September 2, 2009; doi:10.1152/ajpregu.00343.2009.-Gastric bypass surgery efficiently and lastingly reduces excess body weight and reverses type 2 diabetes in obese patients. Although increased energy expenditure may also play a role, decreased energy intake is thought to be the main reason for weight loss, but the mechanisms involved are poorly understood. Therefore, the aim of this study was to characterize the changes in ingestive behavior in a rat model of Roux-en-Y gastric bypass surgery (RYGB). Obese (24% body fat compared with 18% in chow-fed controls), male Sprague-Dawley rats maintained for 15 wk before and 4 mo after RYGB or sham-surgery on a two-choice low-fat/high-fat diet, were subjected to a series of tests assessing energy intake, meal patterning, and food choice. Although sham-operated rats gained an additional 100 g body wt during the postoperative period, RYGB rats lost ϳ100 g. Intake of a nutritionally complete and palatable liquid diet (Ensure) was significantly reduced by ϳ50% during the first 2 wk after RYGB compared with sham surgery. Decreased intake was the result of greatly reduced meal size with only partial compensation by meal frequency, and a corresponding increase in the satiety ratio. Similar results were obtained with solid food (regular or high-fat chow) 6 wk after surgery. In 12-to 24-h two-choice liquid or solid diet paradigms with nutritionally complete low-and high-fat diets, RYGB rats preferred the low-fat choice (solid) or showed decreased acceptance for the high-fat choice (liquid), whereas sham-operated rats preferred the high-fat choices. A separate group of rats offered chow only before surgery completely avoided the solid high-fat diet in a choice paradigm. The results confirm anecdotal reports of "nibbling" behavior and fat avoidance in RYGB patients and provide a basis for more mechanistic studies in this rat model. obesity; diabetes; bariatric surgery; high-fat diet; food preference; meal patterns; satiety ratio THE DISAPPOINTING EFFECTIVENESS and serious side effects of drugs have made surgical approaches very attractive alternatives for treatment or even prevention of obesity, type 2 diabetes, and other sequelae of the metabolic syndrome. Major progress in surgical methodology and experience with an increasing number of operations each year has resulted in a much-improved rate of serious complications and mortality during the last decade. Large prospective studies with up to 15 years follow-up have shown that an obese patient with a body mass index (BMI) of Ն35 has a longer life expectancy with gastric bypass surgery than without, and a Ͼ80% chance of resolving preexisting diabetes, cardiovascular disease, and sleep apneas (1,5,25,33,42,43).Given these impressive effects and the expected continued rise in the number of bariatric surgeries, it is vexing not to understand the mechanisms involved. Identification of these mechanisms should eventually lead to the development of pharmacological or behavioral tools without the need for surgery, or less invasive surgery...

is an important regulator of nutritional absorptive capacity with antiinflammatory actions. We hypothesized that GLP-2 reduces intestinal mucosal inflammation by activation of vasoactive intestinal polypeptide (VIP) neurons of the submucosal plexus. Ileitis or colitis was induced in rats by injection of trinitrobenzene sulfonic acid (TNBS), or colitis was induced by administration of dextran sodium sulfate (DSS) in drinking water. Subsets of animals received (1-33)-GLP-2 (50 g/kg sc bid) either immediately or 2 days after the establishment of inflammation and were followed for 3-5 days. The involvement of VIP neurons was assessed by concomitant administration of GLP-2 and the VIP antagonist [Lys 1 -Pro 2,5 -Arg 3,4 -Tyr 6 ]VIP and by immunohistochemical labeling of GLP-2-activated neurons. In all models, GLP-2 treatment, whether given immediately or delayed until inflammation was established, resulted in significant improvements in animal weights, mucosal inflammation indices (myeloperoxidase levels, histological mucosal scores), and reduced levels of inflammatory cytokines (IFN-␥, TNF-␣, IL-1␤) and inducible nitric oxide synthase, with increased levels of IL-10 in TNBS ileitis and DSS colitis. Reduced rates of crypt cell proliferation and of apoptosis within crypts in inflamed tissues were also noted with GLP-2 treatment. These effects were abolished with coadministration of GLP-2 and the VIP antagonist. GLP-2 was shown to activate neurons and to increase the number of cells expressing VIP in the submucosal plexus of the ileum. These findings suggest that GLP-2 acts as an anti-inflammatory agent through activation of enteric VIP neurons, independent of proliferative effects. They support further studies to examine the role of neural signaling in the regulation of intestinal inflammation. vasoactive intestinal peptide; trinitrobenzene sulfonic acid colitis; dextran sodium sulfate colitis; Crohn's disease THE ENTEROENDOCRINE HORMONE glucagon-like peptide-2 (GLP-2) is thought to act primarily as a regulator of intestinal nutrient absorption and as an intestinal-specific trophic factor (10, 12, 26). As a trophic factor, GLP-2 stimulates crypt cell proliferation, nutrient transporter expression, and intestinal blood flow (27) through actions on a specific receptor system primarily localized to enteric neurons and enteroendocrine cells (4,20,35). In studies using dextran sodium sulfate (DSS) and indomethacin models of intestinal inflammation, GLP-2 stimulation has been shown to improve mucosal healing (6, 13, 24); mechanistically, this was ascribed to an increased crypt cell proliferation rate (13).Given the evidence that GLP-2 receptors appear to be localized to the enteric nervous system, we speculated that GLP-2 may induce anti-inflammatory effects via this pathway. Specifically, vasoactive intestinal polypeptide (VIP) has been shown to act as an anti-inflammatory agent (2), and so we hypothesized that GLP-2 may act by stimulating neuronal VIP release in the intestinal submucosa and mucosa. Subsequently, it has bee...

Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a total parenteral nutrition (TPN)-supported model of experimental short bowel syndrome. Juvenile Sprague-Dawley rats underwent a 90% small intestinal resection and jugular catheter insertion. Rats were randomized to three groups: enteral diet and intravenous saline infusion, TPN only, or TPN + 10 μg·kg−1·h−1 GLP-2. Nutritional maintenance was isocaloric and isonitrogenous. After 7 days, intestinal permeability was assessed by quantifying the urinary recovery of gavaged carbohydrate probes. The following day, animals were euthanized, and intestinal tissue was processed for morphological and crypt cell proliferation (CCP) analysis, apoptosis (caspase-3), and expression of SGLT-1 and GLUT-5 transport proteins. TPN plus GLP-2 treatment resulted in increased bowel and body weight, villus height, intestinal mucosal surface area, CCP, and reduced intestinal permeability compared with the TPN alone animals ( P < 0.05). GLP-2 treatment induced increases in serum GLP-2 levels and intestinal SGLT-1 expression ( P < 0.01) compared with either TPN or enteral groups. No differences were seen in the villus apoptotic index between resection groups. Enterally fed resected animals had a significant decrease in crypt apoptotic indexes compared with nontreated animals. This study demonstrates that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation. Secondly, villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates. Further studies are warranted to establish the mechanisms of action and therapeutic potential of GLP-2.

Compared with Intralipid, SMOFlipid reduces the risk of progressive IFALD in children with intestinal failure. This trial was registered at clinicaltrials.gov as NCT00793195.

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