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Kisspeptin and gonadotropin-releasing hormone signaling in skeletal muscle
Get PDFChronic inflammation contributes to skeletal muscle atrophy and impaired regenerative capacity. Previous research has identified skeletal muscle inflammatory susceptibility (MuIS), or the ability to manage and respond to inflammation, as a predictor of failed skeletal muscle regeneration and regrowth following surgery. This inflammatory susceptibility is associated with human aging and likely contributes to the adverse structural, metabolic, and functional tissue remodeling that occurs in aged adults. The etiology for heightened inflammation in skeletal muscle is unclear, particularly in healthy young adults. Research that elucidates the mechanisms by which inflammation impairs skeletal muscle regeneration is necessary for identifying potential therapeutic targets. Previous research from our laboratory identified kisspeptin-1 (KISS1) as a highly differentially expressed gene (DEgene) associated with lower inflammatory susceptibility (MuIS-) in human skeletal muscle. When the MuIS- group was compared to a group with an improved hypertrophic response to resistance training, gonadotropin-releasing hormone (GnRH) signaling emerged as a top canonical pathway. In the present study, we aimed to investigate the potential relationship between KISS1/GnRH signaling and inflammation in skeletal muscle and elucidate the relevant signaling pathways. The presence of the GnRH receptor (GnRHr) was assessed in the skeletal muscle of mice genetically modified to constitutively express β-galactosidase at the GnRHr promoter (RG) and wild type (WT) mice using a β-galactosidase gene detection assay. Cell culture experiments using differentiated human muscle progenitor cells (hMPCs) and immortalized mouse skeletal muscle stem cells (C2C12 cells) were performed to determine activation of canonical GnRH signaling (i.e., mitogen-activated protein kinases [MAPKs]), following treatment with Buserelin, a GnRH analog. The National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) datasets were searched for pathological conditions in which KISS1, KISS1 receptor (KISS1r), GnRH, or GnRHr was differentially expressed in skeletal muscle and under inflammatory conditions in other organs. Results were analyzed using the NCBI software GEO2R, which contains R packages from the Bioconductor project. Lastly, the potential relationship between GnRH and inflammatory signaling was assessed using reverse transcription-polymerase chain reaction (RT-PCR) analysis of interleukin 6 (IL-6) following treatment with Buserelin and the inflammatory cytokine tumor necrosis factor alpha (TNF). GnRHr was detected at the protein level in RG but not WT muscle, which validates the presence of GnRHr in skeletal muscle tissue. GnRH signaling may activate extracellular signal-related kinase (ERK) in human skeletal muscle. Additionally, the transcription factor cAMP response element-binding protein (CREB) and Jun N-terminal kinase (JNK) have the capability to respond to Buserelin and Antide treatments in differentiated C2C12 cells. KISS1/GnRH expression was found to be downregulated in several inflammatory myopathies, including juvenile dermomyositis, Duchenne muscular dystrophy, amyotrophic lateral sclerosis, facioscapulohumeral dystrophy, tibial muscular dystrophy, and myotonic dystrophy type 2. GnRH did not impact the acute TNF-mediated increase in IL-6 mRNA levels in skeletal muscle. Our data confirm that GnRHr protein is present and functional in skeletal muscle. Further, our results demonstrate that KISS1/GnRH have a relationship with inflammation that is impacted with inflammatory susceptibility and myopathies with signaling that may occur through the MAPK signaling pathway. Future research should focus on identifying phenotypes associated with a lack of KISS1 or GnRH signaling in skeletal muscle; KISS1/GnRH is a potential therapeutic target to attenuate heightened inflammation in disease states
Chitosan, Skeletal Muscle Regeneration And Fibrosis Inhibition
No full textTreatment of ventral hernias frequently employs use of synthetic and biological meshes, which often results in scar tissue formation and incomplete muscle regeneration, leading to high recurrence rates. A new generation of mesh or scaffold that promotes muscle tissue ingrowth and reduces fibrosis is needed. Chitosan, a co-polymer of N-acetyl glucosamine and N-glucosamine units, has been previously shown to elicit a regenerative response instead of a fibrotic response. In this dissertation, the effects of chitosan on skeletal muscle regeneration, fibrosis formation, and inflammatory response was characterized. The underlying mechanisms were also examined. We found that chitosan coating preferentially promoted murine myoblast adhesion with higher expression of integrin [beta]3 and inhibited murine fibroblast adhesion with reorganization of actin and integrin [beta]1 network. We demonstrated that chitosan may be a promising biomaterial for ventral hernia repair as it reduced mechanisms of fibrosis with increased expression of MMP1 (matrix metalloproteinase 1, a collagenase that also functions as a myokine), reduced expression of vimentin (an intermediate filament that provides mechanical support to cells), and reduced fibroblast adhesion and viability in human fibroblasts, while not affecting human myoblast adhesion and viability in an in-vitro model of acute inflammation. Reduced inflammatory response was observed with chitosan coating on polypropylene meshes at 2 weeks after implantation in a partial thickness defect in rat abdominal wall compared to uncoated polypropylene meshes, with reduced expression of cytokine, TWEAK (tumor necrosis factor-like weak inducer of apoptosis) and its receptor, Fn-14. Chitosan impaired fibroblast adhesion, which was possibly due to reduced expression of integrins, promotion of cell-cell adhesion and reorganization of extracellular matrix and cytoskeletal proteins in human fibroblasts. Human myoblast adhesion was not negatively impacted by chitosan coating. However, myotube formation was impaired with chitosan coating, due to the possible changes in surface bound calcium ions, integrin expression and loss of serum proteins in differentiation media. By characterizing the attachment of myoblasts and fibroblasts to chitosan, and the inflammatory response, I hope to provide insights into developing a new generation of biomaterials for functional wound healing
Effects of Methionine Supplementation on Broilers Raised under High Stocking Density and High Ambient Temperature
No full text113 pagesTwo studies were conducted to investigate effects of supplementing 100 or 130% of the required digestible methionine to corn-soybean meal-based grower and finisher diets (1) as DL-methionine (DL-MET) for broilers housed in a higher density and (2) as either DL-MET or 2-hydroxy-4-(methylthio)butanoate (HMTBA) for broilers exposed to a high ambient temperature. In the first study, the high density impaired (P < 0.05) growth performance in both phases, decreased (P < 0.05) liver and adipose tissue fatty acid concentrations, and increased (P < 0.05) glutathione (GSH) in all assayed tissues except for the liver of the growers. The 130% DL-MET supplementation decreased (P < 0.05) feed intake of the finishers as well as the finisher breast and thigh malondialdehyde (MDA) levels. DL-MET elevated (P < 0.05) GSH in the grower thigh and fatty acid concentrations in the finisher liver. The hepatic expressions of heat shock protein 90 (HSP90) was decreased (P < 0.05) by the extra methionine supplementation. In the second study, the 130% methionine supplementations of both forms enhanced (P < 0.05) hepatic GSH concentrations of the growers and ferric reducing ability of plasma (FRAP) of the finishers. The DL-MET-fed growers had greater (P < 0.05%) muscle GSH and hepatic unsaturated fatty acid concentrations than those fed HMTBA. Expression of inflammation-related genes in the liver of finishers was affected (P < 0.05) by interaction effects of the methionine form and concentration. In summary, extra methionine supplementation showed moderate beneficial effects on tissue antioxidant status and growth performance of broilers under environmental stresses
VALIDATION OF NOVEL TECHNIQUES TO EVALUATE NUTRITIONAL STATUS IN ADULT FEMALES IN RURAL, HIGHLAND ETHIOPIA
No full text163 pagesAddressing malnutrition in Ethiopia is complex because the prevalence of underweight persists as overweight/obesity increases. A limitation in understanding and addressing malnutrition in adults is that body mass index (BMI) is frequently the only measure of nutritional status. Therefore, researchers need tools to assess body composition, measure physical activity, and understand the functional significance of malnutrition. However, a significant limitation to using these tools is that they have not been validated in many low- and middle-income settings. This research evaluated existing bioelectrical impedance analysis (BIA) and skinfold thickness (SFT) prediction equations that calculated fat mass (FM), fat-free mass (FFM), and percent body fat using air displacement plethysmography (ADP). The study participants consisted of 125 females and 129 males residing in Jimma City, Ethiopia. The second aim evaluated the Global Physical Activity Questionnaire (GPAQ) and a 24-hour recall of time use and perceived exertion in measuring the proportion of time spent at moderate and vigorous physical activity (MVPA) using accelerometry. The third aim evaluated the sit-to-stand test (STS), usual gait speed (UGS), and activities of daily living (ADLs) questionnaire as measures of physical function for feasibility, reliability, and validity. The second and third aims took place in rural Tigray, Ethiopia. The study population consisted of females between 18 and 45 years. One existing BIA prediction equation was validated for adult males. No BIA prediction equations were valid for females, and no SFT prediction equations were valid for males or females. New equations were created. The GPAQ was found to have low validity. The 24-hour recall had a fair agreement with accelerometry. The agreement improved by controlling for BMI. STS was a feasible, reliable, and valid measure of physical function. UGS lacked feasibility and reliability. The validity of the ADL questionnaires was inconclusive. This research will provide researchers with better tools to understand and address malnutrition in rural highland Ethiopia. The body composition equations will improve the identification of people who are malnourished. Quantifying physical activity and assessing physical function will enable researchers to understand the causes and consequences of malnutrition, guiding effective interventions to address malnutrition
INTRACELLULAR AND CIRCULATING METABOLIC MEDIATORS OF SKELETAL MUSCLE PROGENITOR CELL FUNCTION
No full text175 pagesSkeletal muscle progenitor cells (MPCs) are essential to repair muscle tissue damage after injury and maintain muscle composition with advancing age. Metabolism, including glucose uptake and breakdown, and mitochondrial substrate interconversion, is increasingly recognized as a key contributor to MPC function. Additionally, circulating factors (e.g., hormones, nutrients, peptides in the blood) regulate muscle regenerative capacity. Metabolic pathway use and circulating factors are altered in MPCs from populations with impairment. Thus, furthering understanding of the role of intracellular and circulating metabolic mediators may lead to therapies to improve MPC function. This dissertation explores the role of two metabolic proteins in MPCs: pyruvate kinase M2 (PKM2) and Sirtuin 5 (SIRT5). MPCs from PKM2 null mice were previously shown to have severely impaired proliferation. PKM2 is the enzyme responsible for the conversion of phosphoenolpyruvate into pyruvate (canonical activity) and interacts with other proteins to control a variety of cellular functions (non-canonical activity). We attribute the non-canonical function of PKM2 to its role in MPC proliferation and further identify glutamate dehydrogenase (GLUD1) as a PKM2 binding partner. SIRT5, an enzyme that removes succinyl- post-translational modifications, regulates proliferation in numerous cancer cells but had never been explored in MPCs. We identified that SIRT5 levels increase during MPC differentiation. We further show that serine hydroxymethyltransferase (SHMT2) is desuccinylated during MPC differentiation. Lastly, we test the capacity of a dietary intervention, consumption of freeze-dried blueberries to modify MPC function, and find beneficial effects in young but not old adults
Phosphatidylcholines: Beyond the Membrane
No full textPhosphatidylcholines (PC) are the most abundant phospholipids in mammalian cells, where they serve well-characterized structural roles, maintaining membrane integrity, facilitating lipoprotein assembly and serving as a surfactant in the lung. Over the past decade, seminal papers have been published that describe novel roles for specific PC species derived from both the cytidine diphosphate-choline (CDP-choline) and phosphatidylethanolamine N-methyltransferase (PEMT) pathways of PC synthesis; these roles include both nuclear receptor agonism and generating critical physiological pools of the omega 3 fatty acid, docosahexaenoic acid (DHA). In addition to these novel functions, complex interactions between PC and its substrate, choline, with growth and energetic status have emerged, following the observation that the mammalian target of rapamycin complex 1 (mTORC1) is a major regulator of PC synthesis through the CDP-choline pathway. Presented in this dissertation are the tests of our primary hypotheses informed directly from these emerging areas of phosphatidylcholine biology. Chapter 2 of this dissertation examines the impact of diet on the production of dilauroylphosphatidylcholine (DLPC), a phosphatidylcholine species enriched in lauric acid that was recently identified as a ligand for the nuclear receptor, liver receptor homolog-1 (LRH-1). DLPC binding to LRH-1 results in modulation of LRH-1-dependent hepatic gene expression and improvements in glucose and lipid handling. While DLPC has been convincingly shown to bind and activate LRH-1 when provided exogenously to cultured cells and mice, endogenous production of DLPC has not been observed, questioning its significance in the regulation of mammalian physiology. We hypothesized that the absence of DLPC in mammalian tissues results from substrate insufficiency (i.e. low lauric acid supply) and that provision of lauric acid, either in the culture media or the mammalian diet, will result in endogenous DLPC production, and be associated with functional LRH-1 activation. Cell culture models, animal feeding experiments, and a single-blind, randomized, controlled crossover acute feeding study in human participants were used to test this hypothesis. As hypothesized, provision of lauric acid in the cell culture media, animal diet, and human diet resulted in the acute and chronic production of DLPC. In cultured cells, this was associated with upregulation of LRH-1 dependent transcripts, an effect that was blunted by co-treatment with a LRH-1 antagonist. In animals, feeding of high fat diets containing lauric acid, utilizing purified lauric acid or coconut oil-based diets, resulted in substantial improvements in glucose handling as indicated by an oral glucose tolerance test. Chapter 3 of this dissertation examines the association of dietary choline intake and reproductive stage with plasma lysophosphatidylcholine (LPC)-DHA among women participants of a 10 week controlled feeding study. LPC-DHA has been recently highlighted as a physiological pool of DHA for maintaining the supply of this critical polyunsaturated fatty acid to extrahepatic organs during growth and development. We hypothesized that reproductive life-stage, dietary choline intake (22% provided as deuterium-labeled choline) and genetic variants in one-carbon metabolism would impact plasma unlabeled and labeled LPC-DHA in response to controlled feeding. To address these hypotheses, we measured unlabeled and deuterium-labeled plasma LPC-DHA in samples from a previously conducted controlled feeding study performed in non-pregnant, pregnant, and lactating women randomized to either 480 or 930mg of choline per day. Consistent with our hypotheses, we observed a significant reduction in unlabeled plasma LPC-DHA in pregnant and lactating women relative to non-pregnant women at week 10; only non-pregnant women exhibited significant increases in LPC-DHA from baseline to week 10 while consuming the study diets. Choline intake and one-carbon metabolism variants were not associated with unlabeled plasma LPC-DHA. However, both choline intake and reproductive life-stage altered the enrichment of PEMT- and CDP-choline-derived LPCs. In Chapter 4 of this dissertation, we explore roles for choline and phospholipid metabolism in the context of a novel animal model of adolescent severe acute malnutrition (aSAM). This complex disorder is characterized by negative energy balance, impaired growth, and multiple micronutrient deficiencies; severe forms of aSAM, namely kwashiorkor, are further complicated by an idiopathic fatty liver. The sensitivity of this fatty liver to dietary choline remains unknown. To characterize the potential for choline supplementation to serve as a metabolic therapy in aSAM, we developed a maize vegetable diet (MVD), comprised of foods typically consumed by children who will go on to develop kwashiorkor. The MVD was fed to weanling mice with or without choline supplementation, and compared to typical chow diets, to determine impacts on growth, body composition, and potential to alleviate the hallmark characteristic of kwashiorkor, fatty liver. We further explored the metabolic fate of dietary choline, hypothesizing that choline would be oxidized to betaine to support PC synthesis through the PEMT pathway in this context of lower mTORC1 activity and reduced CDP-choline pathway activity. Mice consuming our novel maize vegetable diet exhibited impaired growth relative to chow fed mice, and developed hepatic steatosis, consistent with human kwashiorkor. The addition of choline to the maize vegetable diet resulted in amelioration of the hepatic steatosis, and a greater hepatic concentration of betaine; choline partitioning to betaine is consistent with a role for the PEMT pathway in supporting PC synthesis in the context of malnutrition
ULTRASONOGRAPHIC IMAGING OF OVARIAN MORHPOLOGY FOR THE DIAGNOSIS AND EVALUATION OF ANOVULATORY CONDITIONS ACROSS THE ADIPOSITY SPECTRUM IN WOMEN AND ADOLESCENTS
No full textULTRASONOGRAPHIC IMAGING OF OVARIAN MORHPOLOGY FOR THE DIAGNOSIS AND EVALUATION OF ANOVULATORY CONDITIONS ACROSS THE ADIPOSITY SPECTRUM IN WOMEN AND ADOLESCENTS Heidi Vanden Brink, MS, RDMS Cornell University 2019 The leading cause of reproductive disturbance in women is polycystic ovary syndrome (PCOS), afflicting up to 10% of women. Hyperandrogenic anovulatory phenotypes (HA-Anov) of PCOS exhibit a heightened risk of cardiometabolic comorbidities. In contrast, normoandrogenic anovulatory (NA-Anov) phenotypes of PCOS experience less severe comorbidities. Therefore, we propose that these two conditions should be considered separately to initiate treatment and preventative measures appropriate for the risks associated with the clinical conditions. However, current limitations in the reliability of androgen assays to diagnose hyperandrogenism necessitate alternative biomarkers which accurately reflect NA- and HA-Anov conditions. Unique morphological (structural) descriptions on ultrasonography have been described in the ovaries of women with NA- and HA-Anov phenotypes. However, the degree to which they specifically capture androgen status over other concurrent comorbidities is unclear. There is growing evidence that obesity and hyperinsulinemia influence the development of hyperandrogenism, folliculogenesis, and ovarian morphology. Thus, ovarian morphology may capture the integration of reproductive and metabolic signals. The degree to which these competing influences enhance or impair the utility of ultrasonographic evaluations of ovarian morphology to guide diagnoses and treatment is an important area of consideration. In this dissertation, we tested the hypothesis that sonographic evaluations of the ovary using reproducible measures provide robust morphologic biomarkers that effectively inform the diagnosis and prognosis of reproductive and metabolic disturbances in women. In Chapter 1, we undertake a series of experiments to establish the reproducibility of several new or commonly used, two- (2D) and three-dimensional (3D) sonographic methods to evaluate ovarian morphology. We conduct a method comparison study to test the agreement of various approaches for obtaining follicle number per ovary (FNPO) versus an established, but time-consuming reproducible method generated by our group. 2D counts of FNPO made in real-time exhibit poor agreement and the data do not support continued use of this method in clinical practice or research. Other 2D and 3D methods are appropriate for the categorization of ovarian dysmorphology, however substantial over- and under-counting across 2D and 3D methods hinder their utility when a precise estimate of FNPO is needed. We subsequently tested the reliability and agreement of ovarian stromal assessments. Although we did not identify a reproducible method to evaluate the stroma, we provide evidence that increased stromal area is a consistent finding in women with anovulation. A method which obtains total stromal area by subtraction of follicular area was shown to be promising under certain imaging conditions, but ultimately there was justification to test the overarching hypothesis of this dissertation using metrics related to ovarian size and follicle number, not stromal features, which showed adequate reproducibility. In Chapter 2 we test whether reproducible methods to evaluate the ovary on ultrasound can discriminate between anovulatory conditions in lean and overweight women. We report that the ovary exhibits diagnostic potential for anovulatory conditions. We also show that thresholds to define ovulatory disorders were impacted by BMI. However, the impact of BMI on the diagnostic accuracy of ovarian features was variable and did not lead to the development of BMI-specific thresholds for ovulatory disorders. Rather, the findings point to a possibility that consideration of metabolic consequences of obesity and/or metabolic pathways impacting hyperandrogenism and ovarian morphology are relevant to improve diagnostic accuracy of ovulatory disorders. In Chapter 3, we focus on insulin resistance (IR) as a metabolic disturbance suspected to contribute to the pathogenesis of androgen excess and abnormal ovarian morphology. We show that the degree of metabolic risk perceived in women with ovulatory disorders depends on how both hyperandrogenism and IR are defined. The data also suggest that IR may influence the reproductive axis predominantly through increasing free, but not total, androgens. Whether the diagnosis and evaluation of ovulatory disturbances using ovarian morphology are possible over the life course remains an important point of consideration. In Chapter 4 we conducted a secondary analysis on data obtained from adolescents with PCOS to explore relationships between ovarian markers and aspects of reproductive and metabolic disturbance. We show that sonographic imaging using transabdominal ultrasound is possible and that features of the ovary reflect reproductive and metabolic disturbances in adolescents. The demonstration that the ovary can serve as a biomarker at such early stages of reproductive development justifies its consideration as a diagnostic feature during the adolescent reproductive transition
The Effects Of Single Amino Acid Deprivation On Translation And The Integrated Stress Response
No full textMetabolic and transcriptional regulation of muscle stem cell state transition
No full text246 pagesMaintenance of skeletal muscle (SkM) mass and strength throughout the lifespan is dependent on post-injury tissue regeneration, a process that is diminished with aging. Muscle-specific adult stem cells (MuSCs) and their committed progeny, muscle progenitor cells (MPCs), are required for SkM regeneration. After injury, MuSCs transition through a number of cell states, first they must activate from quiescence, giving rise to MPCs that undergo rapid proliferation prior to commitment to differentiation with a small number of MuSCs returning to quiescence. Using human and mouse models as well as immortalized cell lines this dissertation identifies novel regulators and requirements for MuSC state transitions and SkM regeneration. This dissertation identifies metabolism and mRNA modifications as central regulators of MuSC function and consequently SkM regeneration. First, expression of Peptide Tyrosine Tyrosine (PYY), a gut peptide implicated in post-prandial metabolism, was demonstrated in human SkM and MPCs. During proliferation, PYY expression was dynamic in young and old human derived MPCs and regulated by metabolic stress. Next, the non-essential amino acid serine was discovered as the only amino acid reduced in the aged human MuSC microenvironment. Availability of extracellular serine and the metabolically linked amino acid glycine were shown to be required for the synthesis of glutathione, and decreased serine/glycine concentrations were sensed in an EIF2_-dependent manner resulting in human MPC proliferation arrest, in vitro. Building on these findings, dietary restriction of serine/glycine in mice was shown to reduce MuSC abundance in young and aged mice, 3 days post injury (dpi), and to promote SkM fat infiltration 28 dpi in aged mice. The final chapter of this dissertation established that the most abundant internal mRNA modification, N6-methyladenosine (m6A), regulates MuSC/MPC state transitions. m6A-modification was greater during MPC proliferation (vs. differentiation) and m6A-specific sequencing (MeRIP-seq) revealed specific patterns of m6A-modified transcripts distinguishing proliferating and differentiating MPCs. Reducing m6A-modification abundance by methyltransferase-like 3 (METTL3) knockdown forced MPCs to prematurely differentiate in vitro and enhanced MuSC engraftment capacity after transplant. This dissertation demonstrates that nutrient availability (serine and glycine) and the expression of key proteins (PYY and METTL3) are integral in MPC/MuSC proliferation and subsequently SkM regeneration
VERTICAL SLEEVE GASTRECTOMY IMPROVES GLUCOSE HOMEOSTASIS VIA [beta]- CELL GLUCAGON-LIKE PEPTIDE-1 RECEPTOR SIGNALING BUT PROMOTES COLITIS DEVELOPMENT IN MICE
No full textBariatric surgery is defined as the surgical manipulation of the gut for the purpose of weight loss. Currently, it is the most effective long-term treatment for obesity and results in multiple cardiometabolic benefits. However, the mechanisms by which these benefits occur remain incompletely defined. In order to identify these mechanisms our lab has developed and validated a murine model of vertical sleeve gastrectomy (VSG), a type of a bariatric surgery. This model recapitulates many of the changes observed in humans after VSG. These include body weight loss, decreases in food intake, decreases in adiposity, improved glucose homeostasis, improved glucose stimulated insulin secretion, increases in post-prandial glucagon-like peptide-1 (GLP-1) secretion, changes in the bile acid pool/profile, and remission of hypertension. Utilizing this model we have investigated the role of β-cell glucagon-like peptide-1 receptor (GLP-1R) signaling in the glucoregulatory benefits of VSG and have also explored the effect of VSG on colitis development. One of the most remarkable changes seen after VSG is high rates of type 2 diabetes (T2DM) remission. This remission occurs hours to days after surgery, prior to significant body weight loss, and the mechanisms by which this occurs remain incompletely defined. The mechanisms that cause remission of T2DM are thought to be multi-factorial. One of these mechanisms is thought to involve increases in endogenous postprandial GLP-1 secretion, which has been shown to occur after multiple types of bariatric surgery. GLP-1R signaling is important for a variety of functions including the potentiation of glucose stimulated insulin secretion (GSIS), enhancement of insulin sensitivity, and decreases in appetite. Given the known role of β-cell GLP-1R signaling in the potentiation of GSIS we investigated its role in the glucoregulatory benefits of VSG utilizing an inducible β-cell GLP-1R mouse model. Utilizing this model, we defined the effect of increased endogenous GLP-1 signaling via β-cell GLP-1R on increases in GSIS, improvements in glucose tolerance, body weight loss in mice after VSG, and the following in pancreatic islets: insulin, glucagon, GLP-1, and prohormone convertase 1/3 (Chapters Two and Three). A growing number of people suffering from irritable bowel disease (IBD) also suffer from obesity and are candidates for bariatric surgery. Bariatric surgery has multiple beneficial effects, however; there is limited and conflicting literature on the effect of bariatric surgery on IBD. In order to investigate this we performed VSG in mice and chemically induced colitis with dextran sodium sulfate (DSS) three weeks after surgery (Chapter Four). The present dissertation describes the contributions of β-cell GLP-1R signaling in the glucoregulatory benefits of VSG surgery; demonstrates β-cell GLP-1R signaling is a novel regulator of α-cell proglucagon processing after VSG; and demonstrates VSG surgery aggravates colitis in mice. The knowledge gained from this research is novel and serves as an anchor for further elucidating the mechanisms by which VSG surgery improves conditions such as T2DM but exacerbates conditions such as IBD
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