Publications by authors named "Mohammed Hankir"

43 Publications

Leptin Receptors Are Not Required for Roux-en-Y Gastric Bypass Surgery to Normalize Energy and Glucose Homeostasis in Rats.

Nutrients 2021 May 4;13(5). Epub 2021 May 4.

Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Wuerzburg, 97080 Wuerzburg, Germany.

Sensitization to the adipokine leptin is a promising therapeutic strategy against obesity and its comorbidities and has been proposed to contribute to the lasting metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We formally tested this idea using Zucker fatty rats as an established genetic model of obesity, glucose intolerance, and fatty liver due to leptin receptor deficiency. We show that the changes in body weight in these rats following RYGB largely overlaps with that of diet-induced obese Wistar rats with intact leptin receptors. Further, food intake and oral glucose tolerance were normalized in RYGB-treated Zucker fatty rats to the levels of lean Zucker fatty controls, in association with increased glucagon-like peptide 1 (GLP-1) and insulin release. In contrast, while fatty liver was also normalized in RYGB-treated Zucker fatty rats, their circulating levels of the liver enzyme alanine aminotransferase (ALT) remained elevated at the level of obese Zucker fatty controls. These findings suggest that the leptin system is not required for the normalization of energy and glucose homeostasis associated with RYGB, but that its potential contribution to the improvements in liver health postoperatively merits further investigation.
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http://dx.doi.org/10.3390/nu13051544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147759PMC
May 2021

Protein Kinase D2 drives chylomicron-mediated lipid transport in the intestine and promotes obesity.

EMBO Mol Med 2021 May 5;13(5):e13548. Epub 2021 May 5.

Rudolf-Virchow-Zentrum, Center for Integrative and Translational Bioimaging, University of Würzburg, Würzburg, Germany.

Lipids are the most energy-dense components of the diet, and their overconsumption promotes obesity and diabetes. Dietary fat content has been linked to the lipid processing activity by the intestine and its overall capacity to absorb triglycerides (TG). However, the signaling cascades driving intestinal lipid absorption in response to elevated dietary fat are largely unknown. Here, we describe an unexpected role of the protein kinase D2 (PKD2) in lipid homeostasis. We demonstrate that PKD2 activity promotes chylomicron-mediated TG transfer in enterocytes. PKD2 increases chylomicron size to enhance the TG secretion on the basolateral side of the mouse and human enterocytes, which is associated with decreased abundance of APOA4. PKD2 activation in intestine also correlates positively with circulating TG in obese human patients. Importantly, deletion, inactivation, or inhibition of PKD2 ameliorates high-fat diet-induced obesity and diabetes and improves gut microbiota profile in mice. Taken together, our findings suggest that PKD2 represents a key signaling node promoting dietary fat absorption and may serve as an attractive target for the treatment of obesity.
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http://dx.doi.org/10.15252/emmm.202013548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103097PMC
May 2021

Leaky Gut as a Potential Culprit for the Paradoxical Dysglycemic Response to Gastric Bypass-Associated Ileal Microbiota.

Metabolites 2021 Mar 8;11(3). Epub 2021 Mar 8.

Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Blegdamsvej 3B, 2200 København, Denmark.

Altered host-intestinal microbiota interactions are increasingly implicated in the metabolic benefits of Roux-en-Y gastric bypass (RYGB) surgery. We previously found, however, that RYGB-associated ileal microbiota can paradoxically impair host glycemic control when transferred to germ-free mice. Here we present complementary evidence suggesting that this could be due to the heightened development of systemic endotoxemia. Consistently, application of ileal content from RYGB-treated compared with sham-operated rats onto Caco-2 cell monolayers compromised barrier function and decreased expression of the barrier-stabilizing proteins claudin-4 and desmoglein-2. Our findings raise the possibility that RYGB-associated ileal microbiota produce and release soluble metabolites which locally increase intestinal permeability to promote systemic endotoxemia-induced insulin resistance, with potential implications for the treatment of RYGB patients who eventually relapse onto type 2 diabetes.
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http://dx.doi.org/10.3390/metabo11030153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998592PMC
March 2021

Roux-en-Y gastric bypass contributes to weight loss-independent improvement in hypothalamic inflammation and leptin sensitivity through gut-microglia-neuron-crosstalk.

Mol Metab 2021 Jun 16;48:101214. Epub 2021 Mar 16.

Medical Department III, Endocrinology, Nephrology, and Rheumatology, University Hospital of Leipzig, Leipzig, Germany; Division of Endocrinology, Diabetes, and Metabolism, Medical Department I, University Hospital of Bonn, Bonn, Germany. Electronic address:

Objective: Hypothalamic inflammation and endoplasmic reticulum (ER) stress are extensively linked to leptin resistance and overnutrition-related diseases. Surgical intervention remains the most efficient long-term weight-loss strategy for morbid obesity, but mechanisms underlying sustained feeding suppression remain largely elusive. This study investigated whether Roux-en-Y gastric bypass (RYGB) interacts with obesity-associated hypothalamic inflammation to restore central leptin signaling as a mechanistic account for post-operative appetite suppression.

Methods: RYGB or sham surgery was performed in high-fat diet-induced obese Wistar rats. Sham-operated rats were fed ad libitum or by weight matching to RYGB via calorie restriction (CR) before hypothalamic leptin signaling, microglia reactivity, and the inflammatory pathways were examined to be under the control of gut microbiota-derived circulating signaling.

Results: RYGB, other than CR-induced adiposity reduction, ameliorates hypothalamic gliosis, inflammatory signaling, and ER stress, which are linked to enhanced hypothalamic leptin signaling and responsiveness. Mechanistically, we demonstrate that RYGB interferes with hypothalamic ER stress and toll-like receptor 4 (TLR4) signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the altered gut microbial environment upon RYGB surgery.

Conclusions: Our data demonstrate that RYGB interferes with hypothalamic TLR4 signaling to restore the anorexigenic action of leptin, which most likely results from modulation of a circulating factor derived from the post-surgical altered gut microbial environment.
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http://dx.doi.org/10.1016/j.molmet.2021.101214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095174PMC
June 2021

Roux-en-Y gastric bypass surgery in Zucker rats induces bacterial and systemic metabolic changes independent of caloric restriction-induced weight loss.

Gut Microbes 2021 Jan-Dec;13(1):1-20

Department of Metabolism Digestion and Reproduction, Faculty of Medicine, Imperial College London London, UK.

Mechanisms of Roux-en-Y gastric bypass (RYGB) surgery are not fully understood. This study aimed to investigate weight loss-independent bacterial and metabolic changes, as well as the absorption of bacterial metabolites and bile acids through the hepatic portal system following RYGB surgery. Three groups of obese Zucker () rats were included: RYGB (n = 11), sham surgery and body weight matched with RYGB (Sham-BWM, n = 5), and sham surgery fed (Sham-obese, n = 5). Urine and feces were collected at multiple time points, with portal vein and peripheral blood obtained at the end of the study. Metabolic phenotyping approaches and 16S rRNA gene sequencing were used to determine the biochemical and bacterial composition of the samples, respectively. RYGB surgery-induced distinct metabolic and bacterial disturbances, which were independent of weight loss through caloric restriction. RYGB resulted in lower absorption of phenylalanine and choline, and higher urinary concentrations of host-bacterial co-metabolites (e.g., phenylacetylglycine, indoxyl sulfate), together with higher fecal trimethylamine, suggesting enhanced bacterial aromatic amino acid and choline metabolism. Short chain fatty acids (SCFAs) were lower in feces and portal vein blood from RYGB group compared to Sham-BWM, accompanied with lower abundances of , and known to contain SCFA producers, indicating reduced bacterial fiber fermentation. Fecal γ-amino butyric acid (GABA) was found in higher concentrations in RYGB than that in Sham groups and could play a role in the metabolic benefits associated with RYGB surgery. While no significant difference in urinary BA excretion, RYGB lowered both portal vein and circulating BA compared to Sham groups. These findings provide a valuable resource for how dynamic, multi-systems changes impact on overall metabolic health, and may provide potential therapeutic targets for developing downstream non-surgical treatment for metabolic disease.
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http://dx.doi.org/10.1080/19490976.2021.1875108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872092PMC
February 2021

A sympathetic gut connection drives the metabolic benefits of Roux-en-Y gastric bypass.

Cell Stress 2020 Nov 24;4(12):265-269. Epub 2020 Nov 24.

Department of Experimental Surgery, University Hospital Wuerzburg, Wuerzburg, 97080, Germany.

Surgery is regarded by many as the go-to treatment option for severe obesity; yet how physically altering the gastrointestinal tract produces such striking results on body weight and overall metabolic health is poorly understood. In a recent issue of Ye (2020) compare mouse models of Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), the two most commonly performed weight loss surgeries in the clinic today, to show that the former reconfiguring procedure selectively increases resting metabolic rate through splanchnic nerve-mediated browning of mesenteric white fat. More significantly, they demonstrate that this effect for RYGB is required for the maintained negative energy balance and improved glycemic control that it confers.
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http://dx.doi.org/10.15698/cst2020.12.236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713265PMC
November 2020

Simulating the Post-gastric Bypass Intestinal Microenvironment Uncovers a Barrier-Stabilizing Role for FXR.

iScience 2020 Dec 5;23(12):101777. Epub 2020 Nov 5.

Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Center of Operative Medicine, Oberduerrbacherstrasse 6, Wuerzburg, Bavaria 97080, Germany.

Regional changes to the intestinal microenvironment brought about by Roux-en-Y gastric bypass (RYGB) surgery may contribute to some of its potent systemic metabolic benefits through favorably regulating various local cellular processes. Here, we show that the intestinal contents of RYGB-operated compared with sham-operated rats region-dependently confer superior glycemic control to recipient germ-free mice in association with suppression of endotoxemia. Correspondingly, they had direct barrier-stabilizing effects on an intestinal epithelial cell line which, bile-exposed intestinal contents, were partly farnesoid X receptor (FXR)-dependent. Further, circulating fibroblast growth factor 19 levels, a readout of intestinal FXR activation, negatively correlated with endotoxemia severity in longitudinal cohort of RYGB patients. These findings suggest that various host- and/or microbiota-derived luminal factors region-specifically and synergistically stabilize the intestinal epithelial barrier following RYGB through FXR signaling, which could potentially be leveraged to better treat endotoxemia-induced insulin resistance in obesity in a non-invasive and more targeted manner.
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http://dx.doi.org/10.1016/j.isci.2020.101777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689555PMC
December 2020

Higher HbA1c levels associate with lower hippocampal serotonin transporter availability in non-diabetic adults with obesity.

Sci Rep 2020 12 7;10(1):21383. Epub 2020 Dec 7.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

The current study aimed to investigate whether the in vivo availability of central serotonin reuptake transporters (5-HTT) is associated with plasma levels of glycosylated hemoglobin (HbA1c) in non-diabetic humans with obesity. 5-HTT availability was measured by using positron emission tomography (PET) imaging with the 5-HTT selective radiotracer [C]DASB in 23 non-diabetic individuals with obesity and 14 healthy, non-obesity controls. Parametric images of binding potential BP were generated from the PET data and analyzed together with HbA1c levels by using volume of interest analysis for brain areas relevant to appetite control. Voxel-based morphometry (VBM) of individual magnetic resonance imaging data was further performed to correlate grey matter density (GMD) maps with HbA1c. We found significant negative correlations between HbA1c levels and BP in right and left hippocampus in obesity (r = - 0.717, p < 0.001, and r = - 0.557, p = 0.006, respectively). VBM analyses revealed that higher HbA1c levels were associated with GMD in the right para-hippocampal area. Our results indicate that chronically high blood glucose levels may evoke changes in hippocampal 5-HTT levels that are in part tied to local microstructure.
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http://dx.doi.org/10.1038/s41598-020-78227-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7721891PMC
December 2020

Author response to: Comment on: Abdominal fluid samples (negative for SARS-CoV-2) from a critically unwell patient with respiratory COVID-19.

Br J Surg 2020 11 19;107(12):e624. Epub 2020 Sep 19.

Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Oberduerrbacher Str. 6, 97080, Wuerzburg, Germany.

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http://dx.doi.org/10.1002/bjs.11898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7537022PMC
November 2020

Validation of MTL30 as a quality indicator for colorectal surgery.

PLoS One 2020 28;15(8):e0238473. Epub 2020 Aug 28.

Department of General, Visceral, Transplantation, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany.

Background: Valid indicators are required to measure surgical quality. These ideally should be sensitive and selective while being easy to understand and adjust. We propose here the MTL30 quality indicator which takes into account 30-day mortality, transfer within 30 days, and a length of stay of 30 days as composite markers of an uneventful operative/postoperative course.

Methods: Patients documented in the StuDoQ|Colon and StuDoQ|Rectal carcinoma register of the German Society for General and Visceral Surgery (DGAV) were analyzed with regard to the effects of patient and tumor-related risk factors as well as postoperative complications on the MTL30.

Results: In univariate analysis, the MTL30 correlated significantly with patient and tumor-related risk factors such as ASA score (p<0.001), age (p<0.001), or UICC stage (p<0.001). There was a high sensitivity for the postoperative occurrence of complications such as re-operations (p<0.001) or subsequent bleeding (p<0.001), as well as a significant correlation with the CDC classification (p<0.001). In multivariate analysis, patient-related risk factors and postoperative complications significantly increased the odds ratio for a positive MTL30. A negative MTL30 showed a high specify for an uneventful operative and postoperative course.

Conclusion: The MTL30 is a valid indicator of colorectal surgical quality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238473PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7454590PMC
October 2020

Psychophysical tests reveal impaired olfaction but preserved gustation in COVID-19 patients.

Int Forum Allergy Rhinol 2020 09 21;10(9):1105-1107. Epub 2020 Jul 21.

Department of Otorhinolaryngology, Regensburg University Hospital, Regensburg, Germany.

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http://dx.doi.org/10.1002/alr.22655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362102PMC
September 2020

Do Bariatric Surgeries Enhance Brown/Beige Adipose Tissue Thermogenesis?

Front Endocrinol (Lausanne) 2020 30;11:275. Epub 2020 Apr 30.

Department of General, Visceral, Vascular and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg, Germany.

Bariatric surgeries induce marked and durable weight loss in individuals with morbid obesity through powerful effects on both food intake and energy expenditure. While alterations in gut-brain communication are increasingly implicated in the improved eating behavior following bariatric surgeries, less is known about the mechanistic basis for energy expenditure changes. Brown adipose tissue (BAT) and beige adipose tissue (BeAT) have emerged as major regulators of whole-body energy metabolism in humans as well as in rodents due to their ability to convert the chemical energy in circulating glucose and fatty acids into heat. In this Review, we critically discuss the steadily growing evidence from preclinical and clinical studies suggesting that Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), the two most commonly performed bariatric surgeries, enhance BAT/BeAT thermogenesis. We address the documented mechanisms, highlight study limitations and finish by outlining unanswered questions in the subject. Further understanding how and to what extent bariatric surgeries enhance BAT/BeAT thermogenesis may not only aid in the development of improved obesity pharmacotherapies that safely and optimally target both sides of the energy balance equation, but also in the development of novel hyperglycemia and/or hyperlipidemia pharmacotherapies.
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http://dx.doi.org/10.3389/fendo.2020.00275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7203442PMC
May 2021

Partial Leptin Reduction: An Emerging Weight Loss Paradigm.

Trends Endocrinol Metab 2020 06 26;31(6):395-397. Epub 2020 Mar 26.

Department of General, Visceral, Transplant, Vascular, and Pediatric Surgery, University Hospital Wuerzburg, Wuerzburg 97080, Bavaria, Germany.

Leptin-based obesity pharmacotherapies were originally developed according to the lipostatic view that elevated circulating leptin levels promote a negative energy balance. A series of independent preclinical findings suggest, however, that a partial reduction in circulating leptin levels (either by immunoneutralization, a peripherally restricted CB1 receptor inverse agonist, or bariatric surgery) can paradoxically lead to weight loss.
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http://dx.doi.org/10.1016/j.tem.2020.03.001DOI Listing
June 2020

Gastric bypass surgery in a rat model alters the community structure and functional composition of the intestinal microbiota independently of weight loss.

Microbiome 2020 02 7;8(1):13. Epub 2020 Feb 7.

Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research-UFZ, Leipzig, Germany.

Background: Roux-en-Y gastric bypass (RYGB) surgery is a last-resort treatment to induce substantial and sustained weight loss in cases of severe obesity. This anatomical rearrangement affects the intestinal microbiota, but so far, little information is available on how it interferes with microbial functionality and microbial-host interactions independently of weight loss.

Methods: A rat model was employed where the RYGB-surgery cohort is compared to sham-operated controls which were kept at a matched body weight by food restriction. We investigated the microbial taxonomy and functional activity using 16S rRNA amplicon gene sequencing, metaproteomics, and metabolomics on samples collected from theileum, the cecum, and the colon, and separately analysed the lumen and mucus-associated microbiota.

Results: Altered gut architecture in RYGB increased the relative occurrence of Actinobacteria, especially Bifidobacteriaceae and Proteobacteria, while in general, Firmicutes were decreased although Streptococcaceae and Clostridium perfringens were observed at relative higher abundances independent of weight loss. A decrease of conjugated and secondary bile acids was observed in the RYGB-gut lumen. The arginine biosynthesis pathway in the microbiota was altered, as indicated by the changes in the abundance of upstream metabolites and enzymes, resulting in lower levels of arginine and higher levels of aspartate in the colon after RYGB.

Conclusion: The anatomical rearrangement in RYGB affects microbiota composition and functionality as well as changes in amino acid and bile acid metabolism independently of weight loss. The shift in the taxonomic structure of the microbiota after RYGB may be mediated by the resulting change in the composition of the bile acid pool in the gut and by changes in the composition of nutrients in the gut. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-0788-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007695PMC
February 2020

GLP-1 and PYY reduce high-fat food preference additively after Roux-en-Y gastric bypass in diet-induced obese rats.

Surg Obes Relat Dis 2019 09 16;15(9):1483-1492. Epub 2019 Apr 16.

Department of Experimental Surgery, University Hospital Würzburg, Würzburg, Germany. Electronic address:

Background: Roux-en-Y gastric bypass (RYGB) modifies various aspects of eating behavior in morbidly obese individuals to cause marked and lasting weight loss and improvements in metabolic health, but the underlying mechanisms remain poorly understood.

Objectives: To assess the relative contributions of the gut hormones glucagon-like peptide 1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY), whose circulating levels are enhanced by RYGB, in the reduced high-fat (HF) food preference that develops postoperatively.

Setting: University hospital, Würzburg, Germany.

Methods: HF diet-induced obese male Wistar rats underwent RYGB (n = 11) or sham (n = 7) surgeries and were subsequently maintained on a choice of low-fat (10% calories from fat) and HF (60% calories from fat) diets. From postoperative weeks 4 to 6, acute feeding studies were performed in which the selective GLP-1 receptor antagonist exendin-9 (30 μg/kg), the second-generation selective Y2 receptor antagonist JNJ-31020028 (10 mg/kg), or a combination of both drugs was administered intraperitoneally.

Results: During the observational period weight, adiposity and total food intake were lower while postprandial plasma GLP-1 and peptide tyrosine tyrosine levels were higher for RYGB-operated compared with sham-operated rats. There was a gradual shift in preference from HF to low-fat food in RYGB-operated rats by postoperative week 3. Single antagonist treatments had a relatively modest impact on HF food preference in rats from both surgical groups. However, dual antagonist treatment caused a striking increase in HF food preference specifically in RYGB-operated rats.

Conclusions: GLP-1 and peptide tyrosine tyrosine 3-36 reduce HF food preference additively after RYGB supporting the use of gut hormone combination strategies for healthier feeding behavior.
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http://dx.doi.org/10.1016/j.soard.2019.04.008DOI Listing
September 2019

Adiposity Related Brain Plasticity Induced by Bariatric Surgery.

Front Hum Neurosci 2019 27;13:290. Epub 2019 Aug 27.

IFB Adiposity Diseases, Leipzig University Medical Centre, Leipzig, Germany.

Previous magnetic resonance imaging (MRI) studies revealed structural-functional brain reorganization 12 months after gastric-bypass surgery, encompassing cortical and subcortical regions of all brain lobes as well as the cerebellum. Changes in the mean of cluster-wise gray/white matter density (GMD/WMD) were correlated with the individual loss of body mass index (BMI), rendering the BMI a potential marker of widespread surgery-induced brain plasticity. Here, we investigated voxel-by-voxel associations between surgery-induced changes in adiposity, metabolism and inflammation and markers of functional and structural neural plasticity. We re-visited the data of patients who underwent functional and structural MRI, 6 months ( = 27) and 12 months after surgery ( = 22), and computed voxel-wise regression analyses. Only the surgery-induced weight loss was significantly associated with brain plasticity, and this only for GMD changes. After 6 months, weight loss overlapped with altered GMD in the hypothalamus, the brain's homeostatic control site, the lateral orbitofrontal cortex, assumed to host reward and gustatory processes, as well as abdominal representations in somatosensory cortex. After 12 months, weight loss scaled with GMD changes in right cerebellar lobule VII, involved in language-related/cognitive processes, and, by trend, with the striatum, assumed to underpin (food) reward. These findings suggest time-dependent and weight-loss related gray matter plasticity in brain regions involved in the control of eating, sensory processing and cognitive functioning.
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http://dx.doi.org/10.3389/fnhum.2019.00290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718731PMC
August 2019

Homeostatic, reward and executive brain functions after gastric bypass surgery.

Appetite 2020 03 28;146:104419. Epub 2019 Aug 28.

Department of Neurology, BG University Hospital Bergmannsheil, Ruhr-University Bochum, Bochum, Bochum, 44789, North Rhine-Westphalia, Germany; Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, 04103, Saxony, Germany; IFB Adiposity Diseases, University Hospital Leipzig, Leipzig, 04103, Saxony, Germany.

Obesity in part arises from the regular overconsumption of palatable, caloric-dense foods. This maladaptive eating behavior has been described as impulsive, compulsive and even addictive, and has its origins in molecular and cellular aberrations in the gut and brain. Mounting evidence from human and rodent studies suggests that Roux-en-Y gastric bypass (RYGB) surgery persistantly promotes lower caloric intake by modifying gut-brain communication. In this Review, we discuss how the changes in gut hormones, nutrient sensing andmicrobiota brought about by RYGB together favourably regulate homeostatic, reward and executive brain functions. We further speculate on how this lastingly establishes a negative whole-body energy balance in the face of plenty. Future studies will more completely characterize the role of modified gut-brain communication in the healthier eating behavior following RYGB, possibly facilitating the development of more effective, non-surgical weight loss treatments.
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http://dx.doi.org/10.1016/j.appet.2019.104419DOI Listing
March 2020

Roux-en-Y gastric bypass surgery progressively alters radiologic measures of hypothalamic inflammation in obese patients.

JCI Insight 2019 10 3;4(19). Epub 2019 Oct 3.

IFB AdiposityDiseases and.

There is increased interest in whether bariatric surgeries such as Roux-en-Y gastric bypass (RYGB) achieve their profound weight-lowering effects in morbidly obese individuals through the brain. Hypothalamic inflammation is a well-recognized etiologic factor in obesity pathogenesis and so represents a potential target of RYGB, but clinical evidence in support of this is limited. We therefore assessed hypothalamic T2-weighted signal intensities (T2W SI) and fractional anisotropy (FA) values, 2 validated radiologic measures of brain inflammation, in relation to BMI and fat mass, as well as circulating inflammatory (C-reactive protein; CrP) and metabolic markers in a cohort of 27 RYGB patients at baseline and 6 and 12 months after surgery. We found that RYGB progressively increased hypothalamic T2W SI values, while it progressively decreased hypothalamic FA values. Regression analyses further revealed that this could be most strongly linked to plasma CrP levels, which independently predicted hypothalamic FA values when adjusting for age, sex, fat mass, and diabetes diagnosis. These findings suggest that RYGB has a major time-dependent impact on hypothalamic inflammation status, possibly by attenuating peripheral inflammation. They also suggest that hypothalamic FA values may provide a more specific radiologic measure of hypothalamic inflammation than more commonly used T2W SI values.
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http://dx.doi.org/10.1172/jci.insight.131329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795400PMC
October 2019

Could de-stressing the brain be the solution for long-term weight loss?

Cell Stress 2019 Jan 25;3(2):29-37. Epub 2019 Jan 25.

Department of Experimental Surgery, University Hospital Wuerzburg, Wuerzburg, 97080 Bavaria, Germany.

The obese brain is stressed and inflamed. This is mainly at the level of neurons and glial cells in the hypothalamus: a brain region where the adipokine leptin acts to control feeding and body weight. Relieving hypothalamic neuronal endoplasmic reticulum (ER) stress with the natural small molecule drugs celastrol or withaferin-A reverses the leptin resistance commensurate with obesity, producing a degree of weight loss found only with bariatric surgery. Here, recent evidence from rodent models of vertical sleeve gastrectomy (VSG) is brought to the fore which suggests that this particular bariatric surgical procedure may work in a similar fashion to celastrol and withaferin-A alongside remedying hypothalamic inflammation and gliosis. Thus, restoring and preserving healthy hypothalamic neuronal and glial cell function, be it by pharmacological or surgical means, ensures a negative energy balance in an environment constructed to promote a one - possibly through re-establishing communication between adipose tissue and the brain.
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http://dx.doi.org/10.15698/cst2019.02.174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551711PMC
January 2019

Brown adipocyte glucose metabolism: a heated subject.

EMBO Rep 2018 09 22;19(9). Epub 2018 Aug 22.

Chair of Molecular Nutritional Medicine, TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany

The energy expending and glucose sink properties of brown adipose tissue (BAT) make it an attractive target for new obesity and diabetes treatments. Despite decades of research, only recently have mechanistic studies started to provide a more complete and consistent picture of how activated brown adipocytes handle glucose. Here, we discuss the importance of intracellular glycolysis, lactate production, lipogenesis, lipolysis, and beta-oxidation for BAT thermogenesis in response to natural (temperature) and artificial (pharmacological and optogenetic) forms of sympathetic nervous system stimulation. It is now clear that together, these metabolic processes in series and in parallel flexibly power ATP-dependent and independent futile cycles in brown adipocytes to impact on whole-body thermal, energy, and glucose balance.
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http://dx.doi.org/10.15252/embr.201846404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6123662PMC
September 2018

Decreased Chromosomal Damage in Lymphocytes of Obese Patients After Bariatric Surgery.

Sci Rep 2018 07 25;8(1):11195. Epub 2018 Jul 25.

Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Bavaria, Germany.

The number of bariatric surgeries being performed worldwide has markedly risen. While the improvement in obesity-associated comorbidities after bariatric surgery is well-established, very little is known about its impact on cancer risk. The peripheral lymphocyte micronucleus test is a widely used method for the monitoring of chromosomal damage levels in vivo, and micronucleus frequency positively correlates with cancer risk. Therefore, the aim of this study was to compare the micronucleus frequency before and after bariatric surgery in obese subjects. Peripheral blood mononuclear cells were collected from 45 obese subjects before and at two time-points after bariatric surgery (6 and 12 months) to assess spontaneous micronucleus frequency. Consistent with the increased cancer risk previously shown, bariatric surgery-induced weight loss led to a significant reduction in lymphocyte micronucleus frequency after 12 months. Interestingly, comorbidities such as type 2 diabetes mellitus and metabolic syndrome further seemed to have an impact on the lymphocyte micronucleus frequency. Our findings may indicate a successful reduction of cancer risk in patients following weight loss caused by bariatric surgery.
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http://dx.doi.org/10.1038/s41598-018-29581-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060147PMC
July 2018

Brain Feeding Circuits after Roux-en-Y Gastric Bypass.

Trends Endocrinol Metab 2018 04 20;29(4):218-237. Epub 2018 Feb 20.

Metabolic Disease and Obesity Program, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia; Department of Physiology, Monash University, Victoria 3800, Australia.

Metabolic surgical procedures, such as Roux-en-Y gastric bypass (RYGB), uniquely reprogram feeding behavior and body weight in obese subjects. Clinical neuroimaging and animal studies are only now beginning to shed light on some of the underlying central mechanisms. We present here the roles of key brain neurotransmitter/neuromodulator systems in food choice, value, and intake at various stages after RYGB. In doing so, we elaborate on how known signals emanating from the reorganized gut, including peptide hormones and microbiota products, impinge on newly mapped homeostatic and hedonic brain feeding circuits. Continued progress in the rapidly evolving field of metabolic surgery will inform the design of more effective weight-loss compounds.
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http://dx.doi.org/10.1016/j.tem.2018.01.009DOI Listing
April 2018

Loading and firing the brown adipocyte.

Adipocyte 2018 01 22;7(1):4-11. Epub 2017 Dec 22.

a Department of Experimental Surgery , University Hospital Wuerzburg , Wuerzburg , Bavaria , Germany.

Brown adipose tissue (BAT) is specialized to both store and expend chemical energy making it an ideal therapeutic target for various metabolic diseases. Fatty acids derived from lipid droplets within brown adipocytes acting on mitochondrial uncoupling protein 1 (UCP1) were long thought to be essential for non-shivering thermogenesis. Here, the roles of white adipose tissue and the liver in the provision of fuel to BAT as part of a coordinated response to temperature and dietary challenges are described. UCP1-independent modes of brown adipocyte heat production are also highlighted. A model that accommodates the findings obtained so far is further presented in which according to the conditions imposed on brown adipocytes, the relative contributions of circulating lipids and glucose for their normal function varies. Gaining deeper insight into the molecular processes which poise brown adipocytes to protect against whole-body thermal and energy imbalance represents a promising future area of metabolic research.
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http://dx.doi.org/10.1080/21623945.2017.1405879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5915016PMC
January 2018

The association between in vivo central noradrenaline transporter availability and trait impulsivity.

Psychiatry Res Neuroimaging 2017 Sep 23;267:9-14. Epub 2017 Jun 23.

Integrated Treatment and Research Centre (IFB) AdiposityDiseases, Leipzig University Medical Centre, Liebigstraße 20, 04103 Leipzig, Germany; Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.

The brain noradrenaline (NA) system, particularly NA transporters (NAT), are thought to play an important role in modulating impulsive behavior. Impaired impulsivity is implicated in a variety of neuropsychiatric conditions; however, an in vivo link between central NAT availability and human impulsivity has not been shown. Using positron emission tomography (PET) and S,S-[C]O-methylreboxetine (MRB), we tested whether NAT availability is associated with this basic behavioral trait based on the Barratt Impulsiveness Scale (BIS-11) in twenty healthy individuals (12 females, 33.8±9.3, 21-52 years of age) with a body mass index (BMI) ranging from 21.7kg/m to 47.8kg/m. Applying both voxel-wise and volume-of-interest (VOI) based analyses, we found that distribution volume ratios (DVR) used as PET outcome measures negatively correlated with BIS-11 total scores in the orbitofrontal cortex (OFC) and in the hippocampus as well as in parts of the cerebellar cortex. These associations however did not remain after correction for multiple testing. Thus, although it appears that low NAT availability is associated with greater scores of impaired behavioral control, this needs to be confirmed in a larger series of individuals with highly impulsive behavior.
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http://dx.doi.org/10.1016/j.pscychresns.2017.06.013DOI Listing
September 2017

Suppressed Fat Appetite after Roux-en-Y Gastric Bypass Surgery Associates with Reduced Brain μ-opioid Receptor Availability in Diet-Induced Obese Male Rats.

Front Neurosci 2016 13;10:620. Epub 2017 Jan 13.

Department of Medicine, Integrated Research and Treatment Centre for Adiposity Diseases, University of Leipzig Leipzig, Germany.

Brain μ-opioid receptors (MORs) stimulate high-fat (HF) feeding and have been implicated in the distinct long term outcomes on body weight of bariatric surgery and dieting. Whether alterations in fat appetite specifically following these disparate weight loss interventions relate to changes in brain MOR signaling is unknown. To address this issue, diet-induced obese male rats underwent either Roux-en-Y gastric bypass (RYGB) or sham surgeries. Postoperatively, animals were placed on a two-choice diet consisting of low-fat (LF) and HF food and sham-operated rats were further split into fed (Sham-LF/HF) and body weight-matched (Sham-BWM) to RYGB groups. An additional set of sham-operated rats always only on a LF diet (Sham-LF) served as lean controls, making four experimental groups in total. Corresponding to a stage of weight loss maintenance for RYGB rats, two-bottle fat preference tests in conjunction with small-animal positron emission tomography (PET) imaging studies with the selective MOR radioligand [C]carfentanil were performed. Brains were subsequently collected and MOR protein levels in the hypothalamus, striatum, prefrontal cortex and orbitofrontal cortex were analyzed by Western Blot. We found that only the RYGB group presented with intervention-specific changes: having markedly suppressed intake and preference for high concentration fat emulsions, a widespread reduction in [C]carfentanil binding potential (reflecting MOR availability) in various brain regions, and a downregulation of striatal and prefrontal MOR protein levels compared to the remaining groups. These findings suggest that the suppressed fat appetite caused by RYGB surgery is due to reduced brain MOR signaling, which may contribute to sustained weight loss unlike the case for dieting.
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http://dx.doi.org/10.3389/fnins.2016.00620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233681PMC
January 2017

Thyroid hormones and browning of adipose tissue.

Mol Cell Endocrinol 2017 Dec 12;458:156-159. Epub 2017 Jan 12.

Department of Endocrinology and Nephrology, University Hospital, Leipzig, Germany. Electronic address:

Thyroid hormone (TH) disorders are associated with profound changes in whole body energy metabolism. A major TH target is thermogenic brown adipose tissue (BAT), which can be stimulated directly through thyroid hormone receptors (TRs) expressed in brown adipocytes and indirectly, through TRs expressed in hypothalamic neurons. White adipose tissue (WAT) adopts BAT characteristics by a diverse range of stimuli in a process referred to as browning. It is now understood that TH also induce WAT browning through peripheral and central mechanisms. In this review, we discuss evidence from animal and human studies that TH disorders are associated with changes in both BAT thermogenesis and WAT browning, thereby influencing body temperature and body weight regulation.
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http://dx.doi.org/10.1016/j.mce.2017.01.011DOI Listing
December 2017

Dissociation Between Brown Adipose Tissue F-FDG Uptake and Thermogenesis in Uncoupling Protein 1-Deficient Mice.

J Nucl Med 2017 07 12;58(7):1100-1103. Epub 2017 Jan 12.

Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, University of Leipzig, Leipzig, Germany

F-FDG PET imaging is routinely used to investigate brown adipose tissue (BAT) thermogenesis, which requires mitochondrial uncoupling protein 1 (UCP1). It remains uncertain, however, whether BAT F-FDG uptake is a reliable surrogate measure of UCP1-mediated heat production. UCP1 knockout (KO) and wild-type (WT) mice housed at thermoneutrality were treated with the selective β3 adrenergic receptor agonist CL 316, 243 and underwent metabolic cage, infrared thermal imaging and F-FDG PET/MRI experiments. Primary brown adipocytes were additionally examined for their bioenergetics by extracellular flux analysis as well as their uptake of 2-deoxy-H-glucose. In response to CL 316, 243 treatments, oxygen consumption, and BAT thermogenesis were diminished in UCP1 KO mice, but BAT F-FDG uptake was fully retained. Isolated UCP1 KO brown adipocytes exhibited defective induction of uncoupled respiration whereas their glycolytic flux and 2-deoxy-H-glucose uptake rates were largely unaffected. Adrenergic stimulation can increase BAT F-FDG uptake independently of UCP1 thermogenic function.
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http://dx.doi.org/10.2967/jnumed.116.186460DOI Listing
July 2017

Central noradrenaline transporter availability in highly obese, non-depressed individuals.

Eur J Nucl Med Mol Imaging 2017 Jun 9;44(6):1056-1064. Epub 2017 Jan 9.

Department of Nuclear Medicine, University of Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.

Purpose: The brain noradrenaline (NA) system plays an important role in the central nervous control of energy balance and is thus implicated in the pathogenesis of obesity. The specific processes modulated by this neurotransmitter which lead to obesity and overeating are still a matter of debate.

Methods: We tested the hypothesis that in vivo NA transporter (NAT) availability is changed in obesity by using positron emission tomography (PET) and S,S-[C]O-methylreboxetine (MRB) in twenty subjects comprising ten highly obese (body mass index BMI > 35 kg/m), metabolically healthy, non-depressed individuals and ten non-obese (BMI < 30 kg/m) healthy controls.

Results: Overall, we found no significant differences in binding potential (BP) values between obese and non-obese individuals in the investigated brain regions, including the NAT-rich thalamus (0.40 ± 0.14 vs. 0.41 ± 0.18; p = 0.84) though additional discriminant analysis correctly identified individual group affiliation based on regional BP in all but one (control) case. Furthermore, inter-regional correlation analyses indicated different BP patterns between both groups but this did not survive testing for multiple comparions.

Conclusions: Our data do not find an overall involvement of NAT changes in human obesity. However, preliminary secondary findings of distinct regional and associative patterns warrant further investigation.
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http://dx.doi.org/10.1007/s00259-016-3590-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5538358PMC
June 2017

Gastric Bypass Surgery Recruits a Gut PPAR-α-Striatal D1R Pathway to Reduce Fat Appetite in Obese Rats.

Cell Metab 2017 02 5;25(2):335-344. Epub 2017 Jan 5.

Integrated Research and Treatment Centre for Adiposity Diseases, Department of Medicine, Universität Leipzig, Liebigstraße 21, 04103 Leipzig, Germany. Electronic address:

Bariatric surgery remains the single most effective long-term treatment modality for morbid obesity, achieved mainly by lowering caloric intake through as yet ill-defined mechanisms. Here we show in rats that Roux-en-Y gastric bypass (RYGB)-like rerouting of ingested fat mobilizes lower small intestine production of the fat-satiety molecule oleoylethanolamide (OEA). This was associated with vagus nerve-driven increases in dorsal striatal dopamine release. We also demonstrate that RYGB upregulates striatal dopamine 1 receptor (D1R) expression specifically under high-fat diet feeding conditions. Mechanistically, interfering with local OEA, vagal, and dorsal striatal D1R signaling negated the beneficial effects of RYGB on fat intake and preferences. These findings delineate a molecular/systems pathway through which bariatric surgery improves feeding behavior and may aid in the development of novel weight loss strategies that similarly modify brain reward circuits compromised in obesity.
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http://dx.doi.org/10.1016/j.cmet.2016.12.006DOI Listing
February 2017

Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice.

Sci Rep 2016 12 12;6:38124. Epub 2016 Dec 12.

Department of Endocrinology and Nephrology, University Hospital, Leipzig, Germany.

The present study aimed to determine the effect of thyroid hormone dysfunction on brown adipose tissue activity and white adipose tissue browning in mice. Twenty randomized female C57BL/6NTac mice per treatment group housed at room temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal F-FDG PET/MRI was performed to determine the effects of hypo- and hyperthyroidism on BAT mass and BAT activity. Ex-vivoC-acetate loading assay and assessment of thermogenic gene and protein expression permitted analysis of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and hypothyroid mice. F-FDG PET/MRI revealed a lack of brown adipose tissue activity in hypothyroid mice, whereas hyperthyroid mice displayed increased BAT mass alongside enhanced F-FDG uptake. In white adipose tissue of both, hyper- and hypothyroid mice, we found a significant induction of thermogenic genes together with multilocular adipocytes expressing UCP1. Taken together, these results suggest that both the hyperthyroid and hypothyroid state stimulate WAT thermogenesis most likely as a consequence of enhanced adrenergic signaling or compensation for impaired BAT function, respectively.
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http://dx.doi.org/10.1038/srep38124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5150531PMC
December 2016