bluuebunny/crossref_metadata_2025_split huggingface dataset:
225-OR: 5-Methoxytryptamine Improves Obesity-Related Inflammation and Insulin Resistance by Regulating M1/M2 Macrophage Polarization
Authors: LIAO XIAOYU , LIU BINGYAO , ZHENG HONGTING 
Published: May 2022

In our previous study, we demonstrated that hypoglycemic agent DPP-4i changed the gut microbiota composition in diabetic patients and mice, and the DPP-4i-altered microbiome improved glucose tolerance in colonized mice. However, the mediators and their mechanisms remain to be elucidated. Comparing the intestinal metabolite profiles of HFD mice treated with or without sitagliptin (Sit) , we identified tryptophan derivative 5-methoxytryptomine (5-MT) was obviously increased after Sit treatment. In HFD and db/db mice, 5-MT treatment significantly reduced the body weight, improved glucose tolerance and insulin resistance, and ameliorated hepatic steatosis and inflammation. Drug affinity responsive target stability (DARTS) assay demonstrated the interaction between 5-MT and Aryl hydrocarbon receptor (AhR) . Specific inhibition of AhR attenuated the effects of 5-MT on improving insulin resistance. Furthermore, molecular mechanism exploration revealed that 5-MT promoted the expression and secretion of chemokine Cxcl14, which promoted macrophages maturation into alternative activation (M2-like) , subsequently inhibiting the production of inflammatory factors. These data demonstrate novel beneficial roles of 5-MT in improving obesity-related inflammation, insulin resistance and hepatic steatosis.

Funding
National Science Fund for Distinguished Young Scholars of China (No.81925007) , National Natural Science Foundation of China (No.81700757)
228-OR: Differential Expression of miRNA in Human Subcutaneous and Visceral Adipose Tissue Is Related to Insulin Resistance
Authors: SAINI NATESH , DENG ALICIA , CHEN HENRY , XU YUE , TSAO PHILIP S. , MCLAUGHLIN TRACEY 
Published: May 2022

Introduction: Obesity is related to insulin resistance (IR) but not all obese individuals are IR. Differences in regional fat distribution and function contribute to the metabolic heterogeneity of obesity. miRNA is known to regulate mRNA and may play a role in mediating IR by modifying adipose tissue function. We tested the hypothesis that miRNA in human visceral (VAT) and subcutaneous (SAT) fat would be differentially expressed in individuals who were classified as insulin sensitive (IS) or IR.
Methods: 12 participants, classified as IR or IS (top 40 percentile) via steady-state plasma glucose (SSPG) test, were recruited from the Stanford Bariatric Surgery Clinic. Tissue samples (SAT and VAT) were harvested from the greater momentum during bariatric surgery. Total RNA was extracted with QIAGEN RNeasy® Lipid Tissue Mini Kit. The miRNA experiment used QuantStudio™ 12K Flex OpenArray® microRNA Starter Kit with modifications by adding Ath-miR-159a spike-in, and use of SuperScript VILO cDNA Synthesis Kit. Data analysis done via Applied Biosystems™ Relative Quantitation Analysis. miRNA comparisons with fold-change &lt;0.5 or &gt;2 and p&lt;0.were considered statistically significant. Known target genes of significant miRNA were quantified via RT-PCR from tissue samples.
Results: Differential expression in VAT vs. SAT showed one upregulated (miR-885-5p) and 12 downregulated miRNAs. In SAT, for IR vs. IS individuals showed 12 upregulated miRNA, while in VAT, IR vs. IS included one upregulated (miR-30c) and downregulated miRNA.
Conclusion: In VAT relative to SAT, miR-885-5p was a significant predictor of fatty liver and majority of downregulated miRNA (miR-335, 196b, 497, 22, 106b, 340) reduced lipogenesis and increased insulin signaling. In IR vs. IS of SAT, majority of miRNA reduced insulin sensitivity (miR-146b, 29c, 502-3p) . For IR vs. IS of VAT, miR-30c promoted adipocyte differentiation and majority of downregulated miRNA increased insulin sensitivity (miR-106b, 24, 143, 340) .

Disclosure
N.Saini: None. A.Deng: None. H.Chen: None. Y.Xu: None. P.S.Tsao: None. T.Mclaughlin: Board Member; January, Inc., Research Support; Merck & Co., Inc., Novo Nordisk, Stock/Shareholder; Eiger BioPharmaceuticals.
231-OR: Antecedent Hypoglycemia Increases Damage Due to a Subsequent Myocardial Infarction in Rats
Authors: CHRISTENSEN CAMILLE G. , FISHER SIMON , RENO CANDACE M. 
Published: May 2022

Several clinical trials have noted an association between hypoglycemia and major cardiovascular events; however, a direct link between antecedent hypoglycemia and worse cardiac outcomes has not been established. We hypothesized that antecedent recurrent hypoglycemia predisposes the heart to increased damage following a subsequent myocardial infarction. To test this hypothesis, adult Sprague Dawley rats were subjected to 3 days of recurrent insulin-induced hypoglycemia (25-30 mg/dl, 90 minutes each day; n = 6) or saline (control, n = 6) . On the following day, all rats underwent a myocardial infarction (MI) induced by occlusion of the left anterior descending artery for 30 minutes followed by reperfusion for 60 minutes. Electrocardiograms indicated ST elevation during the MI, which returned to normal sinus rhythm upon reperfusion. Hearts were removed immediately and analyzed for damage. MI induced ventricular damage from rats that underwent antecedent recurrent hypoglycemia (39 ± 5%) was significantly higher than control rats (16 ± 4%; p&lt;0.001, Figure) . Additionally, plasma norepinephrine levels were elevated 14-fold in rats that underwent recurrent hypoglycemia. These studies indicate that antecedent hypoglycemia directly contributes to worse outcomes following an MI and that increased norepinephrine is associated with this damage.

Disclosure
C.G.Christensen: None. S.Fisher: None. C.M.Reno: None.

Funding
University of Utah’s Driving Out Diabetes, a Larry H. Miller Family Wellness InitiativeNational Institutes of Health (P30 DK020579) Juvenile Diabetes Research Foundation (1-FAC-2020-984-A-N)
232-LB: Housing Temperature Can Profoundly Influence Pharmacologically Induced Weight Loss Efficacy and Mode of Action in Diet-Induced Mice—A Cautionary Consideration for Human Translation
Authors: PETERSEN NATALIA , TORZ LOLA , GERSTENBERG MARINA K. , PEDERSEN KENT , MADSEN SUZI H. , ØSTERGAARD SØREN , WULFF BIRGITTE S. , JØRGENSEN SEBASTIAN B. , ANDERSEN BIRGITTE S. , CHRISTOFFERSEN BERIT Ø. , JOHN LINU M. , KUHRE RUNE E. 
Published: May 2022

Objectives: Pre-clinical evaluation of drug efficacy on weight loss is usually done in diet-induced obese (DIO) mice housed at room temperature (∼22°C) , where the mice display adaptive thermogenic responses through brown adipose tissue (BAT) activation to increase energy expenditure (EE) and maintain core-temperature. These adaptive responses may influence drug-induced weight loss and ultimately likelihood for translatability to humans, who does not have thermogenic responses at room-temperature. We tested whether the efficacy of diverse weight-reducing pharmaco-therapies with distinct mode of action is impacted by housing temperature.
Methods: Male DIO mice were studied with indirect calorimetry (Sable Systems International) at 22°C or 30°C (thermoneutrality) . Mice were treated daily for 10-21 days with analogues of weight-modulating compounds that have been in clinical development: glucagon-like peptide-1 (GLP-1) , melanocortin-4-receptor (MC4R) agonist, growth differentiation factor 15 (GDF15) , peptide YY (PYY) , and fibroblast growth factor 21 (FGF21) aiming for a weight loss (WL) of 10-25%.
Results: Energy expenditure was ∼30% higher 22°C compared to 30°C. Housing temperature did not affect GLP-1 (∼20%) and MC4R (∼10%) mediated WL. However, FGF21 and PYY-mediated WL was higher at 30°C (∼20% vs. ∼17% for FGF21 and ∼9% vs. ∼1% for PYY) . In contrast, GDF15-mediated WL was higher at 22°C (∼14% vs. ∼8%) . The relative contribution of inhibition of food intake vs. increase in EE differed for FGF21 but not for the other compounds. In this case, increased EE, by BAT, drove more of the weight loss in the 22°C group.
Conclusion: Ambient temperature may affect both efficacy and mode of action of weight-reducing pharmaco-therapies in DIO mice. This may affect human translatability, and we, therefore, suggest that studies at thermoneutrality should be included at an early stage in drug-development programs.

Disclosure
N. Petersen: Employee; Novo Nordisk A/S. B. Ø. Christoffersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S. L. M. John: None. R. E. Kuhre: Employee; Novo Nordisk. L. Torz: Other Relationship; Novo Nordisk A/S. M. K. Gerstenberg: Employee; Novo Nordisk. K. Pedersen: Employee; Novo Nordisk A/S. S. H. Madsen: None. S. Østergaard: Employee; Novo Nordisk A/S. B. S. Wulff: Employee; Novo Nordisk A/S. S. B. Jørgensen: Employee; Novo Nordisk A/S. B. S. Andersen: Employee; Novo Nordisk A/S.

Funding
Novo Nordisk A/S
234-LB: Role of P311 in Adipocyte Plasticity and Metabolic Regulation
Authors: BADRI KAMESWARA R. 
Published: May 2022

The prevalence of obesity in the United States and worldwide has increased dramatically over the past 20 years. Currently it is affecting about 40% of adults and more alarmingly about 20% of children in the US. Obesity is a major risk factor and comorbid condition for chronic metabolic conditions like insulin resistance, Type 2 diabetes and dyslipidemia etcetera. Hence, the increase in the incidence of obesity and the metabolic dysregulation-associated morbidity and mortality and rising costs of treatments warrants a deeper understanding of all aspects of adipocyte biology to develop novel therapeutics to thwart this pandemic. Recent research developments identified three different types of adipose tissues, white adipose tissue (WAT) , beige adipose tissue and brown adipose tissue, increasing the complexity of adipose biology and adipocyte plasticity in metabolic regulation. P311 is a small intrinsically unstructured protein that shows adipogenic properties. We show for the first time that P311 is expressed in white, beige and brown adipose tissue and young P311 knockout mice show increased WAT and/or decreased beige AT implicating that P311 plays a key role in adipocyte plasticity and regulating quality and quantity of the AT. Further, aged P311 KOs are significantly obese with hyperglycemia and deranged glucose tolerance. Our findings are the first to show the role of P311 in adipose biology, adipocyte plasticity and metabolic regulation.

Disclosure
K. R. Badri: None.

Funding
National Institute of Health (U54MD007602, S21MD000101)
237-LB: Weight-Independent Effects of Roux-en-Y Gastric Bypass Surgery on Remission of Nonalcoholic Fatty Liver Disease in Mice
Authors: AXELROD CHRISTOPHER L. , LANGOHR INGEBORG M. , DANTAS WAGNER S. , LEIGH TOWNSEND R. , ALBAUGH VANCE L. , KIRWAN JOHN P. , BERTHOUD HANS-RUDOLF 
Published: May 2022

Introduction: Obesity is the primary determinant of nonalcoholic fatty liver disease (NAFLD) . Interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR) , may serve as effective therapies for NAFLD. The purpose of this study was to compare the effects of Roux-en-Y gastric bypass surgery (RYGB) to CR on hepatic function in mice with obesity and NAFLD.
Methods: 6-week-old male C57BL/6J mice were fed a two-choice chow/high-fat diet (HFD) to promote diet-induced obesity. At 16 weeks of age, mice were randomized to (1) sham surgery (Sham) , (2) RYGB, or (3) sham + weight-matched calorie restriction to RYGB (WM) . Mice were euthanized at 36 weeks for determination of NAFLD/NASH and hepatic function. Body weight/composition and food intake were measured weekly during the treatment period. ANCOVA-adjusted energy expenditure (EE) was determined 3 and 17 weeks after treatment. Hepatic lipid content and NAFLD scores were determined from H&E-stained tissue sections. Hepatic enzymes and glycogen content were determined by ELISA.
Results: RYGB & WM achieved a similar reduction in body weight relative to baseline. RYGB decreased adiposity to a greater extent than WM relative to baseline and Sham (-4.4±0.6 vs. -1.3±0.6 Δg, P&lt;0.001) . Decreased body weight was attributable to lower food intake in WM compared to RYGB and Sham (P&lt;0.0001) . WM decreased EE relative to RYGB and Sham (WM:8.6±0.4 vs. RYGB:10.4±0.4 vs. Sham:10.5±0.6 kcals/day, P&lt;0.001) . RYGB decreased hepatic lipid content to a greater extent than WM (92.6 vs. 76.5 % reduction, P=0.02) . RYGB and WM similarly decreased AST and ALT activity relative to Sham. RYGB increased hepatic glycogen relative to both Sham and WM (P&lt;0.001) .
Conclusions: RYGB and WM improve hepatic function and decrease the severity of NAFLD through shared and discrete mechanisms of action. RYGB decreases hepatic lipid content to a greater extent than WM independent of food intake, indicating that evading the expected metabolic adaptation in EE after weight loss likely accounts for the additive hepatic benefit of RYGB.

Disclosure
C. L. Axelrod: None. I. M. Langohr: None. W. S. Dantas: None. R. Townsend: None. V. L. Albaugh: None. J. P. Kirwan: None. H. Berthoud: None.

Funding
National Institutes of Health (U54GM104940)
238-OR: A Single Hypoglycemic Event Causes a Prolonged Immune Response
Authors: VERHULST CLEMENTINE E. , VAN HECK JULIA , FABRICIUS THERESE W. , STIENSTRA RINKE , TACK CORNELIS , PEDERSEN-BJERGAARD ULRIK , DE GALAN BASTIAAN E. , CONSORTIUM HYPO-RESOLVE 
Published: May 2022

Hypoglycemia acutely activates the immune system and is associated with an increased risk for atherosclerotic disease. Since atherosclerosis is driven by inflammation, we set out to determine the duration of the pro-inflammatory response to a hypoglycemic event in people with and without diabetes. Adults with type 1 diabetes (n = 47) or insulin-treated type 2 diabetes (n = 15) , and age-matched controls without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic (5.2 ± 0.4 mmol/L) -hypoglycemic (2.8 ± 0.1 mmol/L) glucose clamp. Before, during and up to a week thereafter, blood was drawn to determine circulating immune cell composition and function combined with measurements of and circulating hs-CRP concentrations. At baseline, participants with diabetes had higher counts of produced cytokines and hs-CRP compared to individuals without diabetes (all p &lt; 0.01) . In response to hypoglycemia, absolute numbers of lymphocytes (1.57 ± 0.53 vs. 2.69 ± 0.95·103/µL) and monocytes (0.40 ± 0.14 vs. 0.62 ± 0.22·103/µL) increased acutely and remained elevated for one week in all subgroups (all p &lt; 0.001) . During hypoglycemia, the proportion of pro-inflammatory CD16+-monocytes increased from 26.9 ± 13.3% to 38.1 ± 14.9% and the proportion of phagocytotic CD14+-monocytes decreased from 65.2 ± 14.4% to 54.5 ± 15.9% in all subgroups (all p &lt; 0.01) . Stimulated monocytes released more TNF-α and IL-1β, and less IL-during hypoglycemia. Similarly, hs-CRP concentrations increased from 2.± 3.20 µg/mL to 2.71 ± 3.57 µg/mL 1 day after the clamp (p &lt; 0.001) and remained elevated for one week (p &lt; 0.001) thereafter to similar extent in all subgroups.
In conclusion, a single hypoglycemic event induces a prolonged immune response in humans independent of the presence of diabetes.

Disclosure
C.E.Verhulst: None. J.Van heck: None. T.W.Fabricius: None. R.Stienstra: None. C.Tack: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. B.E.De galan: Research Support; Novo Nordisk. Hypo-resolve consortium: n/a.

Funding
The Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement 777460. The JU receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA and T1D Exchange, JDRF, International Diabetes Federation (IDF) , The Leona M. and Harry B. Helmsley Charitable Trust.
240-LB: Adipogenesis in Weight Regain Does Not Accelerate Adiposity in Mice
Authors: GERSTENBERG MARINA K. , BOOKOUT ANGIE , CASTORENA CARLOS M. , TORZ LOLA , DOVMARK TOBIAS H. , LUNDH SOFIA , MADSEN SUZI H. , ANDERSEN BIRGITTE S. , PEDERSEN THOMAS A. , KUHRE RUNE E. , PETERSEN NATALIA 
Published: May 2022

Weight loss and regain are associated with profound cytoskeleton changes in collapsing and re-expanding adipocytes. These drastic changes in the adipose tissue may drive proinflammatory signalling and fibrotic processes during weight regain. It remains unclear how adipose tissue re-expansion affects adipose tissue function and thereby the comorbidities related to obesity. The aim of this study was to characterize structural and metabolic changes in subcutaneous adipose tissue after weight loss and regain in diet-induced obesity (DIO) mice. DIO mice underwent calorie restriction to achieve a 25% weight loss and then returned to ad libitum high fat diet feeding to regain weight. Inguinal adipose tissue was collected and analysed from five groups of mice during the experiment: before high fat diet feeding (Lean) , before weight loss (DIO 1) , after weight loss (WL) , after 3 weeks of weight regain (WR) and age-matched ad libitum DIO mice (DIO 2) . We found that WR group had lower weight and fat mass compared to DIO2 group (31.9±1.6 vs. 23.9±1.9 %) and lower basal lipolysis measured ex-vivo. We detected a larger population of small adipocytes in WR mice compared to DIO2 group, resulting in smaller average adipocyte size (81.6±1.4 vs. 52.5±0.9 µm) and increased expression of cell renewal markers Cidea, Antrx1 and Prkaa in adipose tissue, indicating activation of adipogenesis. Expression of cytokines Il2, Ccl19, Cdc3 in adipose tissue in WR compared to DIO was reduced as well as plasma levels of cytokines Il2, KC/GRO and Inf-γ.
In conclusion, our study does not support that increased adipogenesis in weight regain results in accelerated fat accumulation in mice. Weight regain is accompanied by reduced systemic and adipose inflammation. This suggests in general a beneficial effect of regain-induced adipogenesis resulting in potentially healthier adipose tissue in mice. Weather these findings represent the human situation with weight loss and regain is unknown and is currently under investigation.

Disclosure
M. K. Gerstenberg: Employee; Novo Nordisk. R. E. Kuhre: Employee; Novo Nordisk. N. Petersen: Employee; Novo Nordisk A/S. A. Bookout: Employee; Novo Nordisk. C. M. Castorena: Employee; Novo Nordisk. L. Torz: Other Relationship; Novo Nordisk A/S. T. H. Dovmark: None. S. Lundh: Employee; Novo Nordisk A/S. S. H. Madsen: None. B. S. Andersen: Employee; Novo Nordisk A/S. T. A. Pedersen: Employee; Novo Nordisk A/S, Stock/Shareholder; Novo Nordisk A/S.
241-LB: Significant Worsening of Preexisting Obesity in South Texas Children during COVID-19 Lockdown
Authors: CERVANTES FRANCISCO J. 
Published: May 2022

Background: Obesity has been on the rise for the past several decades, which is associated with increased risk for comorbidities and severe consequences to the individual. In the Mexican American community, obesity has become a serious problem in children. The COVID-19 lockdown order issued in February 2020 caused further challenges for children to engage in regular physical activity.
Objective: To determine if the COVID-19 lockdown impacted the weight of 95% Medicaid-insured Mexican American children at a pediatric clinic in South Texas.
Design and Methods: We identified 417 new patients from March 2019 to February 2020 (with exclusion of 104 newborns) and followed them until December 2021. Height and weight were measured to estimate Body Mass Index (BMI) . The percentage of overweight or obese (OW/OB) children was calculated at the first and last visit.
Results: We had a total of 346 children at the end of the study. The average stature of the whole group was at the 48th percentile with 60% of the children at or below the 50th percentile based on CDC growth charts. Boys increased BMI from the 62.7th to 71.8th percentile (p&lt;0.01) and girls increased from the 60th to the 70th percentile (p&lt;0.02) . The distribution of BMI of the whole group indicated that 34.5% of children were OW/OB on the first visit and 49% were OW/OB at the last visit.
Conclusion (s) : Our study exemplifies that the lockdown during the COVID-19 pandemic, which was associated with decreased physical activity, increased the BMI of children and increased associated comorbidities based on lab values. We have shown in previous studies that when BMI is in the OW/OB category, children have increased blood pressure, decreased high density lipoproteins, elevated liver enzymes, increased insulin resistance, larger kidneys, and fatty liver. These indicators place children at a higher risk for early development of hypertension, renal function decline, diabetes, and cardiovascular disease.

Disclosure
F. J. Cervantes: None.
245-OR: Age and Diabetes Interact to Decrease Muscle Mitochondrial Function
Authors: ABUSHAMAT LAYLA , SCALZO REBECCA L. , RAMIREZ DAVID , SCHAUER IRENE E. , KNAUB LESLIE , CLARK ETHAN , REYES YESENIA GARCIA , CREE-GREEN MELANIE , REUSCH JANE , REGENSTEINER JUDITH G. 
Published: May 2022

People with T2D have lower cardiorespiratory fitness (CRF) than those without diabetes contributing to increased cardiovascular morbidity and mortality. People with T2D have impaired oxidative flux associated with lower CRF. Yet, reports on muscle mitochondrial dysfunction in T2D are mixed. As diabetes duration and age are predictors of poor outcomes, we hypothesized that T2D and increased age associate with impaired mitochondrial function. We assessed post-exercise calf mitochondrial function in overweight sedentary participants (45 with and 54 without T2D) ages 30-50 and 51-70y. Mitochondrial function was measured in vivo by 31Phosphorous magnetic resonance spectroscopy (31P-MRS) before, during and after 90 seconds of isotonic calf press at 70% maximal force and ex vivo by mitochondrial respiration in muscle fibers using the Oroboros Oxygraph-2k. There was no significant effect of age or T2D on ex vivo measures. MRS-measured phosphocreatine synthesis, apparent maximum rate of oxidative ATP synthesis and ADP time constant were worse in those with T2D or age &gt;50 (Figure) . Age and T2D interact to significantly decrease apparent maximum rate of oxidative ATP synthesis. These data suggest that age and T2D decrease in vivo oxidative capacity. Given that impairment is only found in in vivo mitochondrial measures, factors such as micro- and macrovascular function and blood flow, combined with cardiac function, are likely implicated.

Disclosure
L.Abushamat: None. J.G.Regensteiner: None. R.L.Scalzo: None. D.Ramirez: None. I.E.Schauer: None. L.Knaub: None. E.Clark: None. Y.Garcia reyes: None. M.Cree-green: None. J.Reusch: Advisory Panel; Medtronic.

Funding
American Diabetes Association (1-21-CMF-003) (1-12-CT-64) ; Department of Veterans Affairs (BX002046, CX001532)