ResearchPad - lipids-obesity-and-metabolic-disease https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[SAT-657 The Gut Microbiome Regulates Host Glucose Homeostasis via Peripheral Serotonin]]> https://www.researchpad.co/article/elastic_article_8701 The gut microbiome is an established regulator of aspects of host metabolism, such as glucose handling. Despite the known impacts of the gut microbiota on host glucose homeostasis, the underlying mechanisms are unknown. The gut microbiome is also a potent mediator of gut-derived serotonin synthesis, and this peripheral source of serotonin is itself a regulator of glucose homeostasis. Here, we determined whether the gut microbiome influences glucose homeostasis through effects on gut-derived serotonin. Using both pharmacological inhibition and genetic deletion of gut-derived serotonin synthesis, we find [1] that the improvements in host glucose handling caused by antibiotic-induced changes in microbiota composition are dependent on the synthesis of peripheral serotonin.

[1] The gut microbiome regulates host glucose homeostasis via peripheral serotonin. Proc Natl Acad Sci U S A. 2019 Oct 1;116(40):19802-19804. Martin AM, Yabut JM, Choo JM, Page AJ, Sun EW, Jessup CF, Wesselingh SL, Khan WI, Rogers GB, Steinberg GR, Keating DJ.

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<![CDATA[SAT-658 Associations of Serum and CSF Kisspeptin Levels with Metabolic and Reproductive Parameters in Men]]> https://www.researchpad.co/article/elastic_article_8589 Action of kisspeptin in the central nervous system (CNS) is well known on reproductive regulation; however, its peripheral action is not well understood. Recent studies have shown that peripheral kisspeptin might be related to obesity and/or metabolic parameters in humans [1]; however, these associations are still inconclusive. This study aimed to 1) compare serum or cerebrospinal fluid (CSF) kisspeptin levels between different body mass index (BMI) groups 2) compare levels of kisspeptin between serum and CSF, and 3) determine correlations between serum or CSF kisspeptin levels with clinical, metabolic, and reproductive parameters. There were 40 male subjects who underwent an operation with lumbar puncture anesthesia. Subgroup analysis was performed to compare between the lean-normal group (n=13) which included lean and normal weight subjects, the overweight group (n=10), and the obese group (n=17) according to BMI. Blood samples were collected after at least 8-hour fasting before intravenous cannulation prior to the operation while CSF samples were obtained by lumbar puncture before administration of the spinal anesthesia. Serum kisspeptin and leptin levels were significantly higher in the obese group when compared to the lean-normal and overweight groups even after adjusted to age while CSF kisspeptin levels were comparable between different BMI groups (p<0.05 all). Serum kisspeptin levels were significantly higher than CSF kisspeptin levels (p<0.001). Serum kisspeptin was significantly positively correlated with body weight (R= 0.351), BMI (R=0.549), plasma insulin (R=0.393), and serum leptin (R=0.45) (p<0.05 all), and tended to have a positive correlation with the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (R=0.29, p=0.77) but was significantly negatively correlated with plasma LH (R=-0.37) (p<0.05). CSF kisspeptin was significantly positively correlated with plasma LH (R=0.452, p<0.05). These results suggest that serum kisspeptin levels were related to increased obesity, leptin, insulin, and insulin resistance while CSF kisspeptin levels were related to reproductive parameters. In summary, central kisspeptin might have a role on reproductive regulation while peripheral kisspeptin might have a role on metabolic regulation. Reference: (1) Izzi-Engbeaya, C., et al., The effects of kisspeptin on beta-cell function, serum metabolites and appetite in humans. Diabetes Obes Metab, 2018. 20(12): p. 2800–2810.

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<![CDATA[SAT-652 Increased Fibroblast Growth Factor 21 Protein Expression via in Vivo Delivery of a Liver-Specific Expression Plasmid]]> https://www.researchpad.co/article/elastic_article_6855 Fibroblast growth factor 21 (FGF21) is an important liver-secreted hormone that activates thermogenesis in white and brown fat deposits. In various models of obesity, FGF21 administration consistently facilitates weight loss and improved metabolic function. Several FGF21 variants, which have been engineered to improve protein stability and solubility in solutions containing preservatives, are currently in human clinical trials. In addition, in vivo FGF21 gene therapy using viral vector is being explored as an alternative therapeutic approach. In this study, we present a simpler method of in vivo FGF21 gene therapy, in which liver-specific delivery of an unpackaged plasmid construct expressing an HA-tagged FGF21 protein increases de novo hepatic FGF21 production and secretion in mice. Our data show that FGF21 protein expression can be successfully restored into the livers of FGF21 conditional knockout mice for at least two weeks after a single tail vein injection with the expression plasmid, and that the HA-tagged protein is secreted and readily detectable in serum. In wild-type C57BL6/J mice, in vivo plasmid delivery significantly increased hepatic FGF21 protein 2.3-fold after two weeks, and was associated with reduced body mass and a 14% reduction in fasting serum glucose. In addition, elevated hepatic FGF21 levels correlated with a 27% decrease in the ratio of fat to body mass, visibly smaller subcutaneous and visceral white fat adipocytes, and a 3.3-fold increase in uncoupling protein 1-dependent mitochondrial respiration in the white fat. Together, these data suggest that in vivo plasmid delivery may potentially be an effective strategy for promoting hepatic FGF21 expression in models of obesity. We are currently testing this hypothesis with experiments in high-fat diet-challenged mice.

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<![CDATA[SAT-656 Both Neutrophil and Monocyte Ratios to High Density Lipoprotein Cholesterol Are Superior Biomarkers of Metabolic Syndrome]]> https://www.researchpad.co/article/N0f7d4a5f-07c6-4dd9-8562-504c3fc8d083 10mg/L or leukocytosis), smoking, anti-inflammatory and hypolipidemic drug therapies were excluded. Fasting blood samples were obtained for complete blood counts, basic metabolic panel, lipid profile, insulin adiponectin, leptin and chemerin. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from glucose and insulin levels. Ratios of PMN and monocytes to HDL-C and Adiponectin were calculated and compared statistically. PMN: HDL-C and Monocyte: HDL-C, increased in patients with MetS compared to controls (p<0.0001 and p=0.001 respectively).Also the PMN: Adiponectin and monocyte: Adiponectin ratios were significantly increased in MetS (p=0.006 and 0.02 respectively). All ratios increased with increasing severity of MetS (p=0.01). Receiver Operating Characteristic (ROC) curve analysis showed that both the PMN/HDL-C and monocyte: HDL-C area under the curve(AUC)(0.85 and 0.84 respectively) significantly added to the CRP AUC(0.75), p=0.01 for both. Neither leukocyte: Adiponectin AUC was significant compared to hsCRP. Also both ratios to HDL-C correlated with cardio-metabolic features of MetS, hsCRP and insulin resistance(HOMA-IR) (p<0.05). Whilst the PMN:HDL-C ratio correlated with leptin, and chemerin the monocyte: HDL-C ratio correlated significantly with chemerin only (p<0.05) Our cross-sectional study indicates that ratios of neutrophils and monocytes to HDL-C are significantly increased in patients with nascent MetS, increase with severity of MetS, correlate positively with inflammation and insulin resistance and both ratios appear to be better predictors of MetS than hsCRP. In conclusion, they provide a cost-effective measure of Metabolic Syndrome and should be confirmed in larger data bases and prospective studies. ]]> <![CDATA[SAT-LB127 Regulation of ENaC by Exosomal Lipids in the Diabetic Kidney]]> https://www.researchpad.co/article/N5ecf1485-2f88-4b22-8119-0161d71bd320 <![CDATA[SAT-LB124 Phosphatidylcholine Transfer Protein Interacts With PPARδ to Modulate Activity]]> https://www.researchpad.co/article/N690c5cf4-df06-4555-be6c-72641206be20 <![CDATA[SAT-653 Exploring the Role of Brown Adipokines on Hepatic Insulin Resistance Using a Microfluidic Organ-On-Chip]]> https://www.researchpad.co/article/N6a37cb46-9bbc-4ab2-9a59-811c741144fa <![CDATA[SAT-659 Micro/Nanoparticles from Antidiabetic Chinese Herbal Medicine Soup Increase Bioavailability of Phytochemicals and Regulate Glucose and Lipid Metabolism]]> https://www.researchpad.co/article/N5c23bdd0-1f0e-45b4-ad20-6e3dafb6cd40 <![CDATA[SAT-650 Novel Insights into the Entero-Insular Axis in Fibrocalcific Pancreatic Diabetes: An Isoglycemic Intravenous Glucose Infusion (IIGI) Study from India]]> https://www.researchpad.co/article/N9b1d2832-52a2-4e27-aeb6-aff2d997e63d <![CDATA[SAT-LB126 Metformin Attenuates Sodium Retention and Blood Pressure in Hypertensive Diabetic Mice by Reducing the Phosphorylation of Renal NCC and Its Association With the Actin Cytoskeleton]]> https://www.researchpad.co/article/N04b750b7-bd36-4946-ae4a-04455a3a9895 <![CDATA[SAT-651 Ethnic Differences in the Relationship Between Uric Acid Clearance and Insulin Sensitivity]]> https://www.researchpad.co/article/Nb7d81419-2b97-4982-9c05-69f07f94e06d <![CDATA[SAT-LB125 Broad Spectrum Effects of a Ketogenic Diet Delivered by Remote Continuous Care on Inflammation and Immune Modulators in Type 2 Diabetes and Prediabetes]]> https://www.researchpad.co/article/Nd8a92c8c-a3a4-4169-ba52-27a930c9fc59 <![CDATA[SAT-655 Bile Acid Sequestration Synergistically Accelerates Glucagon Receptor-Stimulated Body Weight Loss in Diet-Induced Obese Mice]]> https://www.researchpad.co/article/N73e5700a-0199-4205-8a19-b05668b6f1c4

Abstract

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss in obese mice. We have shown that hepatic Farnesoid X Receptor (FXR, a bile acid receptor) and bile acids (BA) play an important role in the anti-obesity effect of glucagon in mice. Specifically, glucagon-receptor (GCGR) agonism is a potent regulator of BA metabolism, increasing total plasma BA levels and preferentially raising cholic and chenodeoxycholic acid levels. These findings led us to hypothesize that BA, signaling via hepatic FXR, contributes to GCGR-stimulated weight loss. Furthermore, we reasoned that BA sequestration may impair GCGR-mediated weight loss by reducing the availability of BA to stimulate FXR-action. Thus, to elucidate the role of BA in GCGR-mediated weight loss, we utilized anion-exchange BA-binding resins (BARS; Cholestyramine and Colesevelam) to prevent intestinal (ileal) re-uptake and reduce plasma total cholesterol, LDL, and BAs via fecal excretion. Diet-induced obese (DIO) C57Bl/6J mice were randomized to groups matched for body-weight and administered daily GCGR agonism (IUB288, 10 nmol/kg, s.c.) or vehicle, in the presence or absence of BARS. Consistent with our prior findings, IUB288-treatment reduced body weight in DIO mice. Counter to our original hypothesis, IUB288+Cholestyramine (3% in high fat diet, HFD [58% kcal%]) enhanced IUB288-stimulated weight loss. Similar body-weight loss effects following combined IUB288 and BARS treatment were replicated both at a lower dose of Cholestyramine (1.5% in HFD), as well as in combination with both low- (2% in HFD) and high- (4% in HFD) dose Colesevelam. IUB288-stimulated weight loss is accompanied by suppression of food intake (FI), while Colesevelam alone did not significantly lower FI at either dose (2 or 4% in HFD). However, 4% Colesevelam with IUB288 completely suppressed FI, while 2% Colesevelam stimulated a reduced, though not complete suppression. GCGR agonism is a potent stimulus of weight loss; however, its impairment of glucose tolerance reduces its value as a monotherapy. Excitingly, Cholestyramine (3% in HFD) rescued IUB288-induced glucose intolerance, restoring glucose excursion to levels observed in control (vehicle-treated) mice. Together these studies suggest BARS may enhance the anti-obesity effect of GCGR agonism, beneficially regulate feeding behaviors, and prevent GCGR-stimulated glucose dysregulation in DIO mice. Furthermore, these studies argue that GCGR agonsim combined with BARS treatment may represent a novel therapeutic approach for obesity and obesity-associated glucose intolerance.

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