bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Early Origins of NAFLD in Humans and Non‐Human Primates
Authors: Friedman Jacob E 
Published: November 2023

Non‐Alcoholic Fatty Liver Disease (NAFLD) is now the most common liver disease worldwide in children and adults. Even more concerning is that the risk factors for NAFLD may start operating in early life. In the U.S., up to 25% of children are already overweight or obese entering kindergarten, and maternal obesity is consistently one of the most powerful predictors of pediatric obesity and its complications. NAFLD is currently estimated to occur in 25–50% of obese children with lifetime consequences, including liver NASH and hepatic carcinoma risk. Our group has spent the past decade studying developmental programming in humans, non‐human primates (NHP), and transgenic mouse models. We have shown that maternal Western‐Style Diet (WSD) in NHP mothers results in a NAFLD phenotype in the fetus, beginning in the early 3rd trimester. This phenotype persists in juveniles up to 14 months of age despite weaning to a healthy diet, and in the absence of obesity. Our compelling human data in neonates born to obese/Gestational Diabetic mothers demonstrate increased intrahepatic fat using MRI/MRS at 2 wks of life. However not everyone who is born to an obese mother develops disease, with other potential contributing factors particularly excessive maternal insulin resistance, hypoxia, and mitochondria dysfunction important in the fetal development of NAFLD. Our studies in obese NHP mothers using the anti‐oxidant resveratrol, may be able to mitigate some of these complications to prevent the early complications of maternal obesity on the developing liver. Interestingly, founding individual microbiota composition in infants reflects the maternal transfer during or immediately after birth. The intestinal microflora is different between individuals and its composition is largely dependent on a combination of genetics, diet and lifestyle choices. Although no single commensal bacteria species have been conclusively proven to provoke NAFLD, lack of certain bacterial species has been observed with human patients prone to or suffering from this disorder. In cross‐sectional studies comparing vaginally delivered, exclusively breast fed infants we have found a significant reduction in the early pioneering bacteria Gammaproteobacteria in 2 week old infants from obese mothers compared to infants born to normal weight mothers. Further, gnotobiotic transfer of stool from infants of obese mothers into germ‐free mice was associated with a significant reduction in IL‐10 producing anti‐inflammatory Treg cells, as well as CD3+CD4+ helper T‐cells and ER stress in the liver at 21 days post‐transplantation. These findings suggest that early commensal bacteria from obese human infants may be important in conditioning a developing immune system that educates inflammatory cells, leading to inflammation‐linked diseases, including NAFLD, a hypothesis we are currently exploring.Support or Funding InformationNIH‐NIDDK, ADA, and Bill Gates Foundation
Periodontal symptoms and inflammation following non‐surgical treatment and 4 months of fish oil supplementation
Authors: Coates Alison , Fitzsimmons Tracy , Chee Brian , Park Boram , Kapellas Kostas , Howe Peter , Lee Ryan , Ivanovski Saso 
Published: November 2023

Background/AimsPeriodontitis is a chronic inflammatory condition characterised by destruction of the supporting apparatus of teeth, including bone and the periodontal ligament. Long chain omega‐3 polyunsaturated fatty acids (LCn‐3PUFA) in fish oil are beneficial for several inflammatory conditions with mixed findings in periodontitis. We evaluated the clinical efficacy of fish oil supplementation as an adjunct to standard therapy for advanced chronic periodontitis.MethodsIn a 4 month randomised, controlled parallel study participants with advanced chronic periodontitis (10M/23F, mean age 52 ± 10 years) consumed either fish oil (1884 mg LCn‐ 3PUFA /day) or (2000 mg soy oil /day). Patients were assessed at baseline and after 4 months for clinical outcomes, viz. probing pocket depth (PPD) and clinical attachment (CAL), inflammatory cytokines (TNF‐alpha, IL‐1beta and C‐reactive protein) in gingival crevicular fluid (GCF) and fasting blood samples were assessed for LCn‐3PUFA erythrocyte content to determine compliance.ResultsFollowing non‐surgical treatment and 4 months of oil supplementation both groups had improvements in clinical outcomes, with significant reductions in PPD and CAL gain. There was no significant difference between groups in the percentage of sites that had ≥2 mm gain of CAL (P = 0.229) or reduction in PPD (P = 0.264) after 4 months. There were no significant changes in cytokines in GCF in either group. Erythrocyte LCn‐3PUFA increased by 50% in the fish oil supplemented group with no change in the placebo group suggesting good compliance with supplementation.ConclusionsWhilst periodontal treatment was effective in all participants, no additional benefit was observed with fish oil supplementation for 4 months.Support or Funding InformationAustralian Dental Research Foundation grants (2013 and 2014); Novasel Australia LTD donated the capsules.
Initial Results from a Real‐world Pediatric Specialty Weight Management Clinic in a Safety‐net Hospital
Authors: Lenders Carine M , Plourde Kendra Davis , Manders Aaron J , Ireland Kathy 
Published: November 2023

BackgroundThere is limited data available on anthropometric outcomes from specialty pediatric obesity clinics targeting underserved populations. There is increasing evidence that interventions in early childhood are critical.ObjectivesTo identify changes in weight measures in a pediatric obesity specialty clinic (Nutrition and Fitness for Life program, NFL) at a safety‐net hospital (Boston Medical Center, BMC). To determine the prevalence of children with clinically relevant reductions in weight measures.MethodsThis is a prospective observational study using data from a clinical data warehouse. Patients evaluated in the NFL clinic are referred by clinicians from BMC and associated health centers. Data from 795 patients seen between 2003 and 2010 was extracted. The criteria for inclusion in the study was being age 2–18 years old and attending at least two office visits. Data was extracted for weight, height, age at first and last visit, sex, and insurance status. We present data on weight, BMI, and BMI z‐score change and the prevalence of children with more than 5% reduction in BMI and BMI z‐scores. Other weight measures are being examined. CDC references were used and descriptive analyses performed.ResultsGiven the study inclusion criteria, the final sample consisted of 544 patients with a median (IQ) for age of 11.5 (9.1, 13.9) years, 45% were male, 63% were on public insurance, 57% were Black or African American, 29% Hispanic, 7% White, and 7% Other. The median (IQ) treatment period was 6(3; 14.5) months. Baseline BMI was 32.1(28.4; 37.7) kg/m2, percentile was 99.4(98.9; 99.7), and z‐score was 2.5(2.3–2.7) s.d. Overall, patients’ BMI increased by 1 (−1.6; 4.6) kg/m2 and decreased by −0.8 (−4.1; 0.9) z‐score during the treatment period. Weight, BMI and BMI z‐score reductions of more than 5% varied significantly by age group.DiscussionDespite socioeconomic challenges and the lack of exclusions, children were able to improve their weight measures. Overall the results in children less than six years old were encouraging. However, there is a lot of controversies on what weight loss indicator to use given the lack of references for severe obesity. There is a need for standardized measures of effectiveness in specialty obesity clinics that target underserved pediatric populations.Support or Funding InformationSupport from New Balance Foundation.

Percent of children with more than 5% reduction in weight measure

2–5.9 y(N=47)
6–11.9 y (n=247)
12–18.9 y (N=250)

n(%)
n(%)
n(%)
p‐value

>5% wt Loss
2(4%)
1(0.4%)
22(9%)
< 0.0001

>5% BMI Loss
6(13%)
13(5%)
29(12%)
0.0274

>5% BMI z‐score loss
29(62%)
43(17%)
36(14%)
<0.0001
Ablation of BCO2 Leads to Increased Susceptibility to High Fat Diet‐induced Metabolic Disorders in Mice
Authors: Wu Lei , Guo Xin , Davis Abby , Soh Traces Petchdee , Clarke Stephen , Lucas Edralin , Smith Brenda , Wang Weiqun , Medeiros Denis , Lin Dingbo 
Published: November 2023

Objectiveβ,β‐carotene‐9′, 10′‐dioxygenase 2 (BCO2) is a carotenoid cleavage enzyme located on the inner membrane of the mitochondria. We recently reported that BCO2 protein expression is reduced in obese/diabetic mice and ablation of BCO2 impairs mitochondrial function. The purpose of this study is to determine whether ablation of the BCO2 protein leads to increased susceptibility to high fat diet (HFD)‐induced metabolic disorders.MethodsSix week old male BCO2 knockout (KO) and wild type (WT, 129S6) mice were fed a HFD (45 kCal % from fat) or a low fat diet (LFD, 10 kCal % from fat) for 28 weeks. On the 27th week of study, mice were subjected to pyruvate, glucose, and insulin tolerance tests. At termination of the study, blood, liver and white adipose tissues (WAT) were collected. Plasma biomarkers of metabolic disorders were tested, including glucagon, insulin, leptin, cholesterol, lipoproteins, triglycerides (TG), nonesterified fatty acids (NEFA), and inflammatory cytokines. Fresh hepatic mitochondria were isolated and subjected to mitochondrial respiratory function assays. Real time PCR and Western blot were employed to determine altered metabolic pathways. Histological changes and fat deposition in liver tissues were monitored by H &E and oil red O staining, respectively.ResultsAfter the 28‐week intervention, there were no differences in food intake, body and WAT weights in both strains of mice fed LFD. However, the KO mice fed the HFD consumed significantly more food, gained more body and WAT weights, and had a significantly elevated fasting blood glucose level, compared to WT. Tolerance tests showed that KO mice developed intolerance to glucose, insulin, and pyruvate, suggesting enhanced gluconeogenesis, dyslipidemia, and hyperglycemia. Assessment of hepatic mitochondrial function revealed, the KO mice on the HFD, compared to WT mice fed with HFD, exhibited a mitochondrial proton leak, characterized by increased respiratory activity of electron transport chain complex II and IV. These findings are consistent with hyperactive and dysfunctional mitochondria. Further, KO mice fed a HFD had higher levels of circulatory NEFA, cholesterol, LDL and the pro‐inflammatory cytokine, interleukin (IL)‐18, suggestive of chronic inflammation.ConclusionsThe ablation of BCO2 causes mitochondrial dysfunction/hyperactivation and chronic inflammation, which may contribute to the development of metabolic disorders, including dyslipidemia, hyperglycemia and insulin resistance in mice fed a HFD.
Obesity is associated with distinct changes in the human plasma phospholipidome
Authors: Pickens Charles Austin , Jones Daniel , Fenton Jenifer I. 
Published: November 2023

Obesity alters the composition of plasma and tissue fatty acids (FAs), which contributes to inflammation and insulin resistance. Several studies have reported obesity and insulin resistance are associated with altered levels of linoleic (18:2), dihomo‐gamma linolenic (20:3), arachidonic (20:4), and nervonic (24:1) acid in total plasma phospholipids (PPLs). However, few researchers have investigated whether these FA changes are specific to individual phospholipid (PL) classes (e.g., phosphatidylcholines [PCs], sphingomyelins [SMs]). The objective of this study was to determine whether specific PPL species containing 18:2, 20:3, 20:4, and 24:1 in plasma are associated with obesity. At time of enrollment, blood samples were collected from fasting subjects (males ages 48–65). Plasma was separated and stored at −80ºC until analysis. Crude plasma lipid extracts were analyzed using UPLC‐MS on a QTof mass spectrometer using reversed phase UPLC, electrospray ionization, and non‐selective multiplexed collision‐induced dissociation in negative‐ion mode. Data were processed using MarkerLynx version 4.1 which identified 410 lipids. Orthogonal partial least square discriminant analysis (OPLS‐DA) was used to compare obese (n=52) to lean (n=28) individuals and to generate an S‐plot of PL variables of importance (VIP) that distinguish obese from lean PL profiles. VIPs >2 were tested for statistical differences between lean and obese individuals using a Mann‐Whitney nonparametric U‐test. Obesity was inversely associated with the following PL species: lysoPC(18:2) p<0.0005, lysophosphatidylethanolamine(18:2) p<0.01, PC(plasmenyl‐16:0/18:2) p<0.0001, and SM(d18:2/24:1) p<0.05. Obesity was positively associated with PC(16:0/20:3) p<0.0001, PC(18:0/20:3) p<0.0001, and PC(16:0/20:4) p<0.0005. Therefore, we suggest that the previously reported changes in PPL 18:2, 20:3, 20:4, and 24:1 likely occur in these specific PL species. Future studies should investigate whether and how altered levels of these PL species influence obesity‐associated pathologies and examine their usefulness as predictive biomarkers of metabolic dysregulation.Support or Funding InformationResearch Support: NIH R03CA142000 and MSU CTSI
Cholesterol homeostasis alters one carbon metabolism in vitro and in vivo
Authors: Ko Hsin‐An Shawn , Wu Yi‐Ting Isabel , Sou Nga‐Lai Shawn , Chiang En‐Pei Isabel 
Published: November 2023

Cholesterol essential for the synthesis of steroid hormones, bile acids, and lipoproteins. Hyperhomocysteinemia and hypercholesterolemia are both risk factors for human cardiovascular diseases. Previous studies reported that cholesterol biosynthesis can be regulated by homocysteine‐induced endoplasmic reticulum stress in primary human umbilical vein endothelial cells (HUVEC), hepatocellular carcinoma cell line (HepG2), and in murine models. However, the physiological impact of excessive cholesterol exposure on one‐carbon metabolism is unknown. We hypothesize that cholesterol may alter methionine adenosyltransferase 1A (MAT1a) expression via sterol regulatory element‐binding proteins (SREBPs) that have been shown to target the promoter of MAT1a gene. Physiological doses of cholesterol or mevastatin, an inhibitor of cholesterol synthesis, were used to alter cellular cholesterol contents in liver derived cell lines L02. Mice fed high cholesterol diets or cholesterol‐lowering drugs were used as in vivo models. We discovered that ratios of nuclear/ total SREBPs tended were altered by cholesterol and mevestatin treatments in the cell models. Furthermore, reporter assay demonstrated that cholesterol treatment but not mevastatin significantly increased MAT1a promoter activity, supporting our hypothesis. Preliminary data from stable isotopic tracer experiments also showed consistent results that cholesterol alters MAT expression and S‐adenosyl‐ methionine synthesis in vitro. We demonstrated novel findings on how cholesterol homeostasis interacts with methyl group kinetics in mammalian cells. The in vivo kinetics studies on how cholesterol affect one carbon metabolism are underway.Support or Funding InformationMOST 104‐2320‐B005‐010‐MY3; MOST104‐2911‐I005‐301; Ministry of Education, Taiwan, R.O.C. under the ATU plan
One‐Carbon Metabolic Kinetics in Human Disease Models
Authors: Chiang EnPei Isabel , Wang Yi‐Cheng , Wu Ming‐Tsung , Lin Yan‐Jun , Ko Hsin‐An , Huang Yu‐ Hsuan , Sou Nga‐Lai , Chen Yi‐Ming , Tang Feng‐Yao 
Published: November 2023

The polymorphisms in MTHFR have been associated with altered risk of numerous human cancers whereas GNMT is commonly diminished in human hepatoma. Folate‐mediated one‐carbon metabolism is an important therapeutic target of many human diseases including cancer. We extensively investigated how gene‐nutrient interactions may modulate human cancer risk in 2 major folate metabolic genes: MTHFR and GNMT. To further understand the metabolic roles of these genes in human disease progression, the biochemical impacts of gene alterations were carefully investigated: methyl group supply, global DNA methylation, nucleotide biosynthesis, DNA damage, and partitioning of the folate dependent 1‐carbon groups. The distinct model systems used included: EB virus‐transformed lymphoblasts expressing human polymorphic genotypes; liver‐derived transformed cell‐lines with and without overexpression of the target gene; and cells with stabilized inhibition using shRNA. We discovered that the genotype with reduced MTHFR function significantly reduces folate‐dependent remethylation under folate restriction, but it assists purine synthesis when folate is adequate. The advantage of de novo purine synthesis found in the MTHFR TT genotype may account for the protective effect of MTHFR in human hematological malignancies. Furthermore, GNMT affects transmethylation kinetics, S‐adenosylmethionine synthesis, and facilitates the conservation of methyl groups by limiting homocysteine remethylation fluxes. Restoring GNMT assists methylfolate‐dependent reactions and ameliorates the consequences of folate depletion. GNMT expression in vivo improves folate retention and bioavailability in the liver. Loss of GNMT impairs nucleotide biosynthesis. Over‐expression of GNMT enhances nucleotide biosynthesis and improves DNA integrity by reducing uracil misincorporation in DNA both in vitro and in vivo. Our systematic series of studies give new insights into the underlying mechanisms by which MTHFR and GNMT may participate in human tumor prevention and progression.Support or Funding InformationMOST 104‐2320‐B005‐010‐MY3; MOST104‐2911‐I005‐301, Ministry of Education, Taiwan, R.O.C. under the ATU plan
Food Insecurity is Associated with Faster Cognitive Decline: Boston Puerto Rican Health Study
Authors: Wong Janice , Scott Tammy , Wilde Parke , Li Yinge , Tucker Katherine L. , Gao Xiang 
Published: November 2023

BACKGROUNDFood insecurity ‐ living with hunger and fear of not having enough food ‐ is a growing worldwide concern, due to an imbalance between rapidly increasing demand for food and limited access to good quality foods. In our previous cross‐sectional study, we found that food insecurity was associated with poor cognitive function, but the direction of this relationship remains unclear.OBJECTIVESTo investigate whether food insecurity is associated with development of cognitive decline.DESIGNThe current prospective analysis was based on 597 Puerto Rican adults aged 40–75 with mini‐mental status exam (MMSE) ≥ 24 at baseline. Food security was assessed at baseline with the US Household Food Security Scale. Participants completed cognitive batteries (MMSE, word list learning, digit span, Stroop test, verbal fluency, clock drawing, figure copying) at baseline and two‐year follow‐up. The primary outcome was the change in global cognitive function over 2 years, averaging standardized scores across all cognitive tests.RESULTSFood insecurity at baseline was significantly associated with 2 year decline in global cognitive function (p trend = 0.03), after adjusting for baseline global cognitive score, age, education, APOE status, diet quality score, serum homocysteine concentration, depression and other potential confounders. The association between food security and cognitive decline tended to be more pronounced in participants who were below the poverty line or those with better cognitive function at the baseline (MMSE ≥ 27), relative to the other participants (p interaction<0.1 for both).CONCLUSIONSFood insecurity is associated with cognitive decline in this population with high risk of food insecurity and cognitive impairment.Support or Funding InformationThis work was supported by NIH grants P01 AG023394, and P50 HL105185.
EFFECTS OF METFORMIN EXPOSURE DURING LACTATION ON MOUSE OFFSPRING METABOLIC HEALTH AND MATERNAL LACTATION CHARACTERISTICS
Authors: Gregg Brigid , Brill Joshua , Botezatu Nathalie , Smith Michelle R 
Published: November 2023

BackgroundMetformin administration during pregnancy has become more accepted as clinical trials examining metformin use in pregnancy have expanded. New clinical trials are underway to investigate the potential benefits of metformin use during lactation. The importance of insulin signaling in milk secretion raises the possibility that an insulin sensitizer may have an impact on lactation output. We provide new data demonstrating that metformin exposure during lactation in a mouse model causes modifications to lactation leading to programming effects in the murine neonatal pancreas.ObjectiveTo establish how metformin administration during lactation in a rodent model impacts maternal lactation physiology and how this in turn effects pup metabolic health.MethodsMetformin was delivered in drinking water to C57BL/6J mice at either a high or low dose from postnatal day 1 (P1) and continued throughout lactation (Met PN group). Animals were examined for pancreatic morphology at mid‐lactation and for metabolic health during young adulthood. Mothers were also examined for mammary gland characteristics during lactation and upon weaning.ResultsDams given a lower aqueous dose of metformin from P1 showed an indication of increased milk output through estimated milk volume experiments. Metformin exposed pups also had increased body weight during the first 3 weeks of life. In a separate set of experiments, dams given a higher dose of metformin demonstrated decreased cleaved caspase‐3 by western blotting in mammary glands taken 2 days after weaning. Pups that nursed from the mothers that received a higher dose metformin showed increased b‐cell mass at postnatal day 11 (P11). Male offspring exhibited improved glucose tolerance test (GTT) at 2 months of age and an increase in glucose stimulated insulin secretion (GSIS) in vivo. Metformin exposed offspring body weight was lower in these offspring than control pups and remained so throughout the period of the experiment.ConclusionsThese findings suggest that metformin may have an impact on lactation output at lower doses and lead to a delay in involution of the mammary gland at the time of weaning at higher doses. These effects seem to result in long‐term programming of metabolic health in the offspring. These findings could support the use of metformin during lactation to augment milk output and the potential for this exposure to have beneficial effects on offspring metabolism.Support or Funding InformationAmendt‐Heller Award for Newborn Research 1K08 DK102526 01A1