Robert N. Cooney

Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats

Roux-en-Y gastric bypass surgery (GBS) is the most effective treatment for morbid obesity. GBS is a restrictive malabsorptive procedure, but many patients also report altered taste preferences. This study investigated the effects of GBS or a sham operation (SH) on body weight, glucose tolerance, and behavioral and neuronal taste functions in the obese Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-1 receptors and lean controls (LETO). OLETF-GBS rats lost body weight (-26%) and demonstrated improved glucose tolerance. They also expressed a reduction in 24-h two-bottle preference for sucrose (0.3 and 1.0 M) and decreased 10-s lick responses for sucrose (0.3 through 1.5 M) compared with OLETF-SH or LETO-GBS. A similar effect was noted for other sweet compounds but not for salty, sour, or bitter tastants. In lean rats, GBS did not alter responses to any stimulus tested. Extracellular recordings from 170 taste-responsive neurons of the pontine parabrachial nucleus revealed a rightward shift in concentration responses to oral sucrose in obese compared with lean rats (OLETF-SH vs. LETO-SH): overall increased response magnitudes (above 0.9 M), and maximum responses occurring at higher concentrations (+0.46 M). These effects were reversed by GBS, and neural responses in OLETF-GBS were statistically not different from those in any LETO groups. These findings confirm obesity-related alterations in taste functions and demonstrate the ability of GBS to alleviate these impairments. Furthermore, the beneficial effects of GBS appear to be independent of CCK-1 receptor signaling. An understanding of the underlying mechanisms for reduced preferences for sweet taste could help in developing less invasive treatments for obesity.

Apolipoprotein A-IV, a Putative Satiety/Antiatherogenic Factor, Rises After Gastric Bypass

Roux‐en‐Y gastric bypass surgery (RYGBP) leads to improvements in satiety and obesity‐related comorbidities. The mechanism(s) underlying these improvements are not known but may be revealed in part by discovery proteomics. Therefore, fasting plasma was collected from 12 subjects (mean BMI >45) during RYGBP and during a second procedure ∼17 months later. Body weight, obesity‐related comorbidities, and medication use were decreased after RYGBP. Mass spectrometry‐based proteomic analysis was performed on a subset of seven samples using isobaric isotope‐coded affinity tags (four plex iTRAQ). Initial proteomic analysis (n = 7) quantified and identified hundreds of plasma proteins. Manual inspection of the data revealed a 2.6 ± 0.5‐fold increase in apolipoprotein A‐IV (apo A‐IV, gene designation: APOA4), a ∼46‐kDa glycoprotein synthesized mainly in the bypassed small bowel and liver after RYGBP. The change in apo A‐IV was significantly greater than other apolipoproteins. Immunoblot analysis of the full longitudinal sample set (n = 12) indicated even higher increases (8.3 ± 0.2 fold) in apo A‐IV. Thus iTRAQ may underestimate the changes in protein concentrations compared to western blotting of apo A‐IV. Apo A‐IV inhibits gastric emptying and serves as a satiety factor whose synthesis and secretion are increased by the ingestion of dietary fat. It also possesses anti‐inflammatory and antiatherogenic properties. Based on these functions, we speculate changes in apo A‐IV may contribute to weight loss as well as the improvements in inflammation and cardiovascular disease after RYGBP. In addition, the findings provide evidence validating the use of iTRAQ proteomics in discovery‐based studies of post‐RYGBP improvements in obesity‐related medical comorbidities.

TNF-binding protein ameliorates inhibition of skeletal muscle protein synthesis during sepsis.

We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP. Saline (1. 0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis. The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later. Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency. Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight. Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis. We also assessed potential mechanisms regulating translational efficiency. The phosphorylation state of p70(S6) kinase was not altered by sepsis. Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bepsilon (eIF2Bepsilon), but not eIF2alpha. The decrease in eIF2Bepsilon content was prevented by treatment of septic rats with TNFBP. TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process. The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.We examined the effects of TNF-binding protein (TNFBP) on regulatory mechanisms of muscle protein synthesis during sepsis in four groups of rats: Control; Control+TNFBP; Septic; and Septic+TNFBP. Saline (1.0 ml) or TNFBP (1 mg/kg, 1.0 ml) was injected daily starting 4 h before the induction of sepsis. The effect of TNFBP on gastrocnemius weight, protein content, and the rate of protein synthesis was examined 5 days later. Sepsis reduced the rate of protein synthesis by 35% relative to controls by depressing translational efficiency. Decreases in protein synthesis were accompanied by similar reductions in protein content and muscle weight. Treatment of septic animals with TNFBP for 5 days prevented the sepsis-induced inhibition of protein synthesis and restored translational efficiency to control values. TNFBP treatment of Control rats for 5 days was without effect on muscle protein content or protein synthesis. We also assessed potential mechanisms regulating translational efficiency. The phosphorylation state of p70S6 kinase was not altered by sepsis. Sepsis reduced the gastrocnemius content of eukaryotic initiation factor 2Bε (eIF2Bε), but not eIF2α. The decrease in eIF2Bε content was prevented by treatment of septic rats with TNFBP. TNFBP ameliorates the sepsis-induced changes in protein metabolism in gastrocnemius, indicating a role for TNF in the septic process. The data suggest that TNF may impair muscle protein synthesis by reducing expression of specific initiation factors during sepsis.

Revisional bariatric surgery: who, what, where, and when?

BACKGROUNDnRevisional bariatric surgery (RBS) outcomes have been poorly characterized. We compared the RBS and primary bariatric surgery (PBS) outcomes at the Penn State Milton S. Hershey Medical Center in the United States.nnnMETHODSnA total of 72 RBS cases from 2000 to 2007 were reviewed and grouped by indication: failure of weight loss, gastrojejunal complications, or other. The RBS patients were compared with the 856 PBS patients who underwent Roux-en-Y gastric bypass. The mean follow-up time was 12.6 ± 1.2 months for the RBS group and 16 ± 0.5 months for the PBS group. Weight loss was analyzed as the kilograms lost and patients with ≥ 50% excess body weight loss (EBWL). Outcomes included mortality, leaks, surgical site infections, and length of stay.nnnRESULTSnThe weight loss was 23 ± 2.8 kg after RBS and 41.3 ± 0.7 kg after PBS (P <.05 versus PBS). The post-RBS weight loss varied by surgical indication: failure of weight loss, 27.1 ± 2 kg; gastrojejunal complications, 8.7 ± 3.4 kg; and other 23.5 ± 10.6 kg. Also, 29% of the RBS patients had ≥ 50% excess body weight loss (versus the prerevision weight) and 61% (versus the initial weight) compared with 52.7% after PBS. Only age ≤ 50 years was associated with ≥ 50% excess body weight loss after RBS for the failure of weight loss group. No RBS patients died. However, leaks, surgical site infections, and length of stay were increased after RBS.nnnCONCLUSIONnThe results of our study have shown that weight loss after RBS varies with the surgical indication and is affected by age >50 years. Although the RBS patients had decreased weight loss and increased complications compared with the PBS patients, ≥ 50% EBWL was achieved by a significant number of RBS patients.

Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat

The hindgut hypothesis posits improvements in Type 2 diabetes after gastric bypass surgery are due to enhanced delivery of undigested nutrients to the ileum, which increase incretin production and insulin sensitivity. The present study investigates the effect of ileal interposition (IT), surgically relocating a segment of distal ileum to the proximal jejunum, on glucose tolerance, insulin sensitivity, and glucose transport in the obese Zucker rat. Two groups of obese Zucker rats were studied: IT and sham surgery ad libitum fed (controls). Changes in food intake, body weight and composition, glucose tolerance, insulin sensitivity and tissue glucose uptake, and insulin signaling as well as plasma concentrations of glucagon-like peptide-1 and glucose-dependent insulinotropic peptide were measured. The IT procedure did not significantly alter food intake, body weight, or composition. Obese Zucker rats demonstrated improved glucose tolerance 3 wk after IT compared with the control group (P < 0.05). Euglycemic, hyperinsulinemic clamp and 1-[(14)C]-2-deoxyglucose tracer studies indicate that IT improves whole body glucose disposal, insulin-stimulated glucose uptake, and the ratio of phospho- to total Akt (P < 0.01 vs. control) in striated muscle. After oral glucose, the plasma concentration of glucagon-like peptide-1 was increased, whereas GIP was decreased following IT. Enhanced nutrient delivery to the ileum after IT improves glucose tolerance, insulin sensitivity and muscle glucose uptake without altering food intake, body weight, or composition. These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure.

Gastric Bypass Increases Ethanol and Water Consumption in Diet-Induced Obese Rats

BackgroundRoux-en-Y gastric bypass surgery (RYGB) is an effective treatment for morbid obesity. Increased alcohol abuse after RYGB resulted in recommendations to exclude patients with alcohol abuse histories from RYGB. The purpose of our study was to examine the effects of a RYGB on ethanol intake in diet-induced obese rats (high-fat diet).MethodsThe animals underwent RYGB and were habituated along with their sham-operated obese controls and with lean rats to increasing concentrations of ethanol in a two-bottle choice paradigm.ResultsRYGB rats daily consumption of ethanol averaged 2xa0g/kg at 2xa0% habituation and 3.8xa0g/kg at 4xa0% habituation, twice as much as sham-operated obese controls and 50xa0% more than normal-diet lean controls. Obese controls drank on average 1xa0g/kg of ethanol (2 and 4xa0%), significantly less (50xa0%) than lean controls did. RYGB rats when given higher ethanol concentrations (6 and 8xa0%) or no ethanol drank significantly more water than lean and obese controls did (66 and 100xa0%, respectively), and their enhanced total fluid intake was associated with increased food intake, which was significantly higher than in lean (66xa0% more calories; food + alcohol) and obese controls (44xa0% more calories). The lower alcohol intake in the obese controls than in the lean rats suggests that obesity may interfere with alcohols rewarding effects and RYGB may remove this protective effect.ConclusionsThe overall enhancement of consummatory behaviors (both ethanol and water) suggests that RYGB may facilitate alcohol consumption, which in vulnerable individuals could lead to abuse and addiction.

The inhibitory effects of interleukin-1 on growth hormone action during catabolic illness.

Growth hormone (GH) induces the expression of the anabolic genes responsible for growth, metabolism, and differentiation. Normally, GH stimulates the synthesis of circulating insulin-like growth factor-I (IGF-I) by liver, which upregulates protein synthesis in many tissues. The development of GH resistance during catabolic illness or inflammation contributes to loss of body protein, resulting in multiple complications that prolong recovery and cause death. In septic patients, increased levels of proinflammatory cytokines and GH resistance are commonly observed together. Numerous studies have provided evidence that the inhibitory effects of cytokines on skeletal muscle protein synthesis during sepsis and inflammation are mediated indirectly by changes in the GH/IGF-I system. Interleukin (IL)-1, a member of the family of proinflammatory cytokines, interacts with most cell types and is an important mediator of the inflammatory response. Infusion of a specific IL-1 receptor antagonist (IL-1Ra) ameliorates protein catabolism and GH resistance during systemic infection. This suggests that IL-1 is an important mediator of GH resistance during systemic infection or inflammation. Consequently, a better understanding of the interaction between GH, IL-1, and the regulation of protein metabolism is of great importance for the care of the patient.

Determining energy needs in critically ill patients: equations or indirect calorimeters.

Purpose of reviewThe review focuses on current methodology for the most accurate way to determine resting metabolic rate in critically ill patients and to evaluate whether application of any particular method improves clinical outcome. Recent findingsConsensus is that indirect calorimetry is the most accurate method for determining resting metabolic rate. Whenever an alternate method of determining energy expenditure is tested (e.g. equations), the criterion method used in the validation is indirect calorimetry. Of the alternates to indirect calorimetry, the Penn State equation has the strongest validation work supporting it. No study has been undertaken to determine whether the drop in accuracy associated with estimation methods translates into deterioration in clinical outcome compared to nutrition support guided by measurements. SummaryIndirect calorimetry is the most accurate way to determine calorie needs in critically ill patients. Compared to indirect calorimetry, metabolic rate equations are accurate about 75% of the time. No study has been performed to determine whether the measurement or estimation method improves clinical outcome.

Capsaicin-sensitive nerves regulate the metabolic response to abdominal sepsis

BACKGROUNDnBoth the systemic release of inflammatory mediators and activation of the neuroendocrine axis by sensory afferent nerves (SANs) have been implicated as initiators of the metabolic response to infection. In this study, we investigate the role of SANs as mediators of protein catabolism and the insulin-like growth factor (IGF) axis during abdominal sepsis using capsaicin (Cap) to selectively destroy nociceptive sensory axons.nnnMETHODSnFour groups of male Sprague-Dawley rats were studied: Control, Control+Cap, Sepsis, and Sepsis+Cap. Rats were injected with Cap (75 mg/kg) on day 1 and (50 mg/kg) on day 2 to destroy SANs. Time-matched control and septic rats were pair-fed and injected with vehicle on the same schedule. Controls underwent sham laparotomy, while septic rats had a fecal-agar pellet inoculated with Escherichia coli and Bacteroides fragilis implanted in the peritoneal cavity. Blood and tissues were harvested 5 days after the induction of sepsis. Plasma IGF-I, IGFBP-1, and -3 were measured by radioimmunoassay and Western blot analysis. IGF-I, acid-labile subunit (ALS), IGFBP-1 and -3 mRNA levels were determined by Northern blot analysis.nnnRESULTSnMortality was 40% in septic rats vs 0% in the sepsis+Cap group. Capsaicin had no effect on muscle mass, protein content, or the IGF system in control rats. However, sepsis-induced reductions in gastrocnemius mass (25%) and protein content (35%) were ameliorated by capsaicin. The sepsis-induced decrease in hepatic IGF-I mRNA and circulating IGF-I (26%), as well as the 4-fold increase in plasma IGFBP-1 and hepatic IGFBP-1 mRNA were prevented by capsaicin.nnnCONCLUSIONSnCapsaicin-sensitive nerves mediate mortality, the catabolism of skeletal muscle, and selected elements of the IGF system during abdominal sepsis. The results suggest an important role for nociceptive SANs and the neuroendocrine system in mediating the host response to abdominal infection.

Nuclear Factor-κB Mediates the Inhibitory Effects of Tumor Necrosis Factor-α on Growth Hormone-Inducible Gene Expression in Liver

TNF inhibits serine protease inhibitor 2.1 (Spi 2.1) and IGF-I gene expression by GH in CWSV-1 hepatocytes. The current study describes construction of a GH-inducible IGF-I promoter construct and investigates mechanisms by which TNF and nuclear factor-kappaB (NFkappaB) inhibit GH-inducible gene expression. CWSV-1 cells were transfected with GH-inducible Spi 2.1 or IGF-I promoter luciferase constructs, incubated with TNF signaling inhibitors (fumonisin B1 for sphingomyelinase and SP600125 for c-Jun N-terminal kinase), treated with or without TNF, and then stimulated with recombinant human GH. The 5- to 6-fold induction of Spi 2.1 and IGF-I promoter activity by GH was inhibited by TNF. Neither fumonisin B1 nor SP600125 prevented the inhibitory effects of TNF on GH-inducible promoter activity. Dominant-negative inhibitor-kappaBalpha (IkappaBalpha) expression vectors (IkappaBalphaS/A or IkappaBalphaTrunc), p65 and p50 expression vectors, and p65 deletion constructs were used to investigate the NFkappaB pathway. IkappaBalphaS/A and IkappaBalphaTrunc ameliorated the inhibitory effects of TNF on GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection of CWSV-1 cells with expression vectors for p65 alone or p50 and p65 together inhibited GH-inducible Spi 2.1 and IGF-I promoter activity. Cotransfection with a C-terminal p65 deletion (1-450) enhanced GH-inducible promoter activity, whereas the N-terminal deletion (31-551) was inhibitory for IGF-I but not Spi 2.1. Cycloheximide did not antagonize the inhibitory effects of TNF on GH-inducible IGF-I expression. We conclude the inhibitory effects of TNF on GH-inducible promoter activity are mediated by NFkappaB, especially p65, by a mechanism that does not require protein synthesis.