bluuebunny/crossref_metadata_2025_split huggingface dataset:
OR04-02 The Role of the Sympathetic Nervous System in Metabolic Disorder and Adipose Dysfunction in Obesity and Aging
Authors: Sakamoto Kenichi , Zhou Chunxue , Maurizi Giulia , Liberini Claudia , Li Ling , Ruiz Henry H , Buettner Christoph 
Published: May 2020

Abstract
Both obesity and aging increase susceptibility to metabolic disease and type 2 diabetes where adipose tissue dysfunction is a hallmark. In both conditions, impaired autonomic control is believed to play a key role in disrupted CNS control of metabolism. However, the role of the sympathetic nervous system (SNS) and catecholaminergic signaling in metabolic disease has not been well defined in large part due to a lack of suitable animal models(1). Surgical denervation is not specific to the SNS and chemical sympathectomy through 6-hydroxydopamine causes inflammation due to toxic effects. Abrogation of catecholamine (CA) synthesis in the whole body due to genetic deletion of the gene for tyrosine hydroxylase (th), a key enzyme in CA synthesis, results in embryonic lethality likely due to the lack of dopamine and norepinephrine in the CNS where they serve as key neurotransmitters.
Here we studied the role of the SNS and catecholaminergic signaling in metabolic control in both aging as well as high fat diet (HFD) induced obesity. We created a mouse model of inducible th gene deletion that is restricted to the periphery, including sympathetic fibers of the peripheral NS but spares the brain as a pharmaco-genetic model of sympathectomy(2). TH is deleted and CA levels were reduced more than 90% in peripheral tissues of TH KO mice, while intact in the CNS. TH KO mice are cold intolerant consistent with functional sympathectomy. Interestingly, TH KO mice are protected from HFD feeding induced glucose intolerance (AUC during GTT: WT1018.8±42.0 mg/dl/hr vs. TH KO 485.0±85.8 mg/dl/hr; p &lt; 0.0001; n = 6) even though food intake increased in TH KO mice. In 20 months old TH KO mice glucose tolerance was improved and fasting blood glucose levels were reduced (AUC during GTT: WT 357.3±16.2 mg/dl/hr vs. TH KO 254.5±15.6 mg/dl/hr; p &lt; 0.01; n = 12) with higher insulin levels (WT 0.35±0.07 μg/l vs. TH KO 1.28±0.28 μg/l; p &lt; 0.001; n = 9). Of note, insulin tolerance tests did not show marked differences. Both obesity and aging are characterized by impaired adipose tissue function with reduced lipogenic capacity. TH KO mice fed a HFD exhibit increased WAT de novo lipogenesis, lower lipolysis, and trend to exhibit decreased adipose tissue inflammation, suggesting that the SNS is a major culprit for the impaired lipogenic capacity in adipose tissue. Our data provides support for the paradigm that impaired SNS function plays an important role in the dysmetabolic states of obesity and aging.
Reference
1. Ryu V, Buettner C. Fat cells gobbling up norepinephrine? PLoS Biol. 2019;17(2):e3000138.
2. Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nature medicine. 2017;23(5):623-30.
SUN-592 Adipocyte Specific Endothelin a Receptor Knockout Increases Adiposity in Mice
Authors: Rivera-Gonzalez Osvaldo , Speed Joshua S 
Published: May 2020

Abstract
Obesity is associated with increased levels of Endothelin-1 (ET-1). Blockade of ET-1 type A receptors (ETA) improves lipid profile in patients with chronic kidney disease; however the mechanism is unknown.[1] In adipocytes ETA activation increases lipolysis, a potential mechanism for elevated lipids in obese individuals.[2] Therefore, the goal of this study was to determine if adipocyte specific knockout (KO) of the ETA receptor in mice alters genes associated with lipid metabolism in adipose and improves plasma lipids. 24-week old adipocyte ETA knockout mice had significantly elevated body weight compared to floxed controls (32.6±1.0 vs. 29.5±0.7 g respectively). Echo MRI revealed that the increased body weight was due to greater adiposity (10.1±0.9 vs. 14.7±1.8 % body weight; floxed vs. KO), while no statistical difference was observed in lean weight (88.9±2.4 vs. 86.8±2.6 % body weight; floxed vs. KO). Surprisingly, there were no statistical differences in plasma total cholesterol or triglycerides. RNA sequencing indicated downregulation of 597 genes and upregulation of 444 genes in visceral adipose and downregulation of 368 and upregulation of 847 genes in subcutaneous adipose. KEGG pathway analysis revealed that most genes altered in visceral adipose were related to metabolic pathways. These data implicate a role for adipose tissue ETA receptors in regulating adiposity and promoting pathophysiology related to obesity.
1.
Farrah, T.E., et al., Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease. Hypertension, 2019. 74(2): p. 323-330.
2.
Eriksson, A.K., et al., Endothelin-1 stimulates human adipocyte lipolysis through the ET A receptor. Int J Obes (Lond), 2009. 33(1): p. 67-74.
SAT-435 A Direct Comparison of Thyroid Hormone Receptor (THR) Protein Levels in Mice Provides Unexpected Insights into TH Action
Authors: Bansal Sanya , Minakhina Svetlana , Zhang Alice , Brotherton Michael , Janodia Rucha , Oliveira Vanessa De , Tadepalli Shaan , Wondisford Fredric Edward 
Published: May 2020

Abstract
Thyroid Hormone (TH) action is mediated by three major THR isoforms α1, β1 and β2 (THRA1, THRB1 and THRB2), encoded by two genes Thra and Thrb. A fourth non-T3 binding isoform is termed THRA2. Previous characterization and comparison of THR isoform expression using QPCR of mRNA levels does not assess translational or post-translational control of THR protein levels. Moreover, reliable antibodies against all THR isoforms are not currently available. To address these concerns, we generated knock-in mouse models expressing endogenously and identically 2X HA tagged THRs (THRA1/2, THRB1 and THRB2), which could then be detected by commercially available anti-HA antibodies. We characterized THR expression in 16 mouse organs. We found that in all peripheral tissues tested except the liver, the dominant THR isoform is THRA1, and THRB1 and THRA2 are expressed at significantly lower levels or are undetectable. Surprising THRB1 levels were very low in metabolically active organs such fat and muscle. In some organs, mRNA transcript levels predicted THR protein amounts, while in others the prediction was inaccurate. For instance, adipose depots have similar levels of Thrb1 and Thra1 transcripts, however THRA1 protein levels are up to 10-fold higher than THRB1. In contrast to peripheral organs, brain tissues express low levels of both THRB1 and THRA1, but have very high levels of THRA2. As expected and confirmed in this study, THRB2 has limited expression and was only detected in pituitary of the organs tested. Interestingly, THRB2 expression in female was much higher than male mice (the only sex-difference in THR expression found); and expression of the THRB2 target gene, Tshb, was lower in female mice. For the first time, these HA-THR mouse lines can be used to accurately compare isoform-specific actions of THRs in organs. The predominant expression of THRA1 in most peripheral organs, for example, suggests that many peripheral actions of THRB1 could be indirectly mediated.
MON-335 Bisphosphonate and Denosumab Refractory Hypercalcemia of Malignancy: What Else Is at Play?
Authors: Patel Reshma , Lopresti Jonathan S 
Published: May 2020

Abstract
Hypercalcemia of Malignancy has been historically responsive to anti-resorptive agents. However, when multiple mechanisms contribute, it may be difficult to treat with one modality. This case highlights the importance of the work up in treatment of hypercalcemia in a low PTH state. A 44 yo M with h/o high grade metastatic spindle cell neoplasm with skeletal metastasis was admitted with hypercalcemia. He reported some constipation prior to presentation, however denied confusion. His vital signs were notable for HR of 86 bpm and BP of 112/75 mmHg. Labs at admission were remarkable for an uncorrected Ca of 16.1 (8.8-10.3 ng/mL), a phosphorus (Phos) level of 3.3 mg/dL (2.5-4.5 mg/dL), a PTH level of 11 pg/mL (15-65 pg/mL), PTHrP level of 134 pg/mL (14-27 pg/mL), a 25 OH vit D level of 11 ng/mL (30-100 ng/mL), and a BUN/Cr and GFR of 34/2.38 (8-22 mg/dL/0.5-1.3 mg/dL) and 32 ml/min/m2. He was given intranasal calcitonin and ergocalciferol, then received 2mg IV of zolendronic acid, which reduced the patient’s Ca level to a nadir of 6.6 ng/mL in 5 days. On the next admission serum Ca was elevated to 15.7 ng/dL, which did not respond to zolendronic acid. Given that patient’s Ca was refractory to zolendronic acid, denosumab was given but had no response. He then underwent surgery for cord compression and was given dexamethasone (dex) 4mg IV Q6h post-op. His Ca responded quickly to dex, with a nadir to 9.2 ng/dL, however his Ca became elevated after cessation. Given response to dex, vit D 1,25 OH level was sent and was elevated at 94 pg/mL (18-72 pg/mL). In addition, given his inappropriately normal Phos level in the setting of low PTH, FGF23 was sent and came back elevated at 473 RU/mL (&lt;180 RU/mL). This was likely due to increased bone turnover and release of FGF23. He was discharged with a Ca level of 12.5 ng/mL, however was found to have an elevated Ca to 14.9 ng/mL on presentation to clinic. Given concern that Vit D 1,25 OH, PTHrP and direct bony involvement were all contributing to his hypercalcemia, patient was started on IVF and dex IV. His calcium responded 11.5 ng/mL and was then transitioned to PO dexamethasone and plaquenil. The most likely explanation for this phenomenon is malignancy induced cytokine/PAMP release, which stimulates 1-alpha hydroxylase in tumor macrophages to convert 25 OH D to 1,25 OH D. This was supported by his elevated 1,25 OH D level and a decreased 25 OH D, which suggests that 25 OH D was used as substrate by activated macrophages. This case highlights the importance of ancillary work up of hypercalcemia when a patient’s calcium is refractory to standard anti-resorptive therapy. Moreover, it shows the need for a systematic approach when treating hypercalcemia.
MON-648 Chronic Unpredictable Environmental Stress May Induce Predisposition to Diabetes Mellitus
Authors: Raghav Alok 
Published: May 2020

Abstract
Title: Chronic Unpredictable Environmental Stress may induce predisposition to diabetes mellitus Objective: Chronic unpredictable environmental stress (CUES) may induce predisposition to diabetes mellitus. Material & Methods: This study investigates the role of CUES on impaired homeostasis. Stressed group mice (n=20) were exposed to CUES for 16 weeks. Weekly body weight, feed consumption, feed efficiency ratio, fasting blood glucose were monitored. Plasma HbA1c, plasma cortisol, plasma epinephrine and plasma insulin, serum lipids, antioxidants and carbohydrate metabolizing enzymes activity were assessed along with DNA damage and histopathological examination of liver, kidney, pancreas, spleen and skeletal muscles. Semi-quantitative expression of IL-4, IL-6 and β- actin was also assessed. Results: Fasting blood glucose levels & HbA1c in the stressed were significantly higher compared to control (p&lt;0.001). Serum lipids were found insignificantly higher in stressed mice compared to control. Body weights of the stressed mice and feed efficiency ratio were found significant (p&lt;0.001). Plasma corticosterone, plasma epinephrine, HOMA-IR was found to be significantly higher in the stressed group (p&lt;0.001). Plasma insulin level was found to be significantly lower in the stressed group (p&lt; 0.001). Significant changes were observed in antioxidants level, carbohydrate metabolizing enzymes activity, peripheral tissues and DNA integrity. Expression of IL-4, IL-6 was found significantly higher in the stressed group. Conclusions: CUES initiates pathogenesis of diabetes.
OR03-02 Identification of a Novel Stem/Progenitor Population of the Adrenal Medulla
Authors: Santambrogio Alice , Russell John P , Lodge Emily J , Scriba Laura D , Berger Ilona , Hakansson Hanna , Steenblock Charlotte , Eisenhofer Graeme , Fassnacht Martin , Bornstein Stefan R , Andoniadou Cynthia L 
Published: May 2020

Abstract
The adrenal glands regulate multiple physiological processes including the stress response, the immune system and metabolism. The adrenal is composed of an outer cortex that produces steroids, and an inner medulla that produces catecholamines. Tissue-specific stem/progenitor populations have been identified in the adrenal cortex, while the presence of a functional stem/progenitor population in the adrenal medulla is unclear. The adrenal medulla derives from the neural crest and contains chromaffin cells, neurons and sustentacular (support) cells. Establishing cell hierarchy and elucidating mechanisms of regulation of the different cell types is important to understand normal homeostasis and disease pathogenesis, such as of pheochromocytomas. Using genetic approaches in mouse, we have established that a subpopulation of sustentacular cells express the stem/progenitor marker SOX2. Through genetic lineage-tracing using the Sox2-CreERT2 strain, we demonstrate that these are an expanding population, capable of giving rise to chromaffin cells and neurons throughout life, consistent with a stem/progenitor role in vivo. We further demonstrate the self-renewal and differentiation potential of SOX2+ cells through in vitro isolation and expansion. Through analysis of FFPE sections of human adrenals, we confirm the presence of SOX2+ cells in the normal adult organ, as well as in pheochromocytomas. Taken together, our data support the identification of a previously undescribed stem/progenitor cell in the mammalian adrenal medulla, and confirm its functional relevance.
MON-251 Xanthogranulomatous Hypophysitis: A Rare Case of Hypopoituitarism
Authors: Romero Fabiola , Lopez Helen , Terwindt Natalia , Sanchez Humberto , Ocampos Sara , Avalos Andres , Boggino Hugo , Pfannl Rolf , Ayala Alejando 
Published: May 2020

Abstract
The patient is a 54-year-old male with type 2 diabetic treated with insulin who presented with a two-week history of fever nausea and vomiting. He subsequently developed seizure episodes with changes in mental status prompting a visit to the emergency room. Upon admission the patient was hypotensive and lethargic. After an initial improvement, he developed polyuria (14-15 liters per day) in the context of eunatremia and specific gravity of 1010. His initial evaluation revealed a serum a.m. cortisol of 1.2 mcg/dL (6.2 to 19.4), low free T4 of 0.64 Ng/dl) 0.9-1.7) and secondary hypogonadism with a total testosterone of less than 2.5 ng/dL (181-772). Hormonal replacement was initiated. MRI of the brain revealed heterogeneous sellar lesion measuring 2.1 x 2.0 x 2.0 cm with peripheral enhancement following contrast administration and deviation of the pituitary stalk to the right. The lesion invaded the left cavernous sinus (Knosp III) and abutted the optic chiasm. He underwent an uneventful transsphenoidal tumorectomy revealing extensive coagulation necrosis with chronic lymphocytic infiltration, numerous macrophages and multinucleated giant cells with deposits of hemosiderin, cellular debris and isolated cholesterol crystals surrounded by granulomatous tissue. The pathology was compatible with xanthogranulomatous hypophysitis. We report a rare case of Xanthogranulomatous hypophysitis (XGH), the least common subtype of pituitary hypophysitis often mistaken by a neoplastic lesion. It is more common in young adults occurring in isolation, as a secondary reaction to a local process such as apoplexy part or as part of a systemic condition with autoimmune aetiology, often resulting in variable degrees of anterior and posterior pituitary deficiencies.
SUN-660 Appetite Suppressing Effects of Glucoregulatory Chimeric Peptides Devoid of Nausea
Authors: Roth Christian Ludwig , Milliken Brandon T , Elfers Clinton , Sweet Ian , Doyle Robert 
Published: May 2020

Abstract
Current treatments for type 2 diabetes (T2D) and obesity do not reliably achieve long-term weight-loss and up to 50% of patients experience nausea and vomiting. Thus, there is a critical need for obesity medications that provide glycemic control with enhanced hypophagic response without nausea. Based on rational design and in silico modelling of the glucagon-like peptide 1-receptor agonist (GLP1RA) exendin-4 (Ex4) and the neuropeptide Y2 receptor (Y2R) agonist peptide YY (PYY) 3-36, our group has developed and tested several new monomeric chimeric peptides that display dual agonism of the anorectic Y2R and the glucoregulatory GLP1R. In addition, we explored a third agonistic behavior at the neuropeptide Y1 receptor (Y1R), which potentially relates to pancreatic beta-cell protection. Our current lead, GEP44, binds and robustly activates the Y2R, Y1R, and GLP1R. In our experiments, half maximal effective concentration (EC50) values for GEP44 were 10 nM at Y2R, 24 nM at Y1R, and 330 pM at GLP1R for dose responses of cell-based fluorescence resonance energy transfer assays. For the control substrates PYY3-36, PYY1-36, and Ex4, EC50 values were 16 nM, 12 nM, and 16 pM at the Y2R, Y1R, and GLP1R, respectively. We tested effects of daily injections of these chimeric peptides in adult Sprague-Dawley rats on food intake (FI), body weight (BW) changes, blood glucose levels and an indicator of nausea (kaolin intake). GEP44 produced profound reduction in FI (2-d average GEP44 at 20 nmol/kg FI -71%; Ex-4 20 nmol/kg FI -40%). Anorectic doses of GEP44 did not trigger a pica response assessed by kaolin consumption in treated rats, while in Ex-4 treated rats, kaolin consumption accounted for 28% of total daily solid intake, indicating a clear nausea response. During 11 d of treatment with GEP44, FI was consistently reduced resulting in a significantly stronger reduction of BW compared to Ex4 at the end of treatment (GEP44 -7.6%, Ex4 -3.7%, p&lt;0.05). Furthermore, 5-day injections of GEP44 showed greater reduction of glucose levels than for Ex4 in diet induced obese rats receiving intraperitoneal glucose. These results were supported by results generated using a customized perifusion system that demonstrated acute stimulation of insulin secretion by exposure of isolated rodent and human islets to GEP44 and Ex4 (both p&lt;0.01 vs. vehicle). In conclusion, simultaneously targeting serial anorectic pathways with single molecule chimeric peptides developed by our group can address multiple coexisting conditions, namely obesity and T2D, to more efficaciously reduce FI, BW and blood glucose levels thereby reducing off target effects.
SUN-211 Active Steroid Hormone Synthesis Renders Adrenocortical Cells Highly Susceptible to Type II Ferroptosis Induction
Authors: Weigand Isabel , Schreiner Jochen , Roehrig Florian , Sun Na , Laura-Sophie Landwehr , Urlaub Hanna , Kiseljak-Vassiliades Katja , Wierman Margaret E , Angeli José Pedro Friedmann , Walch Axel K , Sbiera Silviu , Fassnacht Martin , Kroiss Matthias 
Published: May 2020

Abstract
Context: Cell death in the adrenal cortex is ill understood but of high clinical relevance. Resistance of adrenocortical carcinoma (ACC) to current treatment with mitotane and chemotherapy calls for an improved understanding of adrenal cortical cell death processes. Ferroptosis is an iron-dependent form of regulated cell death which is characterized by polyunsaturated lipids adrenic (AdA) and arachidonic acid (AA) peroxidation. Aim: To address the potential role of ferroptosis in the adrenal gland as a potential treatment target of ACC. Methods: Human ACC cells H295R, CU-ACC1 and 2 were used. Protein expression of key enzymes was determined by western blotting. Lipid peroxidation was quantified with BODIPY 581/591 and cell viability with CellTiterGlo after treatment with known inducers and inhibitors of ferroptosis and steroidogenesis, respectively. Results: Adrenocortical tissues are enriched in AdA and AA and express high levels of genes relevant to ferroptosis, such as glutathione peroxidase 4 (GPX4) and long-chain-fatty-acid CoA ligase 4 (ACSL4). Inhibition of GPX4 with RSL3 led to cell death in H295R, CU-ACC1 and 2 cells at EC50 values of 2.4x10-7, 8.1x10-7 and 1.5x10-8 M, respectively. The steroidogenesis inhibitor ketoconazole completely reversed RSL3 cytotoxicity in all three steroidogenic cell lines by reducing lipid peroxidation. Mitotane induced lipid peroxidation but inhibition of ferroptosis with liproxstatin did not protect mitotane-induced cell death. Conclusion: Adrenocortical cells are highly sensitive to ferroptosis due to active steroidogenesis. Triggering this form of cell death could present future novel treatment options against ACC.
SUN-484 Complex Thyroid Cancer with Several Recurrences and Metastases
Authors: Patel Kruti K , Via Michael 
Published: May 2020

Abstract
56-year-old male with metastatic papillary thyroid cancer who underwent total thyroidectomy in 8/2014, and I-131 ablation in 9/2014, with post-operative pathology revealing multifocal, bilateral papillary thyroid cancer with extrathyroidal extension with surgical resection margins uninvolved. There were positive lymphovascular spread and multiple central compartments and bilateral neck nodes metastases with extranodal extension. Subsequent thyrogen stimulated whole-body scan in 2/2016 showed no areas of uptake.However, in 12/2016 he was found to have right supraclavicular lymph nodes positive for recurrence which was resected and given another 168 mCi I-131 and 33 treatments of XRT to R shoulder.A repeat PET in 7/2019 showed persistent hyper metabolic lesion in C7, multiple hyper metabolic nodules throughout the R lung, and a new 1.1 cm left Hilar lymph node suggesting disease progression. Biopsy of the C7 lesion confirmed dedifferentiated papillary thyroid cancer and demonstrated the presence of an NTRK mutation.This time he was given lenvatinib 24 mg daily for 4 weeks, followed by 200 mCi I-131. Post-treatment whole body scan showed good uptake in all lesions, except the C7 lesion which was treated with external radiation. DiscussionWhile cure is achieved in most cases of differentiated thyroid cancer, a minority of cases demonstrate disease progression. Loss of response to I-131, very low serum thyroglobulin levels despite known disease, and high PET avidity provide clinical evidence of dedifferentiation, confirmed with tissue sampling.If feasible targeted systemic therapy remains the best tolerated treatment option.While several studies demonstrate an increase in iodine avidity in approximately 50-60% of patients with dedifferentiated thyroid cancer that were treated with tyrosine kinase inhibitors (TKI), (cite alan Ho’s 2013 NEJM article, and the 2015 debrafenib study Rothenberg SM et al, clin cancer res 2015), selumetanib remains unavailable for clinical use and dabrafenib may only be beneficial in cases with known BRAF V600E mutations. Moreover, it is unknown whether a planned short course of TKI therapy would potentially induce resistance to future TKI therapy.Therefore, lenvatinib, which inhibits activity of at least 6[VM1] different tyrosine kinase enzymes important in thyroid cancer was chosen rather than entrectanib, which was reserved for use if the need arises. This patient demonstrated excellent response to I-131 therapy with lenvatinib pretreatment.A number of formal studies of various TKIs for thyroid cancer re-differentiation are currently underway. (cite Brown SR, Hall A, et al BMC cancer 2019; and also cite the CIII trial with cabozatanib)Conclusion This case represents the emerging paradigm for the ability of TKI therapy to redifferentiate advanced thyroid cancer and allow for re-treatment with I-131 targeted therapy.