bluuebunny/crossref_metadata_2025_split huggingface dataset:
7624 m6A mRNA Methylation in Brown Adipose Tissue Regulates Systemic Insulin Sensitivity via an Inter-Organ Prostaglandin Signaling Axis
Authors: Xiao Ling , De Jesus Dario F , Ju Cheng-Wei , Wei Jiang-bo , Hu Jiang , DiStefano-Forti Ava , Tsuji Tadataka , Cero Cheryl , Männistö Ville , Manninen Suvi M , Wei Si-Ying , Ijaduola Oluwaseun , Blüher Matthias , Cypess Aaron Martin , Pihlajamäki Jussi , Tseng Yu-Hua , He Chuan , Kulkarni Rohit N 
Published: October 2024

Abstract
Disclosure: L. Xiao: None. D. F De Jesus: None. C. Ju: None. J. Wei: None. J. Hu: None. A. DiStefano-Forti: None. T. Tsuji: None. C. Cero: None. V. Männistö: None. S.M. Manninen: None. S. Wei: None. O. Ijaduola: None. M. Blüher: Consulting Fee; Self; Amgen Inc, AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Lilly USA, LLC, Novo Nordisk, Pfizer, Inc., Sanofi. A.M. Cypess: None. J. Pihlajamäki: None. Y. Tseng: None. C. He: Advisory Board Member; Self; Accent Therapeutics. R.N. Kulkarni: Advisory Board Member; Self; Novo Nordisk, Biomea, Inversago, REDD.
Brown adipose tissue (BAT) has the capacity to regulate systemic metabolism through the secretion of “Batokines” including signaling lipids. N6-methyladenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification and has been reported to regulate BAT adipogenesis and energy expenditure. Here, we demonstrate that the absence of the m6A writer, methyltransferase-like 14 (METTL14), modifies the BAT secretome to initiate inter-organ communication to improve systemic insulin sensitivity. Importantly, these phenotypes are independent of UCP1-mediated energy expenditure and thermogenesis. Using lipidomics, we identified prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) as M14KO-BAT-secreted insulin sensitizers. Notably, circulatory PGE2 and PGF2a levels are inversely correlated with insulin sensitivity in humans. Furthermore, in vivo administration of PGE2 and PGF2a in high-fat diet-induced insulin-resistant obese mice recapitulates the phenotypes of Mettl14-deficient animals. PGE2 or PGF2a improves insulin signaling by suppressing the expression of specific AKT phosphatases. Mechanistically, METTL14-mediated m6A installation promotes decay of transcripts encoding prostaglandin synthases and their regulators in human and mouse brown adipocytes in a YTHDF2/3-dependent manner. Collectively, these findings reveal a novel biological mechanism in the m6A-dependent regulation of the BAT secretome in modulating systemic insulin sensitivity in both mice and humans.
Presentation: 6/1/2024
8700 Mono(ADP-Ribosyl)ation of Ribosomal Proteins Promotes Differentiation During Adipogenesis
Authors: Tan X , Challa S , Camacho C V , Nandu T S , Stokes M S , Kraus W L 
Published: October 2024

Abstract
Disclosure: X. Tan: None. S. Challa: None. C.V. Camacho: None. T.S. Nandu: None. M.S. Stokes: None. W.L. Kraus: Other; Self; W.L.K. is a founder and stockholder for Ribon Therapeutics, Inc; a founder, member of the SAB, member of the BOD, and a stockholder for and ARase Therapeutics, Inc. He is also coholder of U.S. Patent.
ADP-ribosylation, a crucial post-translational modification, involves the covalent attachment of ADP-ribose units to amino acids on proteins through ADP-ribosyl transferase (ART) enzymes, utilizing NAD+ synthesized by nicotinamide mononucleotide adenylyl transferases (NMNATs). We previously showed that NMNAT-2, a cytoplasmic NAD+ synthase, increases during adipogenesis, leading to reduced nuclear NAD+ levels through compartmentalized NMN depletion and enhanced differentiation of preadipocytes. However, the implications of increased cytoplasmic NAD+ synthesis by NMNAT-2 in adipocytes remain unknown. Our current findings demonstrate elevated ribosome MARylation during 3T3-L1 preadipocyte differentiation, driven by NMNAT-2 induction. Inhibiting NAD+ biosynthesis by knockdown of NMNAT-2 or FK866 results in reduced ribosome MARylation, with PARP16 identified as the primary ART mediating MARylation. Knockdown of NMNAT-2 or PARP16 impaired global protein synthesis and preadipocyte differentiation. Treatment with the PARP16 inhibitor DB008 hindered ribosomal MARylation and preadipocyte differentiation. Immunofluorescence and subcellular fractionation analysis demonstrated that MARylated ribosomes are mostly associated with the endoplasmic reticulum. Using TMT mass spectrometry, we identified numerous high-confidence ADP-ribosylation sites on glutamate and aspartate residues in both undifferentiated and differentiated cells. We examined five proteins with specific sites of MARylation that are consistently more modified in the differentiated state. Among these, ADP-ribosylation of RPSA significantly promote preadipocyte differentiation; mutation of the site inhibits this effect. Ongoing investigations involve studying the impact of Parp16 knockout on high fat diet-induced obesity in mice to further determine the biological role of ribosome protein MARylation during adipogenesis.
This work is supported by a grant from the NIH/NIDDK (R01 DK069710) and the DOD OCRP (OC200311).
Presentation: 6/1/2024
7843 Nephron specific ATP6AP2 knockout reduces renal fat accumulation in mice consuming high fat diet
Authors: Allen Culver Silas , Lois Balugo Jamie Lynne , Jansen Maurits , Harris Thurl , Siragy Helmy M 
Published: October 2024

Abstract
Disclosure: S.A. Culver: None. J. Balugo: None. M. Jansen: None. T. Harris: None. H.M. Siragy: None.
Diet induced obesity causes increased renal fat accumulation in both humans and mice which contributes to obesity related kidney injury. We have previously shown that mice with nephron specific ATP6AP2 knockout (KO) consuming high fat diet (HFD) are resistant to weight gain due to increased urinary excretion of glucose, albumin, and fatty acids. Magnetic resonance imaging (MRI) is a useful imaging modality for quantifying organ fat content in live animals though there are few reports of its use quantifying fat in murine kidney. We hypothesized that nephron specific ATP6AP2 knockout inhibits renal fat accumulation with HFD and that we would be able to detect this using MRI. Eight-week-old male wild type (WT) or inducible nephron specific ATP6AP2 KO mice underwent either induction with oral doxycycline or received sucrose water as controls before being placed on either normal diet (ND) (12% fat) or HFD (45% fat) for 3 months. Mice were then imaged using a 9.4 Tesla Bruker BioSpin MRI to determine both liver and kidney cortex fat content. The mean weight of WT HFD mice was 36.03 g compared to 29.03 g in WT ND controls. ND fed and HFD fed KO mice weighed 22.74 g and 23.03 g respectively. MRI showed significant 67% (p&lt;0.05) increase in liver fat content in WT HFD compared to WT ND fed controls, confirming the ability of our MRI technique to detect expected differences in organ fat content. In renal cortex, MRI detected a 54% (p&lt;0.05) increase in lipid content for WT HFD mice compared to WT ND controls. Nephron specific ATP6AP2 KO on HFD demonstrated reduced renal cortical lipid content by 36% (p&lt;0.05) compared to WT HFD controls. These results indicate that ATP6AP2 KO is associated with reduced renal fat accumulation that is measurable with in vivo MRI. MRI therefore represents a valuable tool for studying renal sequelae of obesity in live murine models. Future investigation should examine whether ATP6AP2 KO prevents renal lipotoxicity and kidney injury in the setting of obesity.
Presentation: 6/3/2024
6468 Once-Weekly Semaglutide and Taste Perception in Women with Obesity
Authors: Sever M Jensterle , Kovac J , Vovk A , Battelino S , Battelino T , Janez A 
Published: October 2024

Abstract
Disclosure: M. Jensterle Sever: None. J. Kovac: None. A. Vovk: None. S. Battelino: None. T. Battelino: None. A. Janez: None.
Objective: Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that causes weight loss by reducing appetite and lowering the desire for energy-dense, salty, and spicy foods, thereby reducing energy intake. We hypothesized that semaglutide would improve the taste sensitivity and modulate the tongue transcriptomic profile associated with gustatory coding in women with obesity.Design: We conducted a 16-week, single-blinded, randomized, placebo-controlled clinical trial involving 30 women aged 33.7 ± 6.1 years with a body mass index of 36.4 ± 4.4 kg/m2, randomized in a 1:1 ratio to once-weekly semaglutide 1.0 mg or a placebo (ClinicalTrials.gov number, NCT04263415). Methods: Taste sensitivity was assessed by strips impregnated with different concentrations of four basic tastes. Biopsies of the tongue were performed for the gene expression analysis. The brain responses were evaluated by functional MRI with the sweet solution dripping onto the tongue before and after a standardized meal intake. Results: Semaglutide improved the taste sensitivity expressed as a mean (± SD) from 11.9 ± 1.9 points to 14.4 ± 1.0 points, with an estimated treatment difference (ETD) of 2.5 points [95% CI, 1.7 to 3.3]. Genes EYA, PRMT8, CRLF1, and CYP1B1, associated with taste signaling transduction pathways, neural plasticity, and renewal of taste buds in the tongue, exhibited differential RNA expression across all tests performed by a multi-tiered analytical pipeline. Semaglutide increased functional activity in the angular gyrus of the parietal cortex in response to tasting the sweet solution compared to the distilled water 30 minutes after a standardized meal intake (semaglutide vs. placebo, p&lt;0.001). Angular gyrus functions as a cross-modal hub where converging multisensory information is combined and integrated to comprehend and give sense to events and stimuli, manipulate mental representations, and solve familiar problems. It expresses GLP-1 receptor and is a part of the default mode network associated with shifting attention between rewarding and neutral stimuli, which has reduced connectivity in people with obesity. Conclusion: The present study provided evidence that semaglutide improved taste sensitivity, altered gene expression in the tongue linked to taste perception, and altered functional brain activity in an integrative hub beyond hypothalamic and midbrain reward circuitry in response to the sweet taste stimulus. Future studies will clarify whether the efficacy of semaglutide in treating obesity is also a »matter of taste«.
Presentation: 6/1/2024
8369 Overexpression of Neurosecretory Protein GL, a Novel Small Secretory Protein, Induces Fat Accumulation in Mice
Authors: Ukena Kazuyoshi , Narimatsu Yuki , Ogasawara Ayano , Furumitsu Megumi , Iwakoshi-Ukena Eiko 
Published: October 2024

Abstract
Disclosure: K. Ukena: None. Y. Narimatsu: None. A. Ogasawara: None. M. Furumitsu: None. E. Iwakoshi-Ukena: None.
Hypothalamic neuropeptides and peripheral factors influence food intake, body mass, and energy expenditure. For instance, neuropeptide Y (NPY)/agouti-related peptide (AgRP) are potent orexigenic factors and α-melanocyte-stimulating hormone (α-MSH) is an anorexigenic factor, respectively. In addition, leptin and insulin derived from peripheral tissues act on the hypothalamus to influence energy homeostasis. Precise hypothalamic control of energy balance affects puberty, thermoregulation, energy storage, and survival during different life-history stages. We have previously discovered a novel cDNA encoding the precursor of a neurosecretory small protein in the hypothalamus of birds and rodents (1, 2). The precursor protein contained a signal peptide sequence, a mature peptide sequence with 80 amino acid residues, a glycine amidation signal, and a dibasic amino acid cleavage site. Because the predicted C-terminal amino acids of the peptide were Gly-Leu-NH2, the small protein was named neurosecretory protein GL (NPGL). Quantitative RT-PCR analysis demonstrated that NPGL mRNA was expressed exclusively in the mediobasal hypothalamus (MBH), including the arcuate nucleus, and the expression was elevated on food deprivation in rodents. This finding led us to predict that NPGL was involved in the regulation of energy homeostasis. Indeed, using NPGL administration and neutralizing antibody administration in rats, we established that NPGL increased lipid accumulation in white adipose tissue (3). In the present study, to investigate the physiological function of NPGL in mice, we induced its overexpression using an adeno-associated virus (AAV) vector in NPGL-Cre driver mice. We then monitored food intake and recorded body mass changes. Npgl overexpression increased body mass. We also found that the overexpression resulted in increased masses of white adipose tissue and interscapular brown adipose tissue. Taken together, these results provide evidence for NPGL as a novel regulator of fat deposition in adipose tissues. Reference: (1) Ukena et al., Biochem. Biophys. Res. Commun. 2014 446:298-303. (2) Ukena, Gen. Comp. Endocrinol. 2018 260:164-170. (3) Iwakoshi-Ukena et al., eLife 2017 6:e28527.
Presentation: 6/3/2024
7215 Skeletal Muscle Mass Loss with Use of Dual GLP-1 GIP Receptor Agonist Tirzepitide
Authors: Zinn Jessica , Poretsky Leonid 
Published: October 2024

Abstract
Disclosure: J. Zinn: None. L. Poretsky: None.
Background: Multiple studies have demonstrated that treatment with tirzepitide results in significant improvement in HgbA1c as well as meaningful weight loss. Although the loss of skeletal muscle mass has been well described with the use of GLP-1 receptor agonists, there is little information regarding the effect of dual GLP-1/GIP receptor agonist tirzepitide on skeletal muscle mass. Clinical Case: A 68- year old male presented with a weight of 204.9 lbs and a BMI of 31.2 kg/m2. On exam, fat distribution was primarily central. Patient had a history of prediabetes, with an HgbA1c of 5.9%. He was unable to lose weight using lifestyle modifications, despite multiple meetings with a registered dietitian and consistent exercise of daily 3-6 mile walks. In the past, he used dulaglutide and semaglutide but had to discontinue these medications because of gastrointestinal side effects such as nausea and abdominal cramping. In June 2022, body composition (assessed using seca mBCA 514) demonstrated total weight of 204.9 lbs, BMI of 31.3 kg/m2, fat mass of 73.5 lbs (35.9%), fat-free mass of 131.4 lbs (64.1%), and skeletal muscle mass of 63.8 lbs (31.1%). He initiated Tirzepitide 2.5 mg weekly and maintained this dose for the duration of his treatment. Over nine months, total body weight decreased by 28.7 lbs or 13.9%. BMI decreased to 26.6 kg/m2 (at this point indicative of overweight status rather than obese). HgbA1c decreased to 5.3% (at this point no longer in the pre-diabetes range). Fat mass decreased by 18.9 lbs or 25.8%. Skeletal muscle mass decreased by 9.9 lbs or 15.5%. During this presentation we will provide a detailed time course of various metabolic and body composition parameters in this case and review relevant literature. Conclusion: We conclude that at least in some cases of patients treated with tirzepitide, up to 1/3 of lost body weight may be due to the loss of skeletal muscle mass. We suggest that, in addition to weight, serial body composition determinations should be obtained in patients on tirzepitide. It remains to be determined if adequate protein consumption and strength based exercise would ameliorate skeletal muscle mass loss observed with tirzepitide treatment. Reference: (1) Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205-216. doi:10.1056/nejmoa2206038
Presentation: 6/1/2024
8480 TIX100, a Novel Small Molecule for the Treatment of MASLD/MASH
Authors: Jo SeongHo , Chen Junqin , Jing Gu , Habegger Kirk M , Shalev Anath 
Published: October 2024

Abstract
Disclosure: S. Jo: None. J. Chen: None. G. Jing: None. K.M. Habegger: None. A. Shalev: Other; Self; TIXiMED, Inc. Founder & CSO.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) (aka NAFLD and NASH) affect over 1 billion people worldwide, yet no approved therapy is currently available. MASLD/MASH is often associated with diabetes and obesity and some diabetes medications have shown some beneficial effects in this context. However, beyond steatosis these drugs are in general unable to prevent all the problems associated with MASH, such as inflammation, hepatocyte injury and especially fibrosis. Interestingly, we have now discovered that the new antidiabetic small molecule thioredoxin-interacting protein (TXNIP) inhibitor, TIX100, effectively protects against high-fat diet-induced hepatic steatosis. Oral TIX100 also protected obese and diabetic db/db mice against steatosis and significantly reduced the elevated expression levels of lipogenic genes found in db/db livers, many of which have been shown to be elevated in human MASLD. In addition though, TIX100 also normalized the blood glucose of db/db mice to the levels observed in lean control animals. Therefore, to address the question of whether TIX100 would still be effective in the absence of diabetes, obesity and any genetic leptin-receptor deficiency, we used a validated choline-deficient, amino acid-defined, high-fat diet to induce MASH. Indeed, compared to control chow, this diet significantly increased plasma liver enzymes indicating liver injury without causing diabetes or obesity. It also led to elevated hepatic expression of inflammatory and fibrogenic markers and histology revealed lipid accumulation and steatosis as well as pronounced fibrosis and upregulation of liver macrophages. Excitingly, all these pathological changes were blunted or improved by oral TIX100 treatment. Taken together, oral TIX100 may provide an attractive and effective novel approach for the treatment of MASLD/MASH that goes beyond the correction of diabetes, obesity, and steatosis.
Presentation: 6/3/2024
12411 Trends In Metabolic Dysfunction-associated Steatotic Liver Disease(MASLD) By Race/ethnicity: Data From NHANES 1988 To 2018
Authors: Shaheen M , Schrode K , Pan D , Najjar S M , Friedman T C 
Published: October 2024

Abstract
Disclosure: M. Shaheen: None. K. Schrode: None. D. Pan: None. S.M. Najjar: None. T.C. Friedman: None.
Societies of the liver recommended replacing the term non-alcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to investigate the trends in the MASLD prevalence by racial/ethnic among the U.S. adult population overtime. We analyzed data from 32,726 adults in National Health and Nutrition Examination Survey 1988-2018. Hepatic steatosis (HS) was diagnosed using the U.S. Fatty Liver Index. MASLD was diagnosed in individuals with both HS and at least one of the following: overweight/obesity, diabetes mellitus, hypertension, high triglyceride or HDL-Cholesterol or in treatment. Logistic regression was used to test for trends over time for the overall sample and for each racial/ethnic group accounting for design and sample weights. Prevalence estimates were age-adjusted using the direct standardization based on census data. We also estimated the percent change in the adjusted prevalence (change in the adjusted prevalence/baseline adjusted prevalence)*100. The study showed that over the study period, the age-adjusted prevalence of MASLD significantly increased from 16% in 1988 to 38% in 2018, representing a 138% percent increase. Concurrently, the age-adjusted prevalence of obesity increased from 23% in 1988 to 40% in 2018 reflecting a 74% increase (p&lt;0.05). Among Mexican Americans, the age-adjusted MASLD prevalence consistently exceeded that of the overall population and other racial/ethnic groups. Significant increase in the percent change of the age-adjusted prevalence of MASLD was observed across all racial/ethnic groups (Mexican Americans=69%; Blacks=117%; Whites=140%) except Other Hispanics (no change). The age adjusted prevalence of obesity also increased significantly in all racial/ethnic groups (% change: Mexican Americans=58%; Other Hispanics=18%; Blacks=59%; Whites=77%) (p&lt;0.05). Our findings indicated an increase in the age-adjusted prevalence of MASLD over time that surpassing the increase in obesity prevalence. These disparities warrant further investigation and targeted interventions to address MASLD effectively. Grants: R01MD012579, R24DA017298, U54MD007598, S21MD000103, UL1TR001881
Presentation: 6/2/2024
7112 A Case of Bilateral Adrenal Insufficiency Associated With Borderline Lupus and Antiphospholipid Syndrome
Authors: Hernandez Mendiola Karla Maria 
Published: October 2024

Abstract
Disclosure: K.M. Hernandez Mendiola: None.
Bilateral adrenal hemorrhage (BAH) is a rare condition leading to acute adrenal insufficiency with a mortality rate of 15%. Known etiologies include abdominal trauma, adrenal vein thrombosis, sepsis, shock, and anticoagulation. Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are uncommon conditions associated with BAH. We describe here a 79-year-old woman with a history of hypertension and a 23-year history of borderline SLE treated with hydroxychloroquine (HCQ) who presented at the ED with epigastric pain, diarrhea, and nausea. Six months before, HCQ was discontinued. The exam showed no abnormal findings, and an abdominal CT showed inflammation of the ascending colon. Augmentin was instituted, and the patient was sent home. After a week, the patient returned to the ED due to the persistence of symptoms, complaining of fatigue and right lower quadrant abdominal pain. Upon examination, the abdomen was soft but tender, with the CT suggesting pancolitis, while an MRI showed BAH. Laboratory findings included anemia, thrombocytopenia, elevated PT, low fibrinogen, and 11 mcg/dl cortisol. The patient was then admitted to the hospital, and hydrocortisone (HCT) therapy was initiated. After 12 hours of glucocorticoid initiation, cortisol level was 37 mcg/dl. On day 1, the patient remained hemodynamically stable. On day 2, a positive lupus anticoagulant was detected, with cortisol level dropping to 2 mcg/dl, warranting the continuation of HCT. From day 3 to 6, the patient suffered worsening coagulation and kidney functions. By day 7, an abdominal CT showed an extension of BAH. On day 8, the patient experienced a cerebral intraparenchymal hemorrhage and was transferred to the ICU, where, after two days passed away. The report presented here describes a catastrophic case of BAH associated with borderline SLE and APS in a patient who previously discontinued long-term treatment with HCQ, thereby enhancing the likelihood of a lupus flare-up. The adrenal glands are susceptible to thrombosis and hemorrhage due to their rich vascularity. In stress, the adrenals receive a significant blood volume, causing vascular congestion, potentially exceeding their capacity for venous drainage, and increasing the risk of hemorrhage. Autoimmune conditions, particularly SLE and APS, have been implicated in the etiology of adrenal hemorrhage. Antiphospholipid antibodies may bind to phospholipid-binding plasma proteins, promoting thrombosis in the adrenal vein by disrupting the coagulation fibrinolysis balance and the adrenal blood outflow, ultimately causing bleeding into the adrenal gland parenchyma. Although in this case, no cardiovascular collapse was observed, when unrecognized or undertreated, adrenal insufficiency complicating BAH can evolve into an adrenal crisis. Infections and medications that increase cortisol metabolism can also contribute to this complication.
Presentation: 6/3/2024