The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.
If you have any questions or comments, please contact us.
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.
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.
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.
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.
Diabetic gastroparesis (GP) is a clinical syndrome characterized by delayed gastric emptying (DGE). Loss of Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) led to reduced nNOSα mediated gastric motility and DGE. The molecular signaling of cinnamaldehyde (CNM) mediated Nrf2 activation and its mechanistic role on DGE were further investigated in obese/T2D female mice. Adult female homozygous Nfe2l2 (C57BL/6J) and their wild-type (WT) littermates (Nfe2l2) mice were fed with high fat diet (HFD; Obese/T2D model), or normal diet (ND) with or without CNM (50 mg/kg b.w; i.p). Supplementation of CNM attenuated (p < 0.05) DGE in WT female but not in Nrf2 KO Obese/T2D mice. CNM (1) normalized serum estradiol-17β levels, (2) induced gastric Nrf2 and phase II antioxidant enzymes through extracellular signal-regulated kinase, (ERK)/c-Jun N-terminal kinase (JNK)/p38 mitogen-activated protein kinase (MAPK), (3) reduced glucose synthase kinase 3 beta (GSK3β) and aryl hydrocarbon receptor (AhR) and this was associated with (4) increased estrogen receptor expression, BH (Cofactor of nNOS) biosynthesis enzyme GCH-1 and nNOSα dimerization in WT Obese/T2 diabetic female mice. In addition, CNM restored impaired nitrergic relaxation in hyperglycemic conditions. These findings emphasize the importance of Nrf2 in maintaining nNOSα mediated GE and may have a translational relevance to treat obese/diabetic gastroparesis in women.
Copyright © 2019. Published by Elsevier Inc.
The NAD+-dependent deacetylase SIRT2 is unique amongst sirtuins as it is effective in the cytosol, as well as the mitochondria. Defining the role of cytosolic acetylation state in specific tissues is difficult since even physiological effects at the whole body level are unknown. We hypothesized that genetic SIRT2 knockout (KO) would lead to impaired insulin action, and that this impairment would be worsened in HF fed mice. Insulin sensitivity was tested using the hyperinsulinemic-euglycemic clamp in SIRT2 KO mice and WT littermates. SIRT2 KO mice exhibited reduced skeletal muscle insulin-induced glucose uptake compared to lean WT mice, and this impairment was exacerbated in HF SIRT2 KO mice. Liver insulin sensitivity was unaffected in lean SIRT2 KO mice. However, the insulin resistance that accompanies HF-feeding was worsened in SIRT2 KO mice. It was notable that the effects of SIRT2 KO were largely disassociated from cytosolic acetylation state, but were closely linked to acetylation state in the mitochondria. SIRT2 KO led to an increase in body weight that was due to increased food intake in HF fed mice. In summary, SIRT2 deletion in vivo reduces muscle insulin sensitivity and contributes to liver insulin resistance by a mechanism that is unrelated to cytosolic acetylation state. Mitochondrial acetylation state and changes in feeding behavior that result in increased body weight correspond to the deleterious effects of SIRT2 KO on insulin action.
BACKGROUND & AIMS - Bile diversion to the ileum (GB-IL) has strikingly similar metabolic and satiating effects to Roux-en-Y gastric bypass (RYGB) in rodent obesity models. The metabolic benefits of these procedures are thought to be mediated by increased bile acids, although parallel changes in body weight and other confounding variables limit this interpretation.
METHODS - Global G protein-coupled bile acid receptor-1 null (Tgr5) and intestinal-specific farnesoid X receptor null (Fxr) mice on high-fat diet as well as wild-type C57BL/6 and glucagon-like polypeptide 1 receptor deficient (Glp-1r) mice on chow diet were characterized following GB-IL.
RESULTS - GB-IL induced weight loss and improved oral glucose tolerance in Tgr5, but not Fxr mice fed a high-fat diet, suggesting a role for intestinal Fxr. GB-IL in wild-type, chow-fed mice prompted weight-independent improvements in glycemia and glucose tolerance secondary to augmented insulin responsiveness. Improvements were concomitant with increased levels of lymphatic GLP-1 in the fasted state and increased levels of intestinal Akkermansia muciniphila. Improvements in fasting glycemia after GB-IL were mitigated with exendin-9, a GLP-1 receptor antagonist, or cholestyramine, a bile acid sequestrant. The glucoregulatory effects of GB-IL were lost in whole-body Glp-1r mice.
CONCLUSIONS - Bile diversion to the ileum improves glucose homeostasis via an intestinal Fxr-Glp-1 axis. Altered intestinal bile acid availability, independent of weight loss, and intestinal Akkermansia muciniphila appear to mediate the metabolic changes observed after bariatric surgery and might be manipulated for treatment of obesity and diabetes.
Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.
BACKGROUND - Exposure of rodents to chronic high-fat diet (HFD) results in upregulation of inflammatory markers and proliferation of microglia within the mediobasal hypothalamus. Such hypothalamic inflammation is associated with metabolic dysfunction, central leptin resistance, and maintenance of obesity. Bariatric surgeries result in long-term stable weight loss and improved metabolic function. However, the effects of such surgical procedures on HFD-induced hypothalamic inflammation are unknown. We sought to characterize the effects of two bariatric surgical procedures, Roux-en-Y gastric bypass (RYGB) and biliary diversion (BD-IL), in female mice with particular emphasis on HFD-induced hypothalamic inflammation and microgliosis.
METHODS - RYGB and BD-IL were performed on diet-induced obese (DIO) mice. Quantitative RT-PCR and fluorescent microscopy were used to evaluate hypothalamic inflammatory gene expression and microgliosis. Results were compared to lean (CD), DIO sham-surgerized mice (DIO-SHAM), and dietary weight loss (DIO-Rev) controls.
RESULTS - In female mice, RYGB and BD-IL result in normalization of hypothalamic inflammatory gene expression and microgliosis within 8 weeks of surgery, despite ongoing exposure to HFD. Paralleling these results, the hypothalamic expression levels of the orexigenic neuropeptide Agrp and the anorexic response of surgical mice to exogenous leptin were comparable to lean controls (CD). In contrast, results from DIO-Rev mice were comparable to DIO-SHAM mice, despite transition back to standard rodent show and normalization of weight.
CONCLUSION - Bariatric surgery attenuates HFD-induced hypothalamic inflammation and microgliosis and restores leptin sensitivity, despite ongoing exposure to HFD.
Adipose tissue (AT) CD4 and CD8 T cells contribute to obesity-associated insulin resistance. Prior studies identified conserved T-cell receptor (TCR) chain families in obese AT, but the presence and clonal expansion of specific TCR sequences in obesity has not been assessed. We characterized AT and liver CD8 and CD4 TCR repertoires of mice fed a low-fat diet (LFD) and high-fat diet (HFD) using deep sequencing of the TCRβ chain to quantify clonal expansion, gene usage, and CDR3 sequence. In AT CD8 T cells, HFD reduced TCR diversity, increased the prevalence of public TCR clonotypes, and selected for TCR CDR3 regions enriched in positively charged and less polarized amino acids. Although TCR repertoire alone could distinguish between LFD- and HFD-fed mice, these properties of the CDR3 region of AT CD8 T cells from HFD-fed mice led us to examine the role of negatively charged and nonpolar isolevuglandin (isoLG) adduct-containing antigen-presenting cells within AT. IsoLG-adducted protein species were significantly higher in AT macrophages of HFD-fed mice; isoLGs were elevated in M2-polarized macrophages, promoting CD8 T-cell activation. Our findings demonstrate that clonal TCR expansion that favors positively charged CDR3s accompanies HFD-induced obesity, which may be an antigen-driven response to isoLG accumulation in macrophages.
© 2018 by the American Diabetes Association.