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Maternal microbial molecules affect offspring health.
Ferguson J
(2020) Science 367: 978-979
MeSH Terms: Animals, Child, Child Health, Diet, High-Fat, Female, Gastrointestinal Microbiome, Mice, Obesity, Phenotype, Pregnancy
Added March 3, 2020
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1 Members
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10 MeSH Terms
Roux-en-Y gastric bypass surgery improves hepatic glucose metabolism and reduces plasma kisspeptin levels in morbidly obese patients with type 2 diabetes.
Flynn CR, Albaugh VL, Tamboli RA, Gregory JM, Bosompem A, Sidani RM, Winnick JJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G370-G374
MeSH Terms: Adolescent, Adult, Anastomosis, Roux-en-Y, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucagon, Glucose, Humans, Insulin, Kisspeptins, Liver, Male, Middle Aged, Obesity, Morbid, Treatment Outcome, Young Adult
Show Abstract · Added November 12, 2019
Roux-en-Y gastric bypass surgery (RYGB) is known to improve whole-body glucose metabolism in patients with type 2 diabetes (T2D), although the mechanisms are not entirely clear and are likely multifactorial. The aim of this study was to assess fasting hepatic glucose metabolism and other markers of metabolic activity before and after RYGB in patients with and without T2D. Methods: Metabolic characteristics of patients who are obese with T2D were compared with those without the disease (non-T2D) before and 1 and 6 mo after RYGB. Fasting plasma insulin and the insulin:glucagon ratio were markedly reduced as early as 1 mo after RYGB in both patients with T2D and without T2D. Despite this reduction, endogenous glucose production and fasting plasma glucose levels were lower in both groups after RYGB, with the reductions being much larger in T2D. Plasma kisspeptin, an inhibitor of insulin secretion, was reduced only in T2D after surgery. Improved hepatic glucose metabolism and lower plasma kisspeptin in T2D after RYGB may link improved hepatic function with enhanced insulin responsiveness after surgery. Our manuscript is the first, to the best of our knowledge, to present data showing that Roux-en-Y gastric bypass surgery (RYGB) lowers fasting kisspeptin levels in patients who are obese with type 2 diabetes. This lowering of kisspeptin is important because it could link improvements in liver glucose metabolism after RYGB with increased insulin responsiveness also seen after surgery.
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17 MeSH Terms
CD8 T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease.
Breuer DA, Pacheco MC, Washington MK, Montgomery SA, Hasty AH, Kennedy AJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G211-G224
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Hepatic Stellate Cells, Hepatitis, Humans, Hyperlipidemias, Interleukin-10, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease, Obesity, Receptors, LDL
Show Abstract · Added March 3, 2020
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8 T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8 T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8 T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8 T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8 T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8 T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8 T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8 T cells may be a novel approach for treatment of obesity-associated NASH. Our study demonstrates that CD8 T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8 T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8 T cells are key players in obesity-associated NASH.
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15 MeSH Terms
Metabolic effects of skeletal muscle-specific deletion of beta-arrestin-1 and -2 in mice.
Meister J, Bone DBJ, Godlewski G, Liu Z, Lee RJ, Vishnivetskiy SA, Gurevich VV, Springer D, Kunos G, Wess J
(2019) PLoS Genet 15: e1008424
MeSH Terms: Animals, Diabetes Mellitus, Type 2, Diet, High-Fat, Disease Models, Animal, Glucose, Glucose Clamp Technique, Glycogen, Humans, Insulin, Insulin Resistance, Male, Mice, Mice, Knockout, Muscle, Skeletal, Obesity, Signal Transduction, beta-Arrestin 1, beta-Arrestin 2
Show Abstract · Added March 18, 2020
Type 2 diabetes (T2D) has become a major health problem worldwide. Skeletal muscle (SKM) is the key tissue for whole-body glucose disposal and utilization. New drugs aimed at improving insulin sensitivity of SKM would greatly expand available therapeutic options. β-arrestin-1 and -2 (Barr1 and Barr2, respectively) are two intracellular proteins best known for their ability to mediate the desensitization and internalization of G protein-coupled receptors (GPCRs). Recent studies suggest that Barr1 and Barr2 regulate several important metabolic functions including insulin release and hepatic glucose production. Since SKM expresses many GPCRs, including the metabolically important β2-adrenergic receptor, the goal of this study was to examine the potential roles of Barr1 and Barr2 in regulating SKM and whole-body glucose metabolism. Using SKM-specific knockout (KO) mouse lines, we showed that the loss of SKM Barr2, but not of SKM Barr1, resulted in mild improvements in glucose tolerance in diet-induced obese mice. SKM-specific Barr1- and Barr2-KO mice did not show any significant differences in exercise performance. However, lack of SKM Barr2 led to increased glycogen breakdown following a treadmill exercise challenge. Interestingly, mice that lacked both Barr1 and Barr2 in SKM showed no significant metabolic phenotypes. Thus, somewhat surprisingly, our data indicate that SKM β-arrestins play only rather subtle roles (SKM Barr2) in regulating whole-body glucose homeostasis and SKM insulin sensitivity.
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MeSH Terms
Impact of Abdominal Obesity on Proximal and Distal Aorta Wall Thickness in African Americans: The Jackson Heart Study.
Mzayek F, Wang LE, Relyea G, Yu X, Terry JG, Carr J, Hundley GW, Hall ME, Correa A
(2019) Obesity (Silver Spring) 27: 1527-1532
MeSH Terms: African Americans, Carotid Intima-Media Thickness, Cohort Studies, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Obesity, Abdominal, Risk Factors
Show Abstract · Added July 23, 2019
OBJECTIVE - Abdominal obesity and wall thickness of the central arteries have been associated with higher risk of cardiovascular disease. Despite the higher burden of overweight and cardiovascular disease among African Americans, limited data are available on the association of abdominal obesity with aortic wall thickness in African Americans. We assessed the cross-sectional and the longitudinal associations of abdominal obesity with aortic intima-media thickness (aIMT) in a cohort of African Americans from the Jackson Heart Study.
METHODS - Data on aIMT and repeated measures of waist circumference (WC) and waist to height ratio from 1,572 participants, as well as on abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and aIMT from 1,223 participants, were analyzed. aIMT was measured at proximal ascending aorta (PA-aIMT), proximal descending aorta (PD-aIMT), and distal aorta (bifurcation) using cardiac magnetic resonance. SAT and VAT were measured using computerized tomography.
RESULTS - WC and WHtR were longitudinally associated with PA-aIMT and PD-aIMT; SAT and VAT were associated with PA-aIMT only. Only WC was associated with distal aIMT.
CONCLUSIONS - Abdominal obesity measures are associated with increased proximal aIMT in adult African Americans. Only WC is associated with wall thickness in all three segments of the aorta.
© 2019 The Obesity Society.
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10 MeSH Terms
The effect of the EP3 antagonist DG-041 on male mice with diet-induced obesity.
Ceddia RP, Downey JD, Morrison RD, Kraemer MP, Davis SE, Wu J, Lindsley CW, Yin H, Daniels JS, Breyer RM
(2019) Prostaglandins Other Lipid Mediat 144: 106353
MeSH Terms: Acrylamides, Animals, Blood Pressure, Body Weight, Diet, High-Fat, HEK293 Cells, Humans, Insulin Resistance, Male, Mice, Muscle, Skeletal, Obesity, Phenotype, Receptors, Prostaglandin E, EP3 Subtype, Sulfones, Triglycerides
Show Abstract · Added September 4, 2019
BACKGROUND/AIMS - The prostaglandin E (PGE) EP3 receptor has a multifaceted role in metabolism. Drugs targeting EP3 have been proposed as therapeutics for diabetes; however, studies utilizing global EP3 knockout mice suggest that EP3 blockade increases obesity and insulin resistance. The present studies attempt to determine the effect of acute EP3 antagonist treatment on the diabetic phenotype.
METHODS - DG-041 was confirmed to be a high affinity antagonist at the mouse EP3 receptor by competition radioligand binding and by blockade of EP3-mediated responses. DG-041 pharmacokinetic studies were performed to determine the most efficacious route of administration. Male C57BL/6 × BALB/c (CB6F1) mice were fed diets containing 10%, 45%, or 60% calories from fat to induce obesity. Changes to the metabolic phenotype in these mice were evaluated after one week treatment with DG-041.
RESULTS - Subcutaneous injections of DG-041 at 20 mg/kg blocked the sulprostone-evoked rise in mean arterial pressure confirming the efficacy of this administration regime. Seven day treatment with DG-041 had minimal effect on body composition or glycemic control. DG-041 administration caused a reduction in skeletal muscle triglyceride content while showing a trend toward increased hepatic triglycerides.
CONCLUSION - Short term EP3 administration of DG-041 produced effective blockade of the EP3 receptor and decreased skeletal muscle triglyceride content but had no significant effects on the diabetic phenotype.
Published by Elsevier Inc.
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16 MeSH Terms
Two-week administration of engineered Escherichia coli establishes persistent resistance to diet-induced obesity even without antibiotic pre-treatment.
Dosoky NS, Chen Z, Guo Y, McMillan C, Flynn CR, Davies SS
(2019) Appl Microbiol Biotechnol 103: 6711-6723
MeSH Terms: Acyltransferases, Animals, Anti-Bacterial Agents, Anti-Obesity Agents, Arabidopsis, Diet, High-Fat, Disease Models, Animal, Escherichia coli, Humans, Metabolic Engineering, Mice, Obesity, Phosphatidylethanolamines, Plant Proteins, Probiotics, Recombinant Proteins, Treatment Outcome
Show Abstract · Added July 17, 2019
Adverse alterations in the composition of the gut microbiota have been implicated in the development of obesity and a variety of chronic diseases. Re-engineering the gut microbiota to produce beneficial metabolites is a potential strategy for treating these chronic diseases. N-acyl-phosphatidylethanolamines (NAPEs) are a family of bioactive lipids with known anti-obesity properties. Previous studies showed that administration of Escherichia coli Nissle 1917 (EcN) engineered with Arabidopsis thaliana NAPE synthase to produce NAPEs imparted resistance to obesity induced by a high-fat diet that persisted after ending their administration. In prior studies, mice were pre-treated with ampicillin prior to administering engineered EcN for 8 weeks in drinking water. If use of antibiotics and long-term administration are required for beneficial effects, implementation of this strategy in humans might be problematic. Studies were therefore undertaken to determine if less onerous protocols could still impart persistent resistance and sustained NAPE biosynthesis. Administration of engineered EcN for only 2 weeks without pre-treatment with antibiotics sufficed to establish persistent resistance. Sustained NAPE biosynthesis by EcN was required as antibiotic treatment after administration of the engineered EcN markedly attenuated its effects. Finally, heterologous expression of human phospholipase A/acyltransferase-2 (PLAAT2) in EcN provided similar resistance to obesity as heterologous expression of A. thaliana NAPE synthase, confirming that NAPEs are the bioactive mediator of this resistance.
1 Communities
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17 MeSH Terms
GLP-1: Molecular mechanisms and outcomes of a complex signaling system.
Smith NK, Hackett TA, Galli A, Flynn CR
(2019) Neurochem Int 128: 94-105
MeSH Terms: Animals, Brain, Diabetes Mellitus, Type 2, Feeding Behavior, Glucagon-Like Peptide 1, Humans, Obesity, Reward, Signal Transduction
Show Abstract · Added December 17, 2019
Meal ingestion provokes the release of hormones and transmitters, which in turn regulate energy homeostasis and feeding behavior. One such hormone, glucagon-like peptide-1 (GLP-1), has received significant attention in the treatment of obesity and diabetes due to its potent incretin effect. In addition to the peripheral actions of GLP-1, this hormone is able to alter behavior through the modulation of multiple neural circuits. Recent work that focused on elucidating the mechanisms and outcomes of GLP-1 neuromodulation led to the discovery of an impressive array of GLP-1 actions. Here, we summarize the many levels at which the GLP-1 signal adapts to different systems, with the goal being to provide a background against which to guide future research.
Copyright © 2019. Published by Elsevier Ltd.
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9 MeSH Terms
Sex modifies placental gene expression in response to metabolic and inflammatory stress.
Barke TL, Money KM, Du L, Serezani A, Gannon M, Mirnics K, Aronoff DM
(2019) Placenta 78: 1-9
MeSH Terms: Animals, Diabetes, Gestational, Diet, High-Fat, Female, Fetal Development, Fetus, Gene Expression, Inflammation, Male, Mice, Mice, Inbred C57BL, Obesity, Placenta, Pregnancy, Pregnancy Complications, Sex Characteristics, Stress, Physiological, Transcriptome
Show Abstract · Added April 15, 2019
INTRODUCTION - Metabolic stress (e.g., gestational diabetes mellitus (GDM) and obesity) and infections are common during pregnancy, impacting fetal development and the health of offspring. Such antenatal stresses can differentially impact male and female offspring. We sought to determine how metabolic stress and maternal immune activation (MIA), either alone or in combination, alters inflammatory gene expression within the placenta and whether the effects exhibited sexual dimorphism.
METHODS - Female C57BL/6 J mice were fed a normal diet or a high fat diet for 6 weeks prior to mating, with the latter diet inducing a GDM phenotype during pregnancy. Dams within each diet group at gestational day (GD) 12.5 received either an intraperitoneal injection of the viral mimic, polyinosinic:polycytidylic acid (poly(I:C)) or saline. Three hours post injection; placentae were collected and analyzed for changes in the expression of 248 unique immune genes.
RESULTS - Placental immune gene expression was significantly altered by GDM, MIA and the combination of the two (GDM+MIA). mRNA expression was generally lower in placentae of mice exposed to GDM alone compared with the other experimental groups, while mice exposed to MIA exhibited the highest transcript levels. Notably, fetal/placental sex influenced the responses of many immune genes to both metabolic and inflammatory stress.
DISCUSSION - GDM and MIA provoke inflammatory responses within the placenta and such effects exhibit sexual dimorphism. The combination of these stressors impacts the placenta differently than either condition alone. These findings may help explain sexual dimorphism observed in adverse pregnancy outcomes in human offspring exposed to similar stressors.
Copyright © 2019. Published by Elsevier Ltd.
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18 MeSH Terms
Extrinsic and Intrinsic Immunometabolism Converge: Perspectives on Future Research and Therapeutic Development for Obesity.
Caslin HL, Hasty AH
(2019) Curr Obes Rep 8: 210-219
MeSH Terms: Adaptive Immunity, Adipose Tissue, Animals, Energy Metabolism, Epigenesis, Genetic, Humans, Immunity, Immunologic Memory, Iron, Macrophages, Metabolic Diseases, Metabolic Networks and Pathways, MicroRNAs, Obesity
Show Abstract · Added March 3, 2020
PURPOSE OF REVIEW - Research over the past decade has shown that immunologic and metabolic pathways are intricately linked. This burgeoning field of immunometabolism includes intrinsic and extrinsic pathways and is known to be associated with obesity-accelerated metabolic disease. Intrinsic immunometabolism includes the study of fuel utilization and bioenergetic pathways that influence immune cell function. Extrinsic immunometabolism includes the study of immune cells and products that influence systemic metabolism.
RECENT FINDINGS - Th2 immunity, macrophage iron handling, adaptive immune memory, and epigenetic regulation of immunity, which all require intrinsic metabolic changes, play a role in systemic metabolism and metabolic function, linking the two arms of immunometabolism. Together, this suggests that targeting intrinsic immunometabolism can directly affect immune function and ultimately systemic metabolism. We highlight important questions for future basic research that will help improve translational research and provide therapeutic targets to help establish new treatments for obesity and associated metabolic disorders.
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MeSH Terms