bluuebunny/crossref_metadata_2025_split huggingface dataset:
1950-P: Effects of Dietary Composition on Intestinal Glucocorticoid Receptor Signaling
Authors: RADLINGER BERNHARD , FOLIE SABRINA , DOBNER JOCHEN , ADOLPH TIMON-ERIK , RESS CLAUDIA , HORNSTEINER FLORIAN , BOENTGES SARAH , SALZMANN KARIN , TILG HERBERT , KASER SUSANNE 
Published: June 2019

Enhanced glucose transport capacity of the intestinal epithelium, specifically enterocytes, is known to significantly contribute to systemic glucocorticoid (GC) - induced hyperglycemia. This effect is mainly dependent on overexpression of sodium glucose transporter 1 (Sglt1) and its enhanced activation by serum and glucocorticoid-regulated kinase 1 (Sgk1). In this work we aimed to investigate whether dietary intake affects intestinal glucocorticoid receptor (Nr3c1) signaling. In male C57/BL6 mice short term feeding of a Western diet (WD) resulted in increased glucocorticoid receptor expression in the ileum which was accompanied by an upregulation of the effector genes Sgk1 and sodium-hydrogen exchanger 3 (Nhe3) and liver receptor homologe 1 (Lrh1). The latter is known as the key regulator of intestinal corticosterone synthesis. Histological analysis showed that glucocorticoid receptor expression was mainly located in enterocytes. Intestinal Sgk1 expression remained significantly, about 2-fold, increased in mice fed a Western diet for 10 weeks, while Nr3c1, Lrh1 and Nhe3 expression levels were not significantly altered after long-term feeding. Further regulatory mechanisms were investigated in immortalized murine small intestine enterocyte cell line Mode-K: Stimulation with palmitic acid resulted in a significant upregulation of Sgk1 expression, while no effect was seen when exposed to oleic acid, arachidonic acid or docosahexanoic acid. In contrast to Sgk1, Nr3c1 expression was downregulated in Mode-K cells exposed to palmitic acid.
In conclusion, our data suggest that dietary fat intake might contribute to GC induced hyperglycemia by modulating intestinal Sgk1 expression in a glucocorticoid receptor-independent way.

Disclosure
B. Radlinger: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. S. Folie: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. J. Dobner: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. T. Adolph: None. C. Ress: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. F. Hornsteiner: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. S. Boentges: Research Support; Self; Boehringer Ingelheim International GmbH, Merck & Co., Inc. K. Salzmann: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. H. Tilg: None. S. Kaser: Research Support; Self; Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp.

Funding
Austrian Federal Ministry of Science, Research and Economy; National Foundation for Research, Technology and Development; Merck Sharp & Dohme Austria; Boehringer Ingelheim RCV
1953-P: PPARγ Agonism and FGF-21 Synergize to Robustly Induce Browning of White Fat
Authors: KROON TOBIAS , HARMS MATTHEW J. , NILSSON DANIEL , LINDBLOM ANNA , GENNEMARK PETER , O'MAHONY GAVIN , OSINSKI VICTORIA , MCNAMARA COLEEN A. , BOUCHER JEREMIE 
Published: June 2019

Increasing brown adipose tissue abundance or activity or converting white into brown adipocytes holds promise for the treatment of type 2 diabetes and obesity. Several PPARγ agonists, including rosiglitazone, have been shown to robustly induce browning of white adipose tissue (WAT) in vitro but their effects in vivo are less pronounced, while PPARα agonists show modest browning effects both in vitro or in vivo. In the present study, we investigated whether PPARα and PPARγ dual agonism would have synergistic effects in inducing browning of WAT. We found that all tested dual PPARα/γ agonists robustly increased uncoupling protein 1 (Ucp1) expression in both mouse and human preadipocytes, with tesaglitazar giving the largest Ucp1 induction. Notably, tesaglitazar also strongly induced browning of WAT in vivo in both lean and obese mice at thermoneutrality, largely exceeding the increase in Ucp1 observed with rosiglitazone. Mechanistically, we found that selective PPARγ agonism was sufficient for the conversion of white into brown-like adipocytes in vitro, but dual PPARα/γ agonism was superior to selective PPARγ agonism at inducing white fat browning in vivo, at least in part via a PPARα-mediated increase in fibroblast growth factor 21 (FGF-21). In human preadipocytes in vitro, combined treatment with rosiglitazone and FGF-21 resulted in a robust and synergistic increase in UCP1 mRNA levels, superior to rosiglitazone- or FGF-21-monotreatments. Tesaglitazar-induced browning in obese mice was associated with increased energy expenditure, enhanced insulin sensitivity, reduced liver steatosis, and an overall improved metabolic profile compared to rosiglitazone and vehicle control groups.
In conclusion, we found that dual PPARα/γ agonism robustly promotes browning of white fat in vivo, via synergistic action of FGF-21 and PPARγ agonism. Our findings identify a novel opportunity to develop compounds with robust browning of WAT, via dual modulation of PPARα and PPARγ.

Disclosure
T. Kroon: Employee; Self; AstraZeneca. M.J. Harms: Employee; Self; AstraZeneca. D. Nilsson: None. A. Lindblom: Employee; Self; AstraZeneca. P. Gennemark: Employee; Self; AstraZeneca. G. O'Mahony: Employee; Self; AstraZeneca. V. Osinski: None. C.A. McNamara: None. J. Boucher: Employee; Self; AstraZeneca.
1979-P: GLP-1 Recruits Skeletal Muscle Microvasculature without Impacting Glucose Uptake or Protein Metabolism in Older Men during Postabsorptive Insulin Clamps
Authors: ABDULLA HAITHAM , PHILLIPS BETHAN E. , LIMB MARIE C. , WILKINSON DANIEL J. , JANDOVA TEREZA , CEGIELSKI JESSICA , BASS JOSEPH J. , RANKIN DEBBIE , LEWIS JONATHAN S. , WILLIAMS JOHN , SMITH KEN , ATHERTON PHILIP J. , IDRIS ISKANDAR RAUF 
Published: June 2019

Introduction: Ageing muscle is associated with impaired blood flow, “anabolic resistance” to dietary protein, and impaired glucose uptake - culminating in muscle atrophy and insulin resistance. Since GLP-1 has been shown to recruit muscle microvasculature, and due to the presence of its receptors in local tissue(s) (e.g., endothelium, myocytes) we hypothesized that GLP-1 infusions in older people, would positively impact muscle microcirculation, protein and/or glucose metabolism - in an insulin-independent fashion.
Methods: We studied seven older men (∼70±1 y, mean±SEM) in a cross-over design. Baseline measures were taken (first 3 h) prior to insulin and glucose clamps where participants received co-infusions of octreotide, Vamin 14-EF (containing essential amino acids and dextrose) - with or without GLP-1, over the next 3 h. Four muscle biopsies were taken over 90-120 minute intervals. Muscle protein turnover was quantified via A-V balance, and direct incorporation of 13C6 phenylalanine via mass spectrometric techniques. Plasma GLP-1 and insulin were quantified via Milliplex Map, ELISA. Muscle microvascular flow was assessed via contrast enhanced ultrasound. Leg glucose uptake was determined via A-V balance.
Results: GLP-1 increased microvascular flow in +GLP-1 vs. -GLP-1 conditions (increase vs. without GLP-1 infusion: 7.2±4.7 vs. 0.40±0.26-fold, p=0.009) while leg glucose uptake was unchanged. Muscle proteolysis (nb. no effects on synthesis) was equally suppressed vs. basal with GLP-1 (32.1±5.3 vs. 67.4±3.2 nmol.100 g leg-1.min-1, p&lt;0.05) and without GLP-1 (32.77±6.1 vs. 57.9±5.1 nmol.100 g leg-1.min-1 p&lt;0.05, respectively).
Conclusion: GLP-1 recruits muscle microcirculation independent of insulin. A lack of impact of GLP-1 on muscle glucose uptake or protein metabolism, could reflect a requirement for fed-state insulin levels. GLP-1 may hold therapeutic value for muscle microvascular health.

Disclosure
H. Abdulla: None. B.E. Phillips: None. M.C. Limb: None. D.J. Wilkinson: None. T. Jandova: None. J. Cegielski: None. J.J. Bass: None. D. Rankin: None. J.S. Lewis: None. J. Williams: None. K. Smith: None. P.J. Atherton: None. I.R. Idris: None.

Funding
Medical Research Council UK; Arthritis Research UK
1981-P: The Regulation of Incretin Secretion in Baby Rats in Response to a Lipid Meal
Authors: QU JIE , YANG QING , KO CHIH-WEI , LIU MIN , BLACK DENNIS D. , TSO PATRICK 
Published: June 2019

Background: Glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are incretin hormones that augment glucose-stimulated insulin secretion, promote pancreatic β-cell proliferation, neogenesis and inhibit β-cell apoptosis. Thus, they are excellent therapeutic targets against type 2 diabetes. Using a lymph fistula rat model, we studied the secretion of incretins into lymph. In adult rats, we found that GIP and GLP-1 concentrations in the fasting lymph were 132 ± 19 pg/ml and 31 ± 8 pM, respectively. After intraduodenal lipid infusion, their concentrations rose to 441 ± 144 pg/ml and 154 ± 23 pM, respectively.
Rationale: However, little is known about nutrient-stimulated secretion of GIP and GLP-1 in baby rats, whose gastrointestinal system and pancreatic β-cells are immature compared to adult rats.
Methods: Using our well-established lymph fistula model with conscious baby rats, just weaned (21 day after birth) and weighing 50-65 g, we assessed the secretion of GIP and GLP-1 in lymph after an intraduodenal challenge of lipid meal.
Results: Fasting GIP and GLP-1 levels were 295.4 ± 48.1 pg/ml and 59.6 ± 16.2 pM, respectively. After lipid infusion, GIP and GLP-1 levels increased to 1052 ± 90.1 pg/ml and 192.0 ± 19.7 pM respectively. Elevated incretin levels in baby rats (relative to adult animals) indicate possible involvement in the maturation of the enteroendocrine system and β-cells. This increase may be also important to ensure the adequate secretion of insulin to regulate blood glucose as the animals shift from a high-fat mother’s milk diet to a chow diet. Further studies are needed to determine the physiological role of the higher incretin levels in baby rats.
Conclusions: Lymph fistula baby rats can serve as an excellent model to study regulation of gut hormones by nutrient absorption at their early developmental stage. This model can also be used to study the influence of mother’s milk on the secretion of gut hormones and their impact on glucose and lipid metabolism in the newborn.

Disclosure
J. Qu: None. Q. Yang: None. C. Ko: None. M. Liu: None. D.D. Black: Advisory Panel; Self; Intercept Pharmaceuticals, Inc. P. Tso: None.

Funding
National Institutes of Health (DK59630)
1986-P: Hippocampal Overexpression of Triggering Receptor Expressed on Myeloid Cell 2 (TREM2) Ameliorates High-Fat Diet-Induced Neurocognitive Impairment via Modulating Microglial M1/M2 Polarization
Authors: WU MIN , XIAO XIAOQIU 
Published: June 2019

Objective: Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) share several common pathophysiological features. It was reported that rare variant of triggering receptor expressed on myeloid cell 2 (TREM2) increases risk of developing AD, suggesting the involvement of TREM2 and microglia in AD development. It is still unknown whether TREM2 is related to neurocognitive impairment of T2DM.
Methods: Male C57BL/6J mice were maintained high fat diet (HFD). TREM2 was overexpressed in hippocampus of mice 40 weeks after HFD feeding, using an adeno-associated virus vector (AAV)-mediated gene delivery. Morris water maze, Y maze-spontaneous alteration test, novel object recognition test, and open field test were performed 32-36 weeks and 48-50 weeks after HFD feeding. Mouse microglial BV-2 cells were used to examine microglial polarization after TREM2 overexpression or knockdown.
Results: HFD feeding caused rapid weight gain, glucose intolerance and significant impairment in learning and memory as well as anxiety-related behaviors. Compared with empty AAV delivery, TREM2 AAV significantly ameliorated glucose homeostasis and neurocognitive impairment without altering body weight in HFD mice. Hippocampal delivery of TREM2 upregulated synaptic protein spinophilin and PSD95, suggesting improvement in synaptic transmission. Microglial M2 polarization markers, such as Arg-1, YM1/2, CD206 and anti-inflammatory cytokines, were positively correlated to TREM2 levels either in the hippocampus of HFD mice or BV-2 cells in vitro.
Conclusion: Hippocampal TREM2 plays an important role in improving obesity-induced cognitive dysfunction and anxiety-like behavior via modulating microglial polarization toward M2 anti-inflammatory subtype. Our study also suggests that TREM2 might be a novel molecular target for the intervention of obesity-associated cognitive decline.

Disclosure
M. Wu: None. X. Xiao: None.

Funding
National Natural Science Foundation of China
1989-P: Ablation of Ghrelin Receptor in Myeloid Cells Attenuates Diet-Induced NAFLD in Mice
Authors: KIM DA MI , LEE JONG HAN , PAN QUAN , NOH JI YEON , WANG HONGYING , HAN HYE WON , WU CHIA-SHAN , GUO SHAODONG , SUN YUXIANG 
Published: June 2019

Chronic low-grade inflammation is a hallmark of obesity, which is directly linked to nonalcoholic Fatty Liver Disease (NAFLD) and systemic insulin resistance. Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), mediates the stimulatory effect of ghrelin on food intake and fat deposition. We previously reported that global ablation of GHS-R in mice decreases adipose inflammation, and GHS-R knockdown in macrophage cell line reduces the expression of pro-inflammatory cytokine genes. To determine the physiological role of GHS-R in macrophages, we generated myeloid-specific GHS-R knockout mice (LysM-Cre;Ghsrf/f). Under diet-induced obesity (DIO), LysM-Cre;Ghsrf/f mice showed reduced circulating inflammatory cytokine levels, attenuated insulin resistance, but no change in body weight. Moreover, DIO-induced NAFLD was ameliorated in LysM-Cre;Ghsrf/f mice, showing reduced inflammation and lipid accumulation in the liver. To understand the regulatory mechanism of macrophage GHS-R in NAFLD pathogenesis and systemic inflammation and insulin sensitivity, we conducted ex vivo studies using bone marrow-derived macrophages (BMDMs). GHS-R deficient BMDMs showed reduced macrophage pro-inflammatory polarization and decreased expression of pro-inflammatory cytokine genes; consistently, exhibiting elevated mitochondrial respiration and improved mitochondrial dynamics. Moreover, the primary hepatocytes treated with conditioned media from BMDMs of LysM-Cre;Ghsrf/f mice showed gene expression of reduced inflammatory cytokines and increased insulin signaling. Taken together, our findings reveal that GHS-R is an important immunometabolic regulator and governs macrophage polarization through regulating mitochondrial function and cellular metabolism of macrophages, moderating hepatic and systemic inflammation and insulin sensitivity. GHS-R antagonist may present a novel therapeutic strategy for the metabolic disorders such as NAFLD.

Disclosure
D. Kim: None. J. Lee: None. Q. Pan: None. J. Noh: None. H. Wang: None. H. Han: None. C. Wu: None. S. Guo: None. Y. Sun: None.

Funding
American Diabetes Association (1-15- BS-177 to Y.S.); National Institutes of Health
1999-P: Cysteine-Rich Protein 2 (CRIP2) Is a Novel Transcriptional Regulator of Uncoupling Protein 1
Authors: DARCY JUSTIN , WANG CHIH-HAO , LUNDH MORTEN , SHAMSI FARNAZ , LYNES MATTHEW , D'APRIGNY THOMAS , EMANUELLI BRICE , TSENG YU-HUA 
Published: June 2019

Since traditional weight loss strategies have been unsuccessful at slowing the increasing rate of obesity, alternative strategies are in high demand. Brown adipose tissue (BAT) is a thermogenic tissue that efficiently expends energy. Thermogenesis in BAT occurs through the action of uncoupling protein 1 (UCP1). Identifying novel transcriptional regulators of UCP1 may lead to potential targets to increase BAT activity since its expression is under tight transcriptional control. Engineered DNA-binding molecule-mediated chromatin immunoprecipitation (enChIP) is a modified CRISPR/Cas9 methodology that identifies novel transcriptional regulators. EnChIP uses dCas9 (lacks endonuclease activity) and guide RNAs (gRNAs) targeting a specific promoter region. The DNA-bound dCas9 can be immunoprecipitated, and the associated promoter region/transcriptional machinery can be sent for proteomic analysis to identify novel transcriptional regulators. Following β-adrenergic stimulation, which activates UCP1 gene transcription in brown adipocytes, we performed enChIP by using five gRNAs targeting the UCP1 promoter. EnChIP analysis of the UCP1 promoter revealed cysteine-rich protein 2 (CRIP2) as a putative transcriptional regulator of UCP1, which was validated by ChIP-PCR. We demonstrated that knocking down CRIP2 in brown adipocytes significantly decreased β-adrenergic-induced UCP1 expression and heat production. Mechanistically, we demonstrated that following β-adrenergic stimulation, CRIP2 was phosphorylated and translocated from the cytosol to the nucleus, where it interacted with peroxisomal proliferator-activated receptor gamma (PPARγ). Taken together, using the unbiased CRISPR-based enChIP approach, we identify CRIP2 as a novel transcriptional regulator that modulates UCP1 expression in response to β-adrenergic stimulation. These findings pave the foundation for developing new anti-obesity and antidiabetes therapies.

Disclosure
J. Darcy: None. C. Wang: None. M. Lundh: Employee; Self; Gubra. F. Shamsi: None. M. Lynes: None. T. d'Aprigny: None. B. Emanuelli: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.

Funding
National Institutes of Health (R01DK077097, R01DK102898, T32DK007260)
20-OR: GPR142 Agonists Increase Glucose-Dependent Insulin Secretion and Differentially Regulate Hormone Secretion in Preclinical and Phase 1 Studies
Authors: PRATT EDWARD J. , OURA TOMONORI , MA XIAOSU , LIN HUA V. , MA TIANWEI , EFANOV ALEXANDER M. , THOMAS MELISSA K. 
Published: June 2019

Agonists of G-protein-coupled receptor 142 (GPR142) are reported to increase insulin secretion and lower glucose in preclinical models. We identified a novel agonist, LY3325656 (LY) that selectively activates GPR142 in humans and mice. In preclinical models, LY increased glucose-dependent insulin secretion (GDIS) and secretion of glucagon and incretin hormones GLP-1 and GIP. To elucidate mechanisms of LY in humans, we designed a multi-part, single-dose study in 24 healthy volunteers (HV) and 12 patients with type 2 diabetes (T2D) (NCT03115099). LY was well tolerated through dose escalation up to 1950 mg in HV, with a median time to peak concentration of 4 hours and half-life of 4.59 hours. A graded glucose infusion evaluated GDIS, and LY demonstrated increased insulin secretion at higher doses (750-1950 mg). A 4-period, crossover design consisting of placebo (Pb), LY (1950mg), LY+DPP-IV inhibitor, and GLP-1R agonist treatment investigated glucose-lowering and incretin pharmacology in patients with T2D. LY significantly reduced post-meal glucose levels (2-hour glucose AUC) by &gt;10% during a mixed meal tolerance test. Increases in post-meal GLP-1 AUC concentrations with LY compared to Pb were seen in a few, but not all patients with T2D. Serum glucagon levels were consistently increased by LY in patients with T2D and HV. We conclude that GPR142 activation in humans increases GDIS and augments glucagon secretion but does not substantively augment GIP or GLP-1 secretion. Our data suggest that acute stimulatory effects of GPR142 on insulin and glucagon secretion translate from preclinical models to man, unlike preclinical effects on gut peptide secretion. Innovative and efficient single-dose studies can provide key mechanistic understanding of the translatability of preclinical findings for the treatment of T2D.

Disclosure
E.J. Pratt: Employee; Self; Eli Lilly and Company. T. Oura: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company. X. Ma: Employee; Self; Eli Lilly and Company. H.V. Lin: Employee; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Employee; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Eli Lilly and Company, Forkhead BioTherapeutics, Inc. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Ma: None. A.M. Efanov: Employee; Self; Eli Lilly and Company. M.K. Thomas: Employee; Self; Eli Lilly and Company. Stock/Shareholder; Self; Eli Lilly and Company.
2003-P: The Role of Re1-Silencing Transcription Factor (REST) in Adipocytes
Authors: FUWA MASAYUKI , KAJITA KAZUO , TAGUCHI KOICHIRO , KITADA YOSHIHIKO , IKEDA TAKAHIDE , ISHIZUKA TATSUO , MORITA HIROYUKI 
Published: June 2019

We have reported that several neuronal genes, glutamate receptor 7 and synuclein γ, are expressed in adipocytes. Since the individual roles of these neuronal genes are different, it is unlikely that these genes carry out any common functions together. Numerous neuronal genes are negatively regulated by REST. Therefore, we generated the mice lacking REST in adipocytes to investigate the role of these genes. Rest2lox/2lox mice were mated with Adipoq-Cre mice, and the resultant Adipoq-Cre/Rest2lox/2lox mice were compared with Adipoq-Cre mice. Male Adipoq-Cre/Rest2lox/2lox mice exceeding 10 weeks of age showed increased body weight and fat mass. There was no difference in food consumption, glucose tolerance evaluated by intraperitoneal GTT (ip-GTT) and adipocyte size. However, glucose tolerance was deteriorated in Adipoq-Cre/Rest2lox/2lox mice after treated with high fat diet (HFD) for 8 weeks. The characteristics of gene expression in epididymal fat isolated from Adipoq-Cre/Rest2lox/2lox mice was examined with microarray with Adipoq-Cre/Rest2lox/2lox mice as a control. Significant increased mRNA levels were detected numerous neuronal genes such as Gdap1, Nrxn1, Nrsn1 and Syn1, in Adipoq-Cre/Rest2lox/2lox mice. In addition, expression of several oncogenes, including Srrm3, Lhfpl5, Stmn3 and Chga (a marker of neuro-endocrine tumor such as pheochromocytoma) were increased in these mice. On the other hand, brown adipose tissue (BAT) in Adipoq-Cre/Rest2lox/2lox mice showed white adipose tissue (WAT)-like appearance. These results suggested that REST might regulate adipocyte differentiation and function in both WAT and BAT.

Disclosure
M. Fuwa: None. K. Kajita: None. K. Taguchi: None. Y. Kitada: None. T. Ikeda: None. T. Ishizuka: None. H. Morita: None.