Jwm Greve

Increased leptin concentrations correlate with increased concentrations of inflammatory markers in morbidly obese individuals

OBJECTIVE: To study whether an increase of plasma leptin concentrations, as observed in the case of increased body weight, is associated with an inflammatory state.SUBJECTS: Sixty-three healthy subjects with body mass index (BMI) ranging from 20 to 61 kg/m2.MEASUREMENTS: Plasma concentrations of leptin, the inflammatory parameter soluble TNF-α receptors (TNFR55 and TNFR75), the acute phase proteins lipopolysaccharide binding protein (LBP), serum amyloid A (SAA), α-acid glycoprotein (AGP), C-reactive protein (CRP), plasminogen activator inhibitor-1 (PAI-1) and the anti-inflammatory soluble Interleukin-1 decoy receptor (sIL-1RII) were measured.RESULTS: As expected, BMI correlated significantly with leptin (r=0.823, P<0.001), but also with all acute phase proteins, both soluble TNF receptors and PAI concentrations. After correction for BMI and sex, no significant correlation between leptin and the acute phase proteins was seen. Interestingly, however, leptin strongly correlated with both TNF receptors (r=0.523, P<0.001 for TNFR55 and r=0.438, P<0.001 for TNFR75).CONCLUSIONS: This study shows the development of a pro-inflammatory state with increasing body weight. The BMI independent relationship between leptin and both soluble TNF-receptors is consistent with a regulatory role for leptin in the inflammatory state in morbidly obese subjects.

Decreased plasma orexin-A levels in obese individuals.

Orexin-A and -B stimulate appetite and food intake in rats. Orexins and orexin receptors are present in the hypothalamus as well as the enteric nervous system, the pancreas and the gut. The presence of orexins in peripheral blood, however, has not yet been reported. To determine whether orexin-A is present in human plasma and is related to body weight, we measured plasma orexin-A and leptin levels in a population with a body mass index (BMI) range from 19.8 to 59 kg/m2. Plasma orexin-A levels correlated negatively and plasma leptin levels correlated positively with BMI. In obese and morbidly obese individuals, orexin-A levels were significantly lower and leptin levels were significantly higher when compared to normal. Our results support previous data suggesting that orexin-A acts also in a peripheral manner. The fact that lower levels of plasma orexin-A are present in obese individuals suggests that it is involved in the regulation of human energy metabolism.

Laparoscopic Adjustable Gastric Banding versus Open Vertical Banded Gastroplasty: A Prospective Randomized Trial

Background: Laparoscopic adjustable gastric banding (LAGB) and open vertical banded gastroplasty (VBG) are treatment modalities for morbid obesity. However, few prospective randomized clinical trials (RCT) have been performed to compare both operations. Methods: 100 patients (50 per group) were included in the study. Postoperative outcomes included hospital length of stay (LOS), complications, percent excess weight loss (%EWL), BMI and reduction in total comorbidities. Follow-up in all patients was 2 years. Results: LOS was significantly shorter in the LAGB group. 3 LAGB were converted to open (1 to gastric bypass). Directly after VBG, 3 patients needed relaparotomies due to leakage, of which one (2%) died. After 2 years, 100% follow-up was achieved. BMI and %EWL were significantly decreased in both groups but significantly more in the VBG group compared to the LAGB group (31.0 kg/m2 and 70.1% vs 34.6 and 54.9% respectively). Co-morbidities significantly decreased in both groups in time. 2 years after LAGB, 20 patients needed reoperation for pouch dilation/slippage (n=12), band leakage (n=2), band erosion (n=2) and access-port problems (n=4). In the VBG group, 18 patients needed revisional surgery due to staple-line disruption (n=15), narrow outlet (n=2) or insufficient weight loss (n=1). Furthermore, 8 VBG patients developed an incisional hernia. Conclusion: This RCT demonstrates that, despite the initial better weight loss in the VBG group, based on complication rates and clinical outcome, LAGB is preferred. It had a shorter LOS and less postoperative morbidity.

Re-operation after Laparoscopic Adjustable Gastric Banding Leads to a Further Decrease in BMI and Obesity-related Co-morbidities: Results in 33 Patients

Background: Laparoscopic adjustable gastric banding (LAGB) is a safe technique with few direct postoperative complications. However, long-term complications such as slippage and pouch dilatation are a well-known problem and re-operations are necessary in a substantial number of patients. In this study, the results of laparoscopic re-operations after LAGB are evaluated. Methods: 33 patients had a re-operation because of failed LAGB. 29 patients had major re-operation and 4 patients minor re-operation under local anesthesia. The charts of these patients were retrospectively studied. Results: Mean time between the first band placement and re-operation was 28.1 ± 17.6 months. The cause of band dysfunction was anterior slippage (n=17), band erosion (n=5), band intolerance (n=3), posterior slippage (n=2) and band leakage (n=2). Symptoms of band dysfunction were vomiting (n=16), pyrosis (n=13), nausea (n=8), retrosternal pain (n=11) and regurgitation (n=5). Laparoscopic refixation of the band was performed in 19 patients: the band was replaced in 4 patients while in 1 patient the band was removed; in 3 patients, the laparoscopic procedure was converted to open surgery; 5 patients underwent conversion to a bypass procedure (biliopancreatic diversion in 3 and gastric bypass in 2). There were no direct postoperative complications except for wound infections (n=2). Postoperative follow-up was 100% with a mean period of 34 ± 19 months. BMI decreased further from 37.5 ± 6.4 kg/m2 before re-operation to 33 ± 7 kg/m2. Obesity-related co-morbidity also decreased further or completely dissolved. 3 patients (9%) again developed anterior slippage and a second laparoscopic re-operation was necessary. Conclusions: A laparoscopic re-operation for band-related complications after LAGB is safe and feasible. With band slippage, a laparoscopic refixation was possible in 89%. Re-operation leads to further decrease in BMI and obesity-related co-morbidities.

Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors

Objective:This study investigates the effect of lipid-rich nutrition on the local inflammatory response and gastrointestinal hypomotility in a rat model of postoperative ileus. Background:Postoperative ileus is a major clinical problem, in which inflammation of the intestinal muscularis plays a key pathogenic event. Previously, administration of lipid-rich nutrition has been shown to reduce inflammation by activation of the autonomic nervous system via cholecystokinin-receptors. Methods:Postoperative ileus was induced by manipulation of the small intestine in rats. Peritoneal lavage fluid, plasma, and jejunal segments were collected at several time points to determine inflammatory mediators in fasted rats and rats fed a lipid-rich or control nutrition. Gastrointestinal transit was measured 24 hours after surgery. Results:Administration of lipid-rich nutrition markedly reduced the manipulation-induced local inflammatory response compared to rats treated with control nutrition. The intervention with lipid-rich nutrition significantly reduced plasma levels of rat mast cell protease-II (P < 0.05) and peritoneal levels of tumor necrosis factor-alpha (P < 0.01) and interleukin-6 (P < 0.05). Furthermore, the influx of neutrophils, expressed as tissue level myeloperoxidase was significantly prevented by lipid-rich nutrition (P < 0.05). Above all administration of lipid-rich enteral nutrition resulted in a significant improvement of gastrointestinal transit compared to control nutrition (P < 0.05). Blocking of cholecystokinin-receptors prevented the anti-inflammatory and motility promoting effect of lipid-rich feeding. Conclusion:Our data demonstrate that nutritional stimulation of the autonomic nervous system with enteral lipids reduces postoperative ileus by inhibition of inflammation. Clinically, lipid-rich enteral nutrition may be a new therapeutic option in the treatment of postoperative ileus.

Cholecystokinin/Cholecystokinin-1 receptor-mediated peripheral activation of the afferent vagus by enteral nutrients attenuates inflammation in rats.

Objective:The current study investigates activation of the nutritional anti-inflammatory pathway by lipid-rich nutrition. Background:Enteral nutrition activates humoral and neural pathways to regulate food intake and sustain energy balance. Recently, we demonstrated that enteral nutrition and in particular lipid-rich nutrition modulates inflammation and prevents organ damage. Methods:Male rats were fasted or fed lipid-rich nutrition before hemorrhagic shock. Disruption of afferent vagal fibers with capsaicin (deafferentation) was used to investigate involvement of afferent fibers. Peripheral activation of afferent vagal fibers via cholecystokinin (CCK)-mediated activation of CCK-1 receptors was investigated using administration of the selectively peripheral acting CCK-1 receptor antagonist, A70104 and PEGylated-CCK9. Tissue and blood were collected 90 minutes after shock to assess systemic inflammation and intestinal integrity. Results:Deafferentation reversed the inhibitory effect of lipid-rich nutrition on systemic levels of tumor necrosis factor-&agr; and interleukin-6, and on intestinal leakage of horseradish peroxidase and bacterial translocation. Furthermore, the protective effects of lipid-rich nutrition were negated by A70104, indicating that lipid-rich nutrition triggers peripheral CCK-1 receptors on vagal afferents to modulate inflammation. These findings were substantiated by the fact that pretreatment of fasted rats with PEGylated-CCK9, which acts on peripheral CCK-1 receptors, attenuated systemic inflammation, and loss of intestinal integrity. Conclusion:These data demonstrate that enteral lipid-rich nutrition modulates inflammation and preserves intestinal integrity via CCK release which activates CCK-1 receptors located on afferent vagal fibers. Taken together, the current study reveals a novel gut-brain-immune axis and provides new insight into the applicability of enteral nutrition to treat inflammatory conditions.

Lipid-enriched enteral nutrition controls the inflammatory response in murine Gram-negative sepsis.

Objectives:Controlling the inflammatory cascade during sepsis remains a major clinical challenge. Recently, it has become evident that the autonomic nervous system reduces inflammation through the vagus nerve. The current study investigates whether nutritional stimulation of the autonomic nervous system effectively attenuates the inflammatory response in murine Gram-negative sepsis. Design:Controlled in vivo and ex vivo experimental study. Settings:Research laboratory of a university hospital. Subjects:Male C57bl6 mice. Interventions:Mice were intraperitoneally challenged with lipopolysaccharide derived from Escherichia coli. Before lipopolysaccharide administration, mice were fasted or enterally fed either lipid-rich nutrition or low-lipid nutrition. Antagonists to cholecystokinin receptors or nicotinic receptors were administered before lipopolysaccharide administration. Blood and tissue samples were collected at 90 mins. Mesenteric afferent discharge was determined in ex vivo preparations in response to both nutritional compositions. Measurements and Main Results:Both lipid-rich and low-lipid nutrition dose-dependently reduced lipopolysaccharide-induced tumor necrosis factor-&agr; release (high dose: both 1.4 ± 0.4 ng/mL) compared with fasted mice (3.7 ± 0.8 ng/mL; p < .01). The anti-inflammatory effect of both nutritional compositions was mediated through cholecystokinin receptors (p < .01), activation of mesenteric vagal afferents (p < .05), and peripheral nicotinic receptors (p < .05). Lipid-rich nutrition attenuated the inflammatory response at lower dosages than low-lipid nutrition, indicating that enrichment of enteral nutrition with lipid augments the anti-inflammatory potential. Administration of lipid-rich nutrition prevented endotoxin-induced small intestinal epithelium damage and reduced inflammation in the liver and spleen compared with fasted (all p < .01) and low-lipid nutrition controls (all p < .05). Conclusions:The current study demonstrates that lipid-rich nutrition attenuates intestinal damage and systemic as well as organ-specific inflammation in murine Gram-negative sepsis through the nutritional vagal anti-inflammatory pathway. These findings implicate enteral administration of lipid-enriched nutrition as a promising intervention to modulate the inflammatory response during septic conditions.

Continuous administration of enteral lipid- and protein-rich nutrition limits inflammation in a human endotoxemia model

Objective:An overzealous inflammatory response is an important cause of morbidity and mortality in surgical, trauma, and critically ill patients. Enteral administration of lipid-rich nutrition was previously shown to attenuate inflammation and reduce organ damage via a cholecystokinin-1 receptor–mediated vagovagal reflex in animal studies. The current preclinical study investigates the immunomodulatory potential of a custom-made enteral nutrition during systemic inflammation in man. Design:Double-blind, randomized controlled trial. Setting:Intensive care research unit. Subjects:Male volunteers. Interventions:After an overnight fast, 18 healthy male subjects received an IV bolus of Escherichia coli lipopolysaccharide (2 ng/kg). Subjects in the fasted group (n = 6) were deprived of food throughout the study, while subjects in the intervention groups were fed either custom-made lipid- and protein-rich nutrition (n = 6) or isocaloric control nutrition (n = 6) via nasojejunal tube, starting 1 hour prior to lipopolysaccharide administration until 6 hours afterward. Measurements and Main Results:Bolus lipopolysaccharide administration resulted in a marked inflammatory response. Continuous postpyloric administration of nutrition significantly increased plasma cholecystokinin levels throughout the lipopolysaccharide-induced inflammatory response. Lipid- and protein-rich nutrition attenuated circulating levels of the proinflammatory cytokines tumor necrosis factor-&agr; and interleukin-6 and the interleukin-1 receptor antagonist compared with control nutrition (all p < 0.05) and fasted subjects (all p < 0.05). In additional, lipid- and protein-rich nutrition augmented the anti-inflammatory response, reflected by increased plasma levels of interleukin-10 compared with fasted subjects (p < 0.0001). Conclusions:The current preclinical study expands the immunomodulating effects of enteral nutrition as previously observed in rodents to man. Continuous administration of enteral nutrition resulted in a rapid anti-inflammatory effect. Furthermore, enrichment of the nutritional composition with lipid and protein was shown to enhance the anti-inflammatory potential. Therefore, continuous enteral administration of lipid- and protein-rich nutrition is a promising intervention to modulate the immune response in the early course of systemic inflammation in man.

Lipid-rich enteral nutrition improves the defense against an opportunistic infection during polymicrobial sepsis

ABSTRACT The development of an immunosuppressive state during the protracted course of sepsis is associated with opportunistic infections and is considered to correlate with the extent of the proinflammatory response during early sepsis. Short-term intervention with enteral lipid-rich nutrition was shown to attenuate the acute inflammatory response. This study investigates the effects of lipid-rich nutrition on the immunosuppression induced by polymicrobial sepsis. Female BALB/c mice were either fasted or fed liquid lipid-rich nutrition or isocaloric control nutrition before and shortly after induction of polymicrobial sepsis through cecal ligation and puncture (CLP) or sham operation. After 4 days, mice were intranasally infected with Pseudomonas aeruginosa. Twenty-four hours after P. aeruginosa infection, fasted and control nutrition-fed CLP mice displayed a significantly higher bacterial load in the lungs than did corresponding sham-operated mice (P < 0.001 and P < 0.05, respectively). Fasted CLP mice expressed reduced pulmonary levels of proinflammatory cytokines interleukin 12 (IL-12) and interferon &ggr; (IFN-&ggr;) in comparison to sham mice (both P < 0.05). Lipid-rich nutrition prevented the increase in bacteria, promoted the IL-12 and IFN-&ggr; production (IL-12 and IFN-&ggr; [P < 0.05] vs. fasted and IFN-&ggr; [P < 0.05] vs. control nutrition), and prevented the expression of the immunosuppressive cytokine IL-10 (P < 0.05 vs. control nutrition) in lungs of CLP mice. The preserved immune defense during late sepsis in lipid-rich fed mice was preceded by attenuation of the early inflammatory response (IL-6 [P = 0.05] and IL-10 [P < 0.01] vs. fasted CLP mice) at 6 h after CLP. In conclusion, short-term treatment with lipid-rich enteral nutrition improves the pulmonary antimicrobial defense during polymicrobial sepsis.

Low number of omental preadipocytes with high leptin and low adiponectin secretion is associated with high fasting plasma glucose levels in obese subjects

Objective:  This study investigates whether fasting plasma glucose (FPG) levels in obese subjects are associated with the number of preadipocytes and their adipokine‐secretion capabilities.