BACKGROUND:The gold standard for treatment of obesity remains bariatric surgery. The mechanisms underlying the effectiveness of these operations remain incompletely understood. Rodent models of these surgeries have proven essential to efforts to elucidate these mechanisms. The most commonly used such model is the mouse vertical sleeve gastrectomy (VSG). OBJECTIVE:This study aimed to evaluate technical approaches and complications of mouse VSG. SETTING:Academic research laboratory, United States. METHODS:Wild-type male mice were subjected to variations of VSG. Important metabolic outcomes, including body weight, body composition, and glucose tolerance, were assessed at relevant time points postoperation. A necropsy was performed on all mice at 2 months postsurgery to evaluate the gastric sleeve for any complications. RESULTS:Chronic, contained gastric leak is a relatively high-frequency complication after mouse VSG. A scoring system was developed to quantify and sort mice with leaks. Data from mouse cohorts performed by different methods demonstrate that no surgical approach used in the study could prevent the risk of leak. It shows that significant leaks impact commonly measured metabolic parameters after VSG, likely secondary to the effects of chronic local and systemic inflammation. CONCLUSIONS:The presence of chronic gastric leak is common after mouse VSG. The effects of these leaks are likely to confound data analysis when using this surgical model. The use of the scoring and sorting approach developed and described in this study provides an important tool for quality control of murine VSG studies. Careful elimination of mice with this complication enables the effective and reliable use of this surgical model.

Gastric bypass and vertical sleeve gastrectomy (VSG) remain the most potent and durable treatments for obesity and type 2 diabetes but are also associated with iron deficiency. The transcription factor HIF2α, which regulates iron absorption in the duodenum, increases following these surgeries. Increasing iron levels by means of dietary supplementation or hepatic hepcidin knockdown does not undermine the effects of VSG, indicating that metabolic improvements following VSG are not secondary to lower iron levels. Gut-specific deletion of Vhl results in increased constitutive duodenal HIF2α signaling and produces a profound lean, glucose-tolerant phenotype that mimics key effects of VSG. Interestingly, intestinal Vhl deletion also results in increased intestinal secretion of GLP-1, which is essential for these metabolic benefits. These data demonstrate a role for increased duodenal HIF2α signaling in regulating crosstalk between iron-regulatory systems and other aspects of systemic physiology important for metabolic regulation.

BACKGROUND & AIMS: Compelling evidence shows that glucagon-like peptide-1 (GLP-1) has a profound effect in restoring normoglycemia in type 2 diabetic patients by increasing pancreatic insulin secretion. Although L-cells are the primary source of circulating GLP-1, the current therapies do not target L-cells to increase GLP-1 levels. Our study aimed to determine the molecular underpinnings of GLP-1 secretion as an impetus to identify new interventions to target endogenous L-cells.& nbsp;METHODS: We used genetic mouse models of intestine-specific overexpression of hypoxia-inducible factor (HIF)-1 alpha & nbsp;and HIF-2 alpha (Vhl(delta IE)), conditional overexpression of intestinal HIF-2 alpha (Hif-2 alpha(LSL;Vilin-Cre/ERT2)), and intestine-specific HIF-2 alpha knockout mice (Hif-2 alpha(delta IE)) to show that HIF signaling, especially HIF-2 alpha, regulates GLP-1 secretion.& nbsp;RESULTS: Our data show that intestinal HIF signaling improved glucose homeostasis in a GLP-1-dependent manner. Intestinal HIF potentiated GLP-1 secretion via the lipid sensor G-protein-coupled receptor (GPR)40 enriched in L-cells. We show that HIF-2 alpha & nbsp;regulates GPR40 in L-cells and potentiates fatty acid-induced GLP-1 secretion via extracellular regulated kinase (ERK). Using a genetic model of intestine-specific overexpression of HIF-2 alpha, we show that HIF-2 alpha is sufficient to increase GLP-1 levels and attenuate diet-induced metabolic perturbations such as visceral adiposity, glucose intolerance, and hepatic steatosis. Lastly, we show that intestinal HIF-2 alpha & nbsp;signaling acts as a priming mechanism crucial for postprandial lipid-mediated GLP-1 secretion. Thus, disruption of intestinal HIF-2 alpha & nbsp;decreases GLP-1 secretion.& nbsp;CONCLUSIONS: In summary, we show that intestinal HIF signaling, particularly HIF-2 alpha, regulates the lipid sensor GPR40, which is crucial for the lipid-mediated GLP-1 secretion, and suggest that HIF-2 alpha & nbsp;is a potential target to induce endogenous GLP-1 secretion.& nbsp;

Alterations in Serum-based Breast Cancer Markers Following Bariatric Surgery in Rodent Models: Are They of Clinical Value? Elika Ridelman 1, Simon S. Evers 2, Mark J. Hoenerhoff 3, Jeffrey E. Green 4 , Randy J. Seeley 2* 1 Department of Surgery, Wayne State School of Medicine, Department of Pediatric Surgery, Detroit, MI, USA. 2 Department of Surgery, University of Michigan, Ann Arbor, MI, USA. 3 Unit for Laboratory Animal Medicine In-Vivo Animal Core, University of Michigan, Ann Arbor, MI, USA. 4 National Cancer Institute (NCI), Bethesda, Maryland, USA. *Corresponding Author : Randy J. Seeley, PhD, Department of Surgery, University of Michigan, Ann Arbor, MI, USA. E-mail: seeleyrj@med.umich.edu

Objective: Post-bariatric surgery hypoglycemia (PBH) is defined as the presence of neuroglycopenic symptoms accompanied by postprandial hypoglycemia in bariatric surgery patients. Recent clinical studies using continuous glucose monitoring (CGM) technology revealed that PBH is more frequently observed in vertical sleeve gastrectomy (VSG) patients than previously recognized. PBH cannot be alleviated by current medication. Therefore, a model system to investigate the mechanism and treatment is required. Methods: We used CGM in a rat model of VSG and monitored the occurrence of glycemic variability and hypoglycemia in various meal conditions for 4 weeks after surgery. Another cohort of VSG rats with CGM was used to investigate whether the blockade of glucagon-like peptide-1 receptor (GLP-1R) signaling alleviates these symptoms. A mouse VSG model was used to investigate whether the impaired glucose counterregulatory system causes postprandial hypoglycemia. Results: Like in humans, rats have increased glycemic variability and hypoglycemia after VSG. Postprandial hypoglycemia was specifically detected after liquid versus solid meals. Further, the blockade of GLP-1R signaling raises the glucose nadir but does not affect glycemic variability. Conclusions: Rat bariatric surgery duplicates many features of human post-bariatric surgery hypoglycemia including postprandial hypoglycemia and glycemic variability, while blockade of GLP-1R signaling prevents hypoglycemia but not the variability. (C) 2020 The Authors. Published by Elsevier GmbH.

Objective: To study the relationship between the amount of surgery-induced gastric volume reduction and long-term weight loss and glucose tolerance. Background Data: Vertical sleeve gastrectomy (VSG) has recently surpassed gastric bypass to become the most popular surgical intervention to induce sustained weight loss. Besides inducing significant weight loss, VSG also improves glucose tolerance. Although no clear correlation has been observed between the size of the residual stomach and sustained weight loss, this begs the question whether less aggressive gastric volume reduction may provide sufficient efficacy when weight loss is not the major goal of the surgical intervention. Methods: A series of strategies to reduce gastric volume were developed and tested in Long Evans male rats, namely: VSG, Fundal (F)-Resection, Gastric Sleeve Plication (GSP), Fundal-Plication, and Fundal-Constrained. Results: All surgical interventions resulted in a reduction of gastric volume relative to sham, but none of the interventions were as effective as the VSG. Gastric volume was linearly correlated to increased gastric emptying rate as well as increased GLP-1 response. Overall, cumulative food intake was the strongest correlate to weight loss and was logarithmically related to gastric volume. Regression modeling revealed a nonlinear inverse relation between body weight reduction and gastric volume, confirming that VSG is the only effective long-term weight loss strategy among the experimental operations tested. Conclusions: The data suggest a minimum threshold volume of the residual stomach that is necessary to induce sustained weight loss. Although all gastric volume interventions increased the GLP-1 response, none of the interventions, except VSG, significantly improved glucose tolerance. In conclusion, if weight loss is the primary goal of surgical intervention, significant volume reduction is required, and this most likely requires excising gastric tissue.

Elevated levels of branched-chain amino acids (BCAAs) and their metabolites are strongly positively associated with obesity, insulin resistance, and type 2 diabetes. Bariatric surgery is among the best treatments for weight loss and associated morbidities. Clinical studies have reported that bariatric surgery decreases the circulating levels of BCAAs. The objective of this study was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements of sustained weight loss and improved glucose tolerance after vertical sleeve gastrectomy (VSG). We find that, as in humans, circulating BCAAs are significantly lower in VSG rats and mice. To increase circulating BCAAs, we tested mice with either increased dietary intake of BCAAs or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C (Pp2cm). Our results show that a decrease in circulating BCAAs is not necessary for sustained body weight loss and improved glucose tolerance after VSG.

To understand hindbrain pathways involved in the control of food intake, we examined roles for calcitonin receptor (CALCR)-containing neurons in the NTS. Ablation of NTS Calcr abrogated the long-term suppression of food intake, but not aversive responses, by CALCR agonists. Similarly, activating CalcrNTS neurons decreased food intake and body weight but (unlike neighboring CckNTS cells) failed to promote aversion, revealing that CalcrNTS neurons mediate a non-aversive suppression of food intake. While both CalcrNTS and CckNTS neurons decreased feeding via projections to the PBN, CckNTS cells activated aversive CGRPPBN cells while CalcrNTS cells activated distinct non-CGRP PBN cells. Hence, CalcrNTS cells suppress feeding via non-aversive, non-CGRP PBN targets. Additionally, silencing CalcrNTS cells blunted food intake suppression by gut peptides and nutrients, increasing food intake and promoting obesity. Hence, CalcrNTS neurons define a hindbrain system that participates in physiological energy balance and suppresses food intake without activating aversive systems.

Background Animal models of non-alcoholic steatohepatitis (NASH) are important tools in preclinical research and drug discovery. Gubra-Amylin NASH (GAN) diet-induced obese (DIO) mice represent a model of fibrosing NASH. The present study directly assessed the clinical translatability of the model by head-to-head comparison of liver biopsy histological and transcriptome changes in GAN DIO-NASH mouse and human NASH patients. Methods C57Bl/6 J mice were fed chow or the GAN diet rich in saturated fat (40%), fructose (22%) and cholesterol (2%) for ≥38 weeks. Metabolic parameters as well as plasma and liver biomarkers were assessed. Liver biopsy histology and transcriptome signatures were compared to samples from human lean individuals and patients diagnosed with NASH. Results Liver lesions in GAN DIO-NASH mice showed similar morphological characteristics compared to the NASH patient validation set, including macrosteatosis, lobular inflammation, hepatocyte ballooning degeneration and periportal/perisinusoidal fibrosis. Histomorphometric analysis indicated comparable increases in markers of hepatic lipid accumulation, inflammation and collagen deposition in GAN DIO-NASH mice and NASH patient samples. Liver biopsies from GAN DIO-NASH mice and NASH patients showed comparable dynamics in several gene expression pathways involved in NASH pathogenesis. Consistent with the clinical features of NASH, GAN DIO-NASH mice demonstrated key components of the metabolic syndrome, including obesity and impaired glucose tolerance. Conclusions The GAN DIO-NASH mouse model demonstrates good clinical translatability with respect to the histopathological, transcriptional and metabolic aspects of the human disease, highlighting the suitability of the GAN DIO-NASH mouse model for identifying therapeutic targets and characterizing novel drug therapies for NASH.

Bariatric surgeries are integral to the management of obesity and its metabolic complications. However, these surgeries cause bone loss and increase fracture risk through poorly understood mechanisms. In a mouse model, vertical sleeve gastrectomy (VSG) caused trabecular and cortical bone loss that was independent of sex, body weight, and diet, and this loss was characterized by impaired osteoid mineralization and bone formation. VSG had a profound effect on the bone marrow niche, with rapid loss of marrow adipose tissue, and expansion of myeloid cellularity, leading to increased circulating neutrophils. Following VSG, circulating granulocyte-colony stimulating factor (G-CSF) was increased in mice, and was transiently elevated in a longitudinal study of humans. Elevation of G-CSF was found to recapitulate many effects of VSG on bone and the marrow niche. In addition to stimulatory effects of G-CSF on myelopoiesis, endogenous G-CSF suppressed development of marrow adipocytes and hindered accrual of peak cortical and trabecular bone. Effects of VSG on induction of neutrophils and depletion of marrow adiposity were reduced in mice deficient for G-CSF; however, bone mass was not influenced. Although not a primary mechanism for bone loss with VSG, G-CSF plays an intermediary role for effects of VSG on the bone marrow niche.

Bariatric surgeries, such as Roux-en-Y gastric bypass and vertical sleeve gastrectomy, produce significant and durable weight loss in both humans and rodents. Recently, these surgical interventions have also been termed metabolic surgery because they result in profound metabolic improvements that often surpass the expected improvement due to body weight loss alone. In this review we focus on the weight-loss independent effects of bariatric surgery, which encompass energy expenditure and macronutrient preference, the luminal composition of the gut (i.e., the microbiota and bile acids), the transformation of the gastrointestinal lining, increases in postprandial gut hormone secretions, glycemic control, pancreas morphology, and micronutrient and mineral absorption. Taken together, these data point to several important physiological changes that contribute to the profound benefits of these surgical procedures. Identifying the underlying molecular mechanisms for these physiological effects will allow better utilization of these existing procedures to help patients and develop new treatments that harness these surgical effects with less invasive interventions.

Olanzapine, an antipsychotic agent mainly used for treating schizophrenia, is frequently associated with body weight gain and diabetes mellitus. Nonetheless, studies have shown that not every individual is equally susceptible to olanzapine’s weight-gaining effect. Therefore, Roman high and low avoidance rat strains were examined on their responsiveness to olanzapine treatment. The Roman high avoidance rat shares many behavioral and physiological characteristics with human schizophrenia, such as increased central dopaminergic sensitivity, whereas the Roman low avoidance rat has been shown to be prone to diet-induced obesity and insulin resistance. The data revealed that only the Roman high avoidance rats are susceptible to olanzapine-induced weight gain and attenuated glucose tolerance. Here it is suggested that the specific olanzapine-induced weight gain in Roman high avoidance rats could be related to augmented dopaminergic sensitivity at baseline through increased expression of prefrontal cortex dopamine receptor D1 mRNA and nucleus accumbens dopamine receptor D2 mRNA expression. Regression analyses revealed that olanzapine-induced weight gain in the Roman high avoidance rat is above all related to increased prolactin levels, whereas changes in glucose homeostasis is best explained by differences in central dopaminergic receptor expressions between strains and treatment. Our data indicates that individual differences in dopaminergic receptor expression in the cortico-mesolimbic system are related to susceptibility to olanzapine-induced weight gain.

Background: One-anastomosis gastric bypass (OAGB) and single-anastomosis duodenal switch (SADS) have become increasingly popular weight loss strategies. However, data directly comparing the effectiveness of these procedures with Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (SG) are limited. Objectives: To examine the metabolic outcomes of OAGB, SADS, RYGB, and SG in a controlled rodent model. Setting: Academic research laboratory, United States. Methods: Surgeries were performed in diet-induced obese Long-Evans rats, and metabolic outcomes were monitored before and for 15 weeks after surgery. Results: All bariatric procedures induced weight loss compared with sham that lasted throughout the course of the study. The highest percent fat loss occurred after OAGB and RYGB. All bariatric procedures had improved glucose dynamics associated with an increase in insulin (notably OAGB and SADS) and/or glucagon-like protein-1 secretion. Circulating cholesterol was reduced in OAGB, SG, and RYGB. OAGB and SG additionally decreased circulating triglycerides. Liver triglycerides were most profoundly reduced after OAGB and RYGB. Circulating iron levels were decreased in all surgical groups, associated with a decreased hematocrit value and increased reticulocyte count. The fecal microbiome communities of OAGB, SADS, and RYGB were significantly altered; however, SG exhibited no change in microbiome diversity or composition. Conclusions: These data support the use of the rat for modeling bariatric surgical procedures and highlight the ability of the OAGB to meet or exceed the metabolic improvements of RYGB. These data point to the likelihood that each surgery accomplishes metabolic improvements through both overlapping and distinct mechanisms and warrants further research. (C) 2018 American Society for Bariatric Surgery. Published by Elsevier Inc.

Second generation antipsychotics, like olanzapine (OLZ), have become the first line drug treatment for patients with schizophrenia. However, OLZ treatment is often associated with body weight (BW) gain and metabolic derangements. Therefore, the search for prospective markers for OLZ's negative side effects as well as adjunctive treatments to inhibit these has been of major interest.The aim of this study was to investigate in healthy male volunteers (age: 36 +/- 11 years; BW: 841 +/- 12 kg; BMI = 25.5 +/- 2.5) whether adjunctive topiramate (TPM) administration opposes OLZ-induced weight gain over the course of 14 days treatment. In addition, we investigated behavioral, endocrine and metabolic characteristics as underlying and potentially predictive factors for weight regulation and/or metabolic derangements associated with OLZ and TPM treatment.While adjunctive TPM indeed reduced OLZ-induced weight gain (P < 0.05, Mann-Whitney U), behavioral/metabolic/endocrine characteristics of OLZ treatment were not affected by TPM. Using multiple regression analysis, BW gain was the key factor explaining metabolic disturbances (e.g., plasma insulin LDL interaction: P < 0.01, R-2 = .320), and cumulative food intake during treatment was the best denominator of BW gain (P < 0.01, R-2 = .534). Neither TPM treatment, nor its circulating levels, contributed to variation observed in Delta BW. In a second multiple regression analysis, we observed that a low baseline thyrotropin profile (TSHAUC) before the start of drug treatment was associated with an increase in Delta BW over the course of drug treatment (P < 0.05, R-2 = .195). Adding TSHAUC as covariate revealed that adjunctive TPM treatment did attenuate OLZ induced BW gain (P < 0.05, ANCOVA). Further exploration of the circulating thyroid hormones revealed that individuals with a low plasma TSH profile were also those that were most sensitive to adjunctive TPM treatment blocking OLZ-induced Delta BW gain. Others have shown that OLZ-induced BW gain is associated with improvement in brief psychiatric rating scores (BPRS); adjunctive TPM treatment may be a solution specifically for those subjects susceptible to OLZ-induced rapid weight gain who on a therapeutic level benefit most of OLZ treatment. (C) 2015 Elsevier Ltd. All rights reserved.

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Zusammenfassung Dieser Artikel stellt die gegenwartige Entwicklung der Krankenhausseelsorge im Kontext des Wandelns des Gesundheitssystems in den Niederlanden dar. Er stellt heraus, welche Bedeutung der Verband der Seelsorger und Seelsorgerinnen im Gesundheitswesen VGVZ fur die Qualitatssicherung hat.

Second generation antipsychotics such as Olanzapine (OLZ) are characterized by undesirable side effects, such as substantial weight gain and insulin resistance.