bluuebunny/crossref_metadata_2025_split huggingface dataset:
1609-P: Neutral Sphingomyelinase Inhibition Limits Hepatic-Lipotoxicity and Inflammation in a Cell Model of Steatosis
Authors: ALRASHED FATEMA , AREFANIAN HOSSEIN , SINDHU SARDAR T. , BAHMAN FATEMAH , ALSAEED HALEMAH , AL MADHOUN ASHRAF , ALZAID FAWAZ , AL-MULLA FAHD , AHMAD RASHEED 
Published: June 2023

Nonalcoholic fatty liver disease (NAFLD) represents a global healthcare challenge; it is the hepatic manifestation of metabolic syndrome and is strongly associated with developing type 2diabetes mellitus (T2DM). Liver fat accumulation is the first step of disease progression that triggers hepatic lipotoxicity. The role of ceramides in inducing deleterious effects on hepatic metabolism is now well-accepted. Yet, the specific role of stress responsive sphingomyelinase activation under lipotoxic conditions remains under-investigated. The complexity of NAFLD pathogenesis contributes to lack of proper investigatory model, limiting progression in developing and testing novel treatment and prevention strategies. Here, we first report a convenient in-vitro human cell-based model with great resemblance to in-vivo NAFLD hallmarks. Neutral Sphingomyelinase (nSMase2) expression and activity was found to be elevated in both the liver of high fat steatosis mouse models and in HepG2-steatosis cell models. Meanwhile, the functional inhibition of nSMase2 prevented hepatotoxicity-induced pathologies by significantly reducing intracellular lipid accumulation and prevented the upregulation of TNF-α triggered inflammation. Furthermore, inhibition of nSMase2 showed significant increase in PPARα at both gene and protein levels, while PPARα reduction was observed under the stimulation of nSMase2 activity by its agonist daunorubicin (DNR). Together the presented data highlight the role of nSMase2 in the pathogenesis of NAFLD and other disorders linked to hepatic steatosis, providing a novel therapeutic target.

Disclosure
F. Alrashed: None. H. Arefanian: None. S.T. Sindhu: None. F. Bahman: None. H. AlSaeed: None. A. Al Madhoun: None. F. Alzaid: None. F. Al-Mulla: None. R. Ahmad: None.

Funding
Kuwait Foundation for the Advancement of Sciences (RA0402021)
1610-P: Fatty Acid–Binding Protein 4 as a Biomarker for Remission of Type 2 Diabetes
Authors: STENTZ FRANKIE B. 
Published: June 2023

Elevated levels of circulating Fatty Acid Binding Protein 4 (FABP4), also named adipocyte FABP (A-FABP), are associated with obesity, diabetes mellitus, insulin resistance, hypertension, and cardiovascular risk. FABP4 is a protein found in high levels in both macrophages and adipocytes. Release of FABP4 from adipocytes via lipolysis, and release from macrophages during inflammation, plays a key role in development of insulin resistance and diabetes mellitus. We studied the effect of a high protein (HP; 30% protein, 40% carbohydrate, 30% fat) diet vs high carbohydrate (HC;15% protein, 55% carbohydrate, 30% fat) diet in patients recently diagnosed with Type 2 Diabetes (T2D). We determined the levels of circulating FABP4 and metabolic parameters in the HP vs HC groups at baseline and 6 months after consuming the respective diets. Participants (14) were randomized to a HP or HC diet for 6 months. All food was provided and designed for weight loss. After 6 months on the HP diet, 100% of the subjects had remission of T2D to Normal Glucose Tolerance (NGT), whereas only 16.6% of subjects on HC diet had remission of T2D. The HP diet group exhibited significant improvement in a) insulin sensitivity (p=0.001), b) inflammatory cytokines (p=0.001), C) cardiovascular risk factors (p=0.004) compared to the HC diet group at 6 months. Although weight loss in both groups was around 10% at 6 months, the HP group lost % fat mass, whereas, the HC group lost both % muscle and fat mass. Average level of FABP4 decrease after 6 months was 12,831 pg/ml in the 8 participants on the HP diet, compared to only a 1183 pg/ml average decrease after 6 months for the 6 HC participants. Conclusions: These data showed a significant decrease of circulating FABP4 in the HP but not HC diet group and suggests that a high protein diet could be an optimal way to reduce FABP4 levels in the blood. This could subsequently lower the risk of development/progression of insulin resistance, T2D, inflammation and cardiovascular risk conditions and serve as a biomarker.

Disclosure
F.B.Stentz: None.

Funding
AD Baskin
1615-P: The Peripheral and Central Cross Talk Mediated by Adipose MIF—A Novel Mechanism of Hyperphagia following Olanzapine Treatment
Authors: CHEN XI , HUANG YIHENG , QI YADAN , CHEN LIUJUN , LI LISHA , GAO PINGYI , CUI DONGHONG , QI DAKE 
Published: June 2023

Olanzapine is one of the first-line antipsychotic medications but it usually induces metabolic side effects, characterized by obesity. We previously indicated that olanzapine leads to hyperphagia through the effects of a proinflammatory cytokine, macrophage migration inhibitory factor (MIF) in the hypothalamus. However, whether olanzapine's upregulated peripheral MIF could affect the central mechanism is currently unknown. Our present study found that olanzapine increases ectopic expression of dopamine receptor 1 (DRD1) in adipocytes which relatively upregulates MIF expression and release through a PKA/CREB signaling pathway. In global MIF knockout mice, MIF accumulation appears in the hypothalamus following peripheral injection of recombinant MIF proteins, suggesting that peripheral MIF indeed travels to the hypothalamus. Mif Lung Tg mice (MIF overexpression in the lung) with increased circulating MIF levels had hyperphagia and activation of the CaMKKβ/AMPK/AgRP signaling pathway in the hypothalamus. Overall, our study for the first time proved that adipose-derived MIF is a crucial factor in regulating metabolic side effects induced by olanzapine.

Disclosure
X.Chen: None. Y.Huang: None. Y.Qi: None. L.Chen: None. L.Li: None. P.Gao: None. D.Cui: None. D.Qi: None.

Funding
National Sciences and Engineering Research Council of Canada (RGPIN-2017-04542); Canadian Institutes of Health Research (PJT-156116); China Scholarship Council (202106230212)
1622-P: Complex Mechanisms Underlie the Antidiabetic Effect of Tempol in Experimentally Induced Diabetes Mellitus
Authors: NAGUIB YAHYA 
Published: June 2023

Diabetes mellitus (DM) is a vastly growing worldwide health problem which imposes public health, social, as well as economic burden. Multifactorial and complicated pathophysiological pathways may underlie DM. Attention has been given for the search of polymodal therapeutic molecules. Herein, we tested the capacity of tempol, a known superoxide dismutase-mimetic in the treatment of experimentally induced DM. Thirty male Wistar rats weighing 150-200 g were equally divided into: 1- Control group (rats received a single intra-peritoneal injection of citrate buffer for 4 weeks), 2- Untreated diabetic group, and 3- Tempol treated diabetic group. At the end of the study blood samples were collected for the measurement of fasting blood glucose, fasting blood insulin, liver function, kidney function, oxidative stress markers, and inflammatory markers. Pancreas, skeletal muscles, and liver were removed for histopathological, immunohistochemical and RT-PCR studies. Treatment with tempol significantly improved glycemic status, insulin secretion, sensitivity and reserve. Tempol preserved both liver and kidney functions. Tempol also significantly enhanced energy status, and countered structural changes, inflammation, and apoptosis of pancreatic tissue. Tempol significantly upregulated pancreatic AMPK, and skeletal muscle and hepatic glucose transporters. Interestingly, tempol demonstrated an endogenous stem cells recruitment capacity. In conclusion, tempol exhibited a potential capacity to counter the complexity of the underlying mechanisms in DM.

Disclosure
Y.Naguib: None.
1623-P: Identification of Gut Microbes That Prevents Metabolic Syndrome in Healthy Japanese Adults
Authors: HONOKI HISAE , FUJISAKA SHIHO , WATANABE YOSHIYUKI , OKU MAKITO , KONDO YUKI , NISHIMURA AYUMI , KADO TOMONOBU , BILAL MUHAMMAD , ENKAKU ASAKO , TAKIKAWA AKIKO , CHUJO DAISUKE , MORINAGA YOSHITOMO , TOBE KAZUYUKI 
Published: June 2023

Gut microbiota is an important driver of metabolic status. Recent studies have demonstrated that dysbiosis precedes the development of metabolic disorders. However, the bacterial species associated with metabolic syndrome and their physiological role in obesity and glucose metabolism have not been fully elucidated. In this study, we performed 16S rRNA sequencing analysis on fecal samples from 49 metabolically healthy volunteers, a detailed lifestyle questionnaire survey including diet, and an analysis on metabolic parameters. We also examined the metabolic effects of some microbes by transplantation into HFD-fed mice. The average age, BMI and HbA1c were 43.5±9.0, 23.9±3.9 and 5.5±0.3, respectively. A clear correlation was observed between lifestyle and metabolic parameters. Analysis of fecal microbial structure divided the participants into three enterotypes according to their predominant phylogenic pattern; 1) Prevotella copri group, 2) Bacteroides group, and 3) others. Enterotype 1 had higher random blood glucose (BG), and lower HDL-C, while enterotype 2 had lower random BG, BMI, and waist circumference. Eleven bacterial species were identified as being positively or negatively correlated with metabolic parameters. Relative abundances of the Family Fusobacteriaceae and Prevotella stercorea were positively correlated with BMI, fasting BG, and visceral fat mass. In contrast, the Family Rikenellaceae and Bacteroides uniformis (Bu) negatively correlated with metabolic parameters. Transplantation of Alistipes indistinctus (Ali), a major bacterium of the Family Rikenellaceae, or Bu into HFD-fed C57BL/6J mice suppressed body weight gain, improved glucose tolerance and histological findings without altering food intake. In summary, our results suggest that microbial community structure can be altered by lifestyle even in good health. Moreover, maintaining microbial species such as Ali and Bu may contribute to the prevention of metabolic disorders in Japanese adults.

Disclosure
H. Honoki: None. S. Fujisaka: None. Y. Watanabe: None. M. Oku: None. Y. Kondo: None. A. Nishimura: None. T. Kado: None. M. Bilal: None. A. Enkaku: None. A. Takikawa: None. D. Chujo: None. Y. Morinaga: None. K. Tobe: Other Relationship; MSD K.K., Novo Nordisk Pharma Ltd., Takeda Pharmaceutical Company Limited, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corporation, Suntory Global Corporation, Ltd.,, Taiho Pharmaceutical Co. Ltd., Japan Diabetes Foundation, Japan Association for Diabetes Education and Care.

Funding
Japan Society for the Promotion of Science (20K10318); Japan Association for Diabetes Education and Care
1626-P: Activation of Cardiac Mitochondrial Akt1 Enhanced Myocardial Fatty Acid Utilization, Protected against Diabetic Cardiomyopathy, and Improved Whole Body Fat Distribution
Authors: TA ALBERT , CHEN YUMAY , LI JUNFENG , SALEM ESAM , WANG PING H. 
Published: June 2023

Insulin stimulates Akt1 translocation to cardiac mitochondria, and we have recently shown that inhibition of cardiac mitochondria Akt1 led to mitochondrial dysfunction and cardiomyopathy. However, whether activation of mitochondrial Akt1 in cardiac muscle can protect against the development of diabetic cardiomyopathy is not known. To this end, we have generated an inducible heart-specific transgenic mouse harboring a mitochondria-targeting constitutively active Akt1 (CAMCAKT). Long-term high fat-high fructose diet (HFFD) caused myocardial hypertrophy, fibrosis and ventricular dysfunction in control mice, but the impact of HFFD were attenuated in the CAMCAKT mice. After just two months on HFFD, expression of Col1a1 and Col3a1 in CAMCAKT mice were lower than controls (p&lt;0.01). After five months on HFFD, ejection fraction in CA mice was 17 % higher than in controls while fractional shortening was 22% higher (p&lt;0.05). This indicated that activation of mitochondrial Akt protected myocardium against the development of cardiomyopathy in diet-induced diabetes. Metabolically, cardiac mitochondrial Akt1 increased fatty acid uptake in the cardiac muscle, which resulted in redistribution of whole-body fatty acid metabolism. Dynamic PET scans revealed a 65% increase (p&lt;0.001) in heart uptake of fatty acid reporter [18F]fluoro-4-thia-oleate in CAMCAKT mice. CAMCAKT mice had 15% less body fat, 30% lower total cholesterol and expended 13% more energy, compared to controls (p&lt;0.05). Interestingly, fatty liver was reduced in the CAMCAKT mice (p&lt;0.05), suggesting that cardiac mitochondrial Akt modulated fat deposition in the liver by higher myocardial fatty acid metabolism. In summary, activating cardiac mitochondrial Akt protected against diabetic cardiomyopathy, attenuated fatty liver, and induced whole body metabolism in this murine model of diet-induced diabetes.

Disclosure
A.Ta: None. Y.Chen: None. J.Li: None. E.Salem: None. P.H.Wang: Research Support; ViaCyte, Inc.

Funding
National Institutes of Health (R01HL096987); Ko Family Foundation
1632-P: Effects of MTOR Signaling in Muscle-Specific Irs1/2 Knockout Mice
Authors: STOEHR OLIVER , COPPS KYLE D. , TAO RONGYA , WHITE MORRIS F. 
Published: June 2023

Disruption of Irs1 and Irs2 expression in skeletal and cardiac muscle (MDKO mice) caused death from dilated cardiomyopathy within the first 30 days of life. MDKO showed muscle atrophy but were not glucose intolerant, despite impaired muscle glucose uptake. Beiging of white adipose fat increased glucose uptake into white adipose tissue of MDKO mice, and glucose uptake into brown adipose was also increased. Knockout of atrophy-driving genes FoxO1 and FoxO3a in MDKO mice (MQKO mice) extended life span to 70 days, when MQKO mice died with cardiomyopathy. High fat diet feeding increased life span in both MDKO and MQKO mice; however, genetic activation of the MTOR pathway in muscle of MDKO mice by Tsc1 knockout (MTKO mice) increased life span to 220 days. Regardless, MTKO mice developed cardiac hypertrophy with reduced ejection fraction by 24 weeks. Cardiac glucose uptake in MTKO mice was impaired during non-insulin as well as during insulin-stimulated conditions. Moreover, fat mass of MTKO mice decreased over time, implying a shift in consumption by MTKO hearts from glucose to fatty acids as source for cardiac energy. Tracing of radiolabeled palmitic acid did not support increased cardiac fatty acid uptake in MTKO mice; however, expression of lactate transporters was significantly elevated in MTKO hearts and circulating lactate generated by skeletal muscle was significantly reduced, indicating a potential use of lactate in MTKO hearts. These results show more robust effects of activating the MTOR pathway in insulin resistant hearts of MDKO mice rather than manipulating atrophy-related genes FoxO1/3a to counter early death from cardiomyopathy. Furthermore, activated MTOR signaling potentiated a metabolic switch in MDKO hearts.

Disclosure
O.Stoehr: None. K.D.Copps: None. R.Tao: None. M.F.White: Board Member; Housey Pharma.
1634-P: Brown Adipose Tissue and Muscle Responses to Tolerable Cold in Black and White Young Lean Men
Authors: THOMAS REED J. , BRYCHTA ROBERT , COURVILLE AMBER B. , MCGEHEE SUZANNE , CYPESS AARON M. , CHEN KONG Y. 
Published: June 2023

There has been a renewed interest in brown adipose tissue (BAT) as a therapeutic target for diabetes and obesity treatments due to its ability to consume glucose and expend energy in response to cold temperatures and Beta-adrenergic stimulation. However, comparisons of BAT in different races are limited. To address this knowledge gap, we directly compared healthy, young, lean Black and White men in a controlled inpatient study using a whole-room indirect calorimeter.
12 Black and 12 White men completed a 6-13-day protocol with randomized calorimeter temperatures between 18-31°C for 5 hours. Resting metabolic rate (RMR) was measured under reclined, fasted conditions with standard clothing. Body composition was measured by dual x-ray absorptiometry and BAT and muscle glucose uptake activity was quantified using 18-F Fluorodeoxyglucose (18-F FDG) PET-CT following the last chamber study where each individual's coldest tolerable temperature (Tct) was used. Basal metabolic rate (BMR) was defined as minimum RMR and the cold-induced thermogenesis (CIT) was calculated as the percentage increase of RMR above BMR in the cold.
The groups were similar in age (23.8±4.7 yrs) and BMI (23.1±1.5 kg/m2) and their Tct (21.0±1.4°C; p=0.54) and CIT (12.1±8.1 kcal/h; p=0.8) were not different. While White males had significantly higher BAT volume (334 ± 188mL vs 242 ± 89mL; p=0.045), BAT volume was comparable between the groups after normalizing to body volume. BAT activity was similar between the groups. Among all muscle activity measured, the intercostal muscles in the Black males had significantly higher activity (p=0.002) and activity was present in all 12 Black participants but only 4 of 12 White males. Individual BAT or muscle activity did not correlate with each other nor with Tct or CIT.
Our data suggest that the cold-induced BAT activity was comparable in Black and White young, lean men. The surprising difference in intercostal muscle activity warrants further investigation.

Disclosure
R.J.Thomas: None. R.Brychta: None. A.B.Courville: None. S.Mcgehee: None. A.M.Cypess: None. K.Y.Chen: None.
1637-P: Acute Hyperinsulinemia Alters Intramuscular 1,2-DAG Species across Metabolic Phenotypes
Authors: MCKENNA COLLEEN , ZEMSKI BERRY KARIN , ZARINI SIMONA , KAHN DARCY , PERREAULT LEIGH , NEWSOM SEAN A. , SNELL-BERGEON JANET K. , BERGMAN BRYAN C. 
Published: June 2023

Intramuscular lipid levels are linked to obesity and type 2 diabetes (T2D). Annotation of the lipid profile is necessary to elucidate the relevance of this association, as certain lipids are more potent in their pathogenic role in insulin resistance. Despite the relationship between insulin action and intramuscular lipid composition, the effect of acute hyperinsulinemia on the myocellular lipid profile is unknown. Basal and insulin-stimulated vastus lateralis muscle was sampled in sedentary lean adults (n = 12), endurance athletes (n = 12), and individuals with obesity with (n = 7) or without T2D (n = 13). A hyperinsulinemic-euglycemic clamp was performed at 40 mU/m2/min insulin with variable dextrose to maintain 90 mg/dL blood glucose. An insulin-stimulated muscle biopsy was performed 1 h into the insulin clamp. Muscle was dissected of extramuscular adipose tissue and then flash frozen. Whole muscle lipidomics analysis was performed by LC-MS/MS. Hyperinsulinemia decreased whole muscle cell total acylcarnitine (AC) levels (p = 0.001) regardless of group. However, only athletes exhibited a decrease in AC C6:0, C14:0, and C16:1 during the insulin clamp (p &lt; 0.001). Triacylglycerol concentrations also decreased during the clamp regardless of group (p = 0.041). There was no significant effect of the clamp on total 1,2-diacylglycerol (DAG). However, many 1,2-DAG species were elevated with acute hyperinsulinemia, such that the change in various long-chain 1,2-DAGs were inversely related to insulin sensitivity (r = -0.35 - -0.45, p &lt; 0.050). Moreover, di-C18:1 and C16:0/20:0 1,2-DAGs were elevated with acute hyperinsulinemia in T2D alone (p &lt; 0.010). Acute hyperinsulinemia did not affect muscle 1,3-DAG, ceramide, nor sphingomyelin total concentrations. While 1,2-DAGs have been implicated in muscle insulin resistance, our results suggest that differential handling of 1,2-DAGs during acute hyperinsulinemia across metabolic phenotypes may further promote decreased insulin sensitivity.

Disclosure
C.Mckenna: None. K.Zemski berry: None. S.Zarini: None. D.Kahn: None. L.Perreault: Advisory Panel; Sanofi, Consultant; Novo Nordisk A/S, Speaker's Bureau; Novo Nordisk A/S, Boehringer Ingelheim Inc., Lilly, Bayer Inc. S.A.Newsom: None. J.K.Snell-bergeon: None. B.C.Bergman: Research Support; Eli Lilly and Company.

Funding
National Institutes of Health (R01DK089170, T32DK007658)
1641-P: C-C Motif Chemokine Ligand 2 Promotes Myogenesis Recovery, Muscle Strength, and Muscle Performance In Vivo and Has Clinical Relevance for Muscle Performance in Human
Authors: HONG EUN-GYOUNG , SUK HA EUN , LEE JIWOO , MI CHOI YUN , LEE KWANWOO , CHUL WON JONG , KYUNG KWAK MI 
Published: June 2023

Muscle mass decreases with aging, while the C-C motif chemokine ligand 2 (CCL2) increases with aging. In our previous study, CCL2 positively affects in vitro myogenesis. In this context, CCL2 can be considered a potential aging-promoting factor. To further confirm the relationship between muscle and CCL2, we sought to establish the role of CCL2 in vivo and in humans. It was divided into Dimethyl Sulfoxide (DMSO) control, dexamethasone (Dexa) intraperitoneal treatment group, and Dexa with the CCL2 treatment group. As a result, grip power and exercise endurance were reduced in the Dexa treatment group compared to the control group but recovered with the CCL2 treatment. In muscle mass, there was no significant difference in mass between groups. We examined the cross-sectional area distribution (CSA) with the tibialis anterior muscle. The Dexa treatment group was distributed between CSA 1000-3000 µm² and was left-shifted. However, the Dexa and CCL2 group was similar or slightly higher than the DMSO group; it was right-shifted and distributed in the 2000-5000 µm². In humans, the median value was 303.8 pg/ml in the no sarcopenia group and 321.7 pg/ml in the sarcopenia group. Subsequently, the CCL2 level was checked by dividing the groups into whether there was sarcopenia, low mass, low strength, or low speed. The CCL2 level was statistically significantly higher in the group showing low speed. In conclusion, CCL2 promotes myogenesis recovery, muscle strength, and muscle performance in vivo and has clinical relevance for muscle performance in humans.

Disclosure
E.Hong: None. E.Ha: None. J.Lee: None. Y.Choi: None. K.Lee: None. J.Won: None. M.Kwak: None.

Funding
Ministry of Education, Republic of Korea (2020R1I1A3073230)