Role of Bile Acids and GLP-1 in Mediating the Metabolic Improvements of Bariatric Surgery.

BACKGROUND & AIMS: Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation. METHODS: Global G protein-coupled bile acid receptor-1 null (Tgr5-/-) and intestinal-specific farnesoid X receptor null (FxrΔ/E) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r-/-) mice on chow diet were characterized following GB-IL. RESULTS: GB-IL induced weight loss and improved oral glucose tolerance in Tgr5-/-, but not FxrΔ/E mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r-/- mice. CONCLUSIONS: Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.

Apolipoprotein A-IV: a protein intimately involved in metabolism.

The purpose of this review is to summarize our current understanding of the physiological roles of apoA-IV in metabolism, and to underscore the potential for apoA-IV to be a focus for new therapies aimed at the treatment of diabetes and obesity-related disorders. ApoA-IV is primarily synthesized by the small intestine, attached to chylomicrons by enterocytes, and secreted into intestinal lymph during fat absorption. In circulation, apoA-IV is associated with HDL and chylomicron remnants, but a large portion is lipoprotein free. Due to its anti-oxidative and anti-inflammatory properties, and because it can mediate reverse-cholesterol transport, proposed functions of circulating apoA-IV have been related to protection from cardiovascular disease. This review, however, focuses primarily on several properties of apoA-IV that impact other metabolic functions related to food intake, obesity, and diabetes. In addition to participating in triglyceride absorption, apoA-IV can act as an acute satiation factor through both peripheral and central routes of action. It also modulates glucose homeostasis through incretin-like effects on insulin secretion, and by moderating hepatic glucose production. While apoA-IV receptors remain to be conclusively identified, the latter modes of action suggest that this protein holds therapeutic promise for treating metabolic disease.

Chronic high-fat feeding increases GIP and GLP-1 secretion without altering body weight.

The incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), enhance postprandial insulin secretion, promote adipogenesis, and regulate gastrointestinal motility and food intake. To date, a consensus on how the incretin response is altered in obesity is lacking. We investigated the effects of chronic high-fat (HF) feeding on incretin secretion in the lymph fistula rat model. Male Sprague-Dawley rats (8 wk) were provided a semipurified AIN93M HF or low-fat (LF) diet ad libitum for 3 or 13 wk; a HF pair-fed (HF-PF) group was included as a control during the 3-wk feeding trial. Energy intake, body weight, and body composition were regularly monitored. At the culmination of the feeding period, an intestinal lymphatic duct cannula and duodenal infusion tube were installed. All animals were challenged with a 3-ml Ensure bolus (3.125 kcal/animal) to measure lymphatic incretin secretion. Despite a significantly higher energy intake, both the 3-wk and 13-wk HF-fed animals did not have an increase in body weight and only a slight increase in body fat compared with LF-fed rats. Following the duodenal Ensure challenge, the 3-wk and 13-wk HF-fed rats had significantly greater lymphatic GIP and GLP-1 secretion than the LF-fed animals. Additionally, the HF-PF group displayed a secretion profile similar to the HF-fed animals for GIP but a similar pattern to the LF-fed animals for GLP-1. The HF-PF data suggest that the increased GIP secretion is driven by the greater percentage of fat intake, whereas the increased GLP-1 secretion is driven by the excess caloric intake.

ApoA-IV: current and emerging roles in intestinal lipid metabolism, glucose homeostasis, and satiety.

Apolipoprotein A-IV (apoA-IV) is secreted by the small intestine on chylomicrons into intestinal lymph in response to fat absorption. Many physiological functions have been ascribed to apoA-IV, including a role in chylomicron assembly and lipid metabolism, a mediator of reverse-cholesterol transport, an acute satiety factor, a regulator of gastric function, and, finally, a modulator of blood glucose homeostasis. The purpose of this review is to update our current view of intestinal apoA-IV synthesis and secretion and the physiological roles of apoA-IV in lipid metabolism and energy homeostasis, and to underscore the potential for intestinal apoA-IV to serve as a therapeutic target for the treatment of diabetes and obesity-related disease.

Omentoplasty for Cervical Lymphocele after Aortic Arch Replacement.

Lymphocele formation is a rare complication after surgical procedures involving the mediastinum. While uncomplicated lymphoceles show high rates of spontaneous closure and are usually treated conservatively, surgical treatment might be required in cases with persistent or recurrent lymphoceles. We present the case of a 53-year-old male with reoccurring cervical swelling after two surgeries of the thoracic aorta. After 1.5 years, the swelling occurred for the first time and appeared for the next 2 years repeatedly without clinical or laboratory signs of infection. A cervical lymphocele was suspected, and the decision for surgical revision was made. Fibrin glue was applied to the potential leakage of the thoracic duct, and the cavity was filled with a free omental flap. This resulted in a complete regression of the swelling.

Identification and characterization of cow's milk proteins from the rat intestinal lymph using a proteomic strategy.

Food proteins were considered to be absorbed into the body after being digested to amino acids, dipeptides, and tripeptides. However, there are studies indicating that some proteins can pass through the intestinal epithelium under normal physiological conditions, perhaps not in sufficient quantities to be of nutritional importance, but in quantities that may be antigenically or biologically active. In the present study, rat intestinal lymph samples were collected using a modified lymph fistula rat model in fasting and cow's milk postprandial states. Low molecular weight proteins were enriched by ultrafiltration and differential solubilization, separated by 1D-SDS-PAGE, digested in-gel based on molecular weight, and identified using nano-LC-MS/MS. In the postprandial rat intestinal lymph, nine bovine-specific proteins (false discovery rate ≤1%) were identified in different molecular weight regions. Most proteins identified in lymph were highly abundant proteins in the milk, such as ß-lactoglobulin and caseins. Seven of the nine identified bovine-specific proteins are allergens in milk. This strategy can be used to search for proteins that can enter the intestinal lymph and analyze their common features. Understanding the common features of these proteins might help to develop protein drugs taken orally, so that therapeutic proteins might embody fusion domains for cross-barrier transport or translocation.

Is apolipoprotein A-IV rate limiting in the intestinal transport and absorption of triglyceride?

Apolipoprotein A-IV (apoA-IV) is synthesized by the intestine and secreted when dietary fat is absorbed and transported into lymph associated with chylomicrons. We have recently demonstrated that loss of apoA-IV increases chylomicron size and delays its clearance from the blood. There is still uncertainty, however, about the precise role of apoA-IV on the transport of dietary fat from the intestine into the lymph. ApoA-IV knockout (KO) mice do not have a gross defect in dietary lipid absorption, as measured by oral fat tolerance and fecal fat measurements. Here, using the in vivo lymph fistula mouse model, we show that the cumulative secretion of triglyceride (TG) into lymph in apoA-IV KO mice is very similar to that of wild-type (WT) mice. However, the apoA-IV KO mice do have subtle changes in TG accumulation in the intestinal mucosa during a 6-h continuous, but not bolus, infusion of lipid. There are no changes in the ratio of esterified to free fatty acids in the intestinal mucosa of the apoA-IV KO, however. When we extended these findings, by giving a higher dose of lipid (6 µmol/h) and for a longer infusion period (8 h), we found no effect of apoA-IV KO on intestinal TG absorption. This higher lipid infusion most certainly stresses the intestine, as we see a drastically lower absorption of TG (in both WT and KO mice); however, the loss of A-IV does not exacerbate this effect. This supports our hypothesis that apoA-IV is not required for TG absorption in the intestine. Our data suggest that the mechanisms by which the apoA-IV KO intestine responds to intestinal lipid may not be different from their WT counterparts. We conclude that apoA-IV is not required for normal lymphatic transport of TG.

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.

Use of Isotope Tracers to Assess Lipid Absorption in Conscious Lymph Fistula Mice.

This protocol provides a comprehensive reference for the evolution of the lymph fistula model, the mechanism of lipid absorption, the detailed procedure for studying lipid absorption using the lymph fistula model, the interpretation of the results, and consideration of the experimental design. The lymph fistula model is an approach to assess the concentration and rate of a range of molecules transported by the lymph by cannulating lymph duct in animals. In this protocol, mice first undergo surgery with the implantation of cannulae in the duodenum and mesenteric lymph duct and are allowed to recover overnight in Bollman restraining cages housed in a temperature-regulated environment. To study in vivo lipid absorption, a lipid emulsion is prepared with labeled tracers, including [3 H]-triolein and [14 C]-cholesterol. On the day of the experiment, mice are continuously infused with lipid emulsion via the duodenum for 6 hr, and lymph is usually collected hourly. At the end of the study, gastrointestinal segments and their luminal contents are collected separately for determination of the digestion, uptake, and transport of exogenous lipids. © 2019 by John Wiley & Sons, Inc.

Effect of a new incision management system (PREVENA®) on wound healing after endophlebectomy of the common femoral vein: a case series.

BACKGROUND: New endovascular techniques facilitate treatment of complex deep vein obstructions in cases of post-thrombotic syndrome. In a relevant number of these patients, endophlebectomy including the implantation of an arteriovenous fistula between the common femoral artery and the femoral vein is indispensable in order to establish a good inflow. These procedures display a high risk of wound complications. Despite conservative efforts to prevent these postoperative complications, wound healing problems occur in more than 20 % of cases. The present case report is the first description of wound dressing using a PREVENA® incision management system in cases of endophlebectomy. CASE PRESENTATION: A single center's experience with the incision management system PREVENA®, which was used after endophlebectomy and venous stenting in complex hybrid procedures in three white men aged 46 years, 53 years, and 61 years is the subject of this case report. Although the surgical procedures were performed under therapeutical anticoagulation and took a couple of hours, no wound complications occurred. CONCLUSIONS: These encouraging results underline a potential benefit of the incision management system PREVENA® in cases of complex venous recanalization including endophlebectomy of the femoral vein as well as the implantation of an arteriovenous fistula.

Treatment options for chylous ascites after major abdominal surgery: a systematic review.

BACKGROUND: Chylous leakage is a relevant clinical problem after major abdominal surgery leading to an increased length of stay. DATA SOURCES: A systematic search of MEDLINE/PubMed and the Cochrane Library was performed according to the PRISMA statement. The search for the MeSH terms "chylous ascites" and/or "lymphatic fistula" retrieved a total of 2,348 articles, of which 36 full-text articles were reviewed by 2 independent investigators. RESULTS: Chylous ascites is described with an incidence of up to 11%, especially after pancreatic surgery. The incidence is increasing with the number of lymph nodes harvested. In patients treated with total parenteral nutrition, conservative treatment is demonstrated to be effective in up to 100% of cases. CONCLUSIONS: The extent of abdominal surgery mainly predicts the risk of chylous ascites. Conservative treatment has been shown to be effective in almost all cases and is the treatment of choice.