addition, intranasally administered insulin, which selectively raises cerebrospinal fluid insulin concentration, suppresses hepatic glucose production in humans; however, its effect on TRL secretion in humans has not previously been examined. In this study, we examined whether intranasal insulin, administered at a dose that has previously been shown to suppress hepatic glucose production, modulates TRL particle secretion by the liver and intestine in humans. APPROACH AND RESULTS: Nine healthy, normolipidemic, and normoglycemic men participated in a study consisting of 2 randomized study arms. Subjects received intranasal lispro insulin (40 IU) or placebo. Because intranasal insulin results in a rapid and transient increase in systemic insulin concentration after administration, we matched systemic insulin concentrations in the 2 study arms by infusing lispro insulin intravenously for 30 minutes together with intranasal placebo administration. Apo (apolipoprotein) B100-containing (hepatically derived) and apoB48-containing (intestinally derived) TRL lipoprotein particle turnover were measured for the ensuing 10 hours under pancreatic clamp conditions and constant fed state, using stable isotope enrichment techniques and multicompartmental modeling. Under these experimental conditions, no significant effects of intranasal insulin versus placebo on TRL apoB100 or B48 concentrations, fractional catabolic rates, or production rates were observed. CONCLUSIONS: Insulin delivered intranasally at a dose that has been shown to raise cerebrospinal fluid insulin concentration and suppress hepatic glucose production does not affect TRL particle production by the liver and intestine in healthy men. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03141827.

Intravenous Glucose Acutely Stimulates Intestinal Lipoprotein Secretion in Healthy Humans.

OBJECTIVE: Increased production of intestinal triglyceride-rich lipoproteins (TRLs) contributes to dyslipidemia and increased risk of atherosclerotic cardiovascular disease in insulin resistance and type 2 diabetes. We have previously demonstrated that enteral glucose enhances lipid-stimulated intestinal lipoprotein particle secretion. Here, we assessed whether glucose delivered systemically by intravenous infusion also enhances intestinal lipoprotein particle secretion in humans. APPROACH AND RESULTS: On 2 occasions, 4 to 6 weeks apart and in random order, 10 healthy men received a constant 15-hour intravenous infusion of either 20% glucose to induce hyperglycemia or normal saline as control. Production of TRL-apolipoprotein B48 (apoB48, primary outcomes) and apoB100 (secondary outcomes) was assessed during hourly liquid-mixed macronutrient formula ingestion with stable isotope enrichment and multicompartmental modeling, under pancreatic clamp conditions to limit perturbations in pancreatic hormones (insulin and glucagon) and growth hormone. Compared with saline infusion, glucose infusion induced both hyperglycemia and hyperinsulinemia, increased plasma triglyceride levels, and increased TRL-apoB48 concentration and production rate (P<0.05), without affecting TRL-apoB48 fractional catabolic rate. No significant effect of hyperglycemia on TRL-apoB100 concentration and kinetic parameters was observed. CONCLUSIONS: Short-term intravenous infusion of glucose stimulates intestinal lipoprotein production. Hyperglycemia may contribute to intestinal lipoprotein overproduction in type 2 diabetes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02607839.

Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism.

PURPOSE OF REVIEW: Insulin resistance and type 2 diabetes, driven largely by obesity, are characterized by an increase in triglyceride-rich lipoproteins (TRLs) due to both reduced TRL clearance from the circulation and increased production by the liver (apoB-100 containing VLDLs) and intestine (apoB-48 containing chylomicrons). Bariatric surgery is the only treatment currently that leads to marked, sustained weight loss. Here, we will review the effects of bariatric surgery on circulating triglyceride/TRL and TRL production and clearance. RECENT FINDINGS: Bariatric surgery leads to a marked reduction in fasting and postprandial plasma triglyceride. Only one study to date has assessed TRL kinetics after bariatric surgery and has reported a reduction in TRL apoB-100 concentration (i.e. the number of VLDL particles) due to reduced production and increased clearance and reduced TRL apoB-48 concentration (the number of chylomicron particles) due to reduced production. Some bariatric surgery studies have reported no/weak correlation between weight loss and improvements in triglyceride/TRL, suggesting that as yet unidentified factors beyond weight loss may contribute to the marked changes in TRL that occur postbariatric surgery. SUMMARY: Available data suggest that bariatric surgery reduces triglyceride and intestinal and hepatic TRL production with increased clearance of hepatic TRL particles. These effects of bariatric surgery on TRL kinetics need to be confirmed with additional studies. Further studies are also needed to compare the effects of various bariatric surgery procedures on TRL kinetics and to elucidate underlying mechanisms.

New Insights into the Regulation of Chylomicron Production.

Dietary lipids are efficiently absorbed by the small intestine, incorporated into triglyceride-rich lipoproteins (chylomicrons), and transported in the circulation to various tissues. Intestinal lipid absorption and mobilization and chylomicron synthesis and secretion are highly regulated processes. Elevated chylomicron production rate contributes to the dyslipidemia seen in common metabolic disorders such as insulin-resistant states and type 2 diabetes and likely increases the risk for atherosclerosis seen in these conditions. An in-depth understanding of the regulation of chylomicron production may provide leads for the development of drugs that could be of therapeutic utility in the prevention of dyslipidemia and atherosclerosis. Chylomicron secretion is subject to regulation by various factors, including diet, body weight, genetic variants, hormones, nutraceuticals, medications, and emerging interventions such as bariatric surgical procedures. In this review we discuss the regulation of chylomicron production, mechanisms that underlie chylomicron dysregulation, and potential avenues for future research.

A low-protein diet combined with low-dose endotoxin leads to changes in glucose homeostasis in weanling rats.

Severe malnutrition is a leading cause of global childhood mortality, and infection and hypoglycemia or hyperglycemia are commonly present. The etiology behind the changes in glucose homeostasis is poorly understood. Here, we generated an animal model of severe malnutrition with and without low-grade inflammation to investigate the effects on glucose homeostasis. Immediately after weaning, rats were fed diets containing 5 [low-protein diet (LP)] or 20% protein [control diet (CTRL)], with or without repeated low-dose intraperitoneal lipopolysaccharide (LPS; 2 mg/kg), to mimic inflammation resulting from infections. After 4 wk on the diets, hyperglycemic clamps or euglycemic hyperinsulinemic clamps were performed with infusion of [U-(13)C6]glucose and [2-(13)C]glycerol to assess insulin secretion, action, and hepatic glucose metabolism. In separate studies, pancreatic islets were isolated for further analyses of insulin secretion and islet morphometry. Glucose clearance was reduced significantly by LP feeding alone (16%) and by LP feeding with LPS administration (43.8%) compared with control during the hyperglycemic clamps. This was associated with a strongly reduced insulin secretion in LP-fed rats in vivo as well as ex vivo in islets but signficantly enhanced whole body insulin sensitivity. Gluconeogenesis rates were unaffected by LP feeding, but glycogenolysis was higher after LP feeding. A protein-deficient diet in young rats leads to a susceptibility to low-dose endotoxin-induced impairment in glucose clearance with a decrease in the islet insulin secretory pathway. A protein-deficient diet is associated with enhanced peripheral insulin sensitivity but impaired insulin-mediated suppression of hepatic glycogenolysis.

Glucagon-like peptide-2 regulates release of chylomicrons from the intestine.

BACKGROUND & AIMS: The intestine efficiently incorporates and rapidly secretes dietary fat as chylomicrons (lipoprotein particles comprising triglycerides, phospholipids, cholesterol, and proteins) that contain the apolipoprotein isoform apoB-48. The gut can store lipids for many hours after their ingestion, and release them in chylomicrons in response to oral glucose, sham feeding, or unidentified stimuli. The gut hormone glucagon-like peptide-2 (GLP-2) facilitates intestinal absorption of lipids, but its role in chylomicron secretion in human beings is unknown. METHODS: We performed a randomized, single-blind, cross-over study, with 2 study visits 4 weeks apart, to assess the effects of GLP-2 administration on triglyceride-rich lipoprotein (TRL) apoB-48 in 6 healthy men compared with placebo. Subjects underwent constant intraduodenal feeding, with a pancreatic clamp and primed constant infusion of deuterated leucine. In a separate randomized, single-blind, cross-over validation study, 6 additional healthy men ingested a high-fat meal containing retinyl palmitate and were given either GLP-2 or placebo 7 hours later with measurement of TRL triglyceride, TRL retinyl palmitate, and TRL apoB-48 levels. RESULTS: GLP-2 administration resulted in a rapid (within 30 minutes) and transient increase in the concentration of TRL apoB-48, compared with placebo (P = .03). Mathematic modeling of stable isotope enrichment and the mass of the TRL apoB-48 suggested that the increase resulted from the release of stored, presynthesized apoB-48 from the gut. In the validation study, administration of GLP-2 at 7 hours after the meal, in the absence of additional food intake, robustly increased levels of TRL triglycerides (P = .007), TRL retinyl palmitate (P = .002), and TRL apoB-48 (P = .04) compared with placebo. CONCLUSIONS: Administration of GLP-2 to men causes the release of chylomicrons that comprise previously synthesized and stored apoB-48 and lipids. This transiently increases TRL apoB-48 levels compared with placebo. Clinical trials number at www.clinicaltrials.gov: NCT 01958775.

Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.

OBJECTIVE: The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. APPROACH AND RESULTS: Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRL-apoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of patients undergoing bariatric surgery. CONCLUSIONS: This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01277068.

Dietary carbohydrates and intestinal lipoprotein production.

PURPOSE OF REVIEW: To review new evidence that dietary monosaccharides enhance intestinal chylomicron secretion. RECENT FINDINGS: There is abundant evidence linking diets that are high in carbohydrate content with hypertriglyceridemia. In addition, epidemiological studies reveal that the increase in dietary sugars and refined carbohydrates are associated with the rising prevalence of the metabolic syndrome and type 2 diabetes. Association studies, however, cannot prove causation. Mechanistic studies to date have focused on the link between carbohydrate ingestion and hepatic very low-density lipoprotein metabolism, with very little appreciation that dietary carbohydrates may also regulate intestinal lipid absorption and chylomicron secretion. We have recently studied this phenomenon in healthy humans and have shown that both glucose and fructose, infused concomitantly with a lipid emulsion directly into the duodenum and under conditions of a pancreatic clamp, stimulate chylomicron particle secretion. There are a paucity of data regarding the cellular and molecular mechanisms of this effect, which remains largely unknown and a matter of speculation. SUMMARY: Sugar in the diet enhances dietary fat absorption and chylomicron secretion. Whether this phenomenon contributes quantitatively to the well described hypertriglyceridemia that occurs with diets high in carbohydrate and low in fat requires further investigation, as does the underlying cellular mechanism. A thorough understanding of this phenomenon could provide useful information to optimize dietary guidelines.

Novel role of enteral monosaccharides in intestinal lipoprotein production in healthy humans.

OBJECTIVE: Overproduction of triglyceride-rich lipoproteins (TRLs) by liver and intestine contributes to hypertriglyceridemia and may increase cardiovascular risk. Dietary carbohydrates, especially fructose, have been shown to amplify postprandial lipemia but little is known about its effect on intestinal TRL particle production. Here, we examined intestinal and hepatic TRL particle production in response to enteral glucose or fructose in the presence of enteral lipid. APPROACH AND RESULTS: In 2 randomized studies, 4 to 6 weeks apart, 7 healthy male subjects received intraduodenal infusion of Intralipid plus saline or glucose. TRL-apolipoprotein (apo) B48 and apoB100 kinetics were assessed under pancreatic clamp conditions. In a separate study of another 7 subjects under similar conditions, glucose was replaced by fructose. When coinfused with Intralipid into the duodenum, glucose markedly stimulated TRL-apoB48 production (P<0.01), with a concomitant moderate increase in fractional clearance (P<0.05), resulting in net elevation of TRL-apoB48 concentration. TRL-apoB100 concentration, fractional clearance, and production were not significantly affected by glucose. When glucose was replaced by fructose, both TRL-apoB100 and apoB48 production (P<0.05), but not fractional clearance, were enhanced compared with Intralipid alone. CONCLUSIONS: These results reveal a novel role of monosaccharides in acutely enhancing intestinal lipoprotein particle production, thereby aggravating hyperlipidemia.

High-dose resveratrol treatment for 2 weeks inhibits intestinal and hepatic lipoprotein production in overweight/obese men.

OBJECTIVE: Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo. APPROACH AND RESULTS: Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04). CONCLUSIONS: These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48. CLINICAL TRIAL REGISTRATION URL: www.clinicaltrials.gov. Unique identifier: NCT01451918.

GLP-2 regulation of intestinal lipid handling.

Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases.