Biochemical Phenomena, Metabolism, and Nutrition Commons^™

Estrogen Receptor-Α Expressing Neurons In The Ventrolateral Vmh Regulate Glucose Balance, Yanlin He, Pingwen Xu, Chunmei Wang, Yan Xia, Meng Yu, Yongjie Yang, Kaifan Yu, Xing Cai, Na Qu, Kenji Saito, Julia Wang, Ilirjana Hyseni, Matthew Robertson, Badrajee Piyarathna, Min Gao, Sohaib A Khan, Feng Liu, Rui Chen, Cristian Coarfa, Zhongming Zhao, Qingchun Tong, Zheng Sun, Yong Xu

Children’s Nutrition Research Center Staff Publications

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERαvlVMH) or glucose-excited neurons (GE-ERαvlVMH). Hypoglycemia activates GI-ERαvlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERαvlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERαvlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERαvlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERαvlVMH …

Discovery Of A Bacterial Peptide As A Modulator Of Glp-1 And Metabolic Disease, Catherine Tomaro-Duchesneau, Stephanie L Levalley, Daniel Roeth, Liang Sun, Frank T Horrigan, Markus Kalkum, Joseph M Hyser, Robert A Britton

Faculty, Staff and Students Publications

Early work in rodents highlighted the gut microbiota's importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1), an incretin secreted by L-cells lining the gastrointestinal epithelium, has important functions: promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to identify microbial strains with GLP-1 stimulatory activity as potential metabolic disease therapeutics. Over 1500 human-derived strains were isolated from healthy individuals and screened for GLP-1 modulation by incubating bacterial cell-free supernatants with NCI H716 L-cells. Approximately 45 strains capable of increasing GLP-1 were discovered. All GLP-1 positive …

The Impact Of Diabetic Foot Ulcers And Unilateral Offloading Footwear On Gait In People With Diabetes, Erica Ling, Brian Lepow, He Zhou, Ana Enriquez, Ashley Mullen, Bijan Najafi

Faculty, Staff and Students Publications

BACKGROUND: Unilateral offloading footwear prescribed to patients with diabetic foot ulcers elevates one limb relative to the other, which may lead to limp and abnormal gait. This study investigated whether the unilateral foot ulcer and offloading combination negatively impacts gait function beyond diabetic peripheral neuropathy.

METHODS: Eighty-six participants were recruited in 3 groups: 12 with diabetic peripheral neuropathy and unilateral foot ulcers wearing offloading footwear (offloading group, age = 55.6 ± 9.5 years, BMI = 30.9 ± 4.5 kg/m

FINDINGS: The offloading group exhibited deteriorated gait function compared to the non-diabetic group (p < 0.005, Cohen's effect size d = 0.90-2.61). They also had decreased gait speed (p < 0.001, d = 1.79) and stride length (p < 0.001, d = 1.76), as well as increased gait cycle time (p < 0.001, d = 1.67) and limp (p < 0.050, d = 0.72-1.49) compared to the neuropathy group. The offloading group showed increased gait unsteadiness compared to the neuropathy group, but the difference did not reach statistical significance in our samples.

INTERPRETATION: This study demonstrated that while diabetic …

Development And Characterization Of A Wee1 Kinase Degrader, Zhengnian Li, Benika J Pinch, Calla M Olson, Katherine A Donovan, Radosław P Nowak, Caitlin E Mills, David A Scott, Zainab M Doctor, Nicholas A Eleuteri, Mirra Chung, Peter K Sorger, Eric S Fischer, Nathanael S Gray

Faculty, Staff and Students Publications

The G1/S cell cycle checkpoint is frequently dysregulated in cancer, leaving cancer cells reliant on a functional G2/M checkpoint to prevent excessive DNA damage. Wee1 regulates the G2/M checkpoint by phosphorylating CDK1 at Tyr15 to prevent mitotic entry. Previous drug development efforts targeting Wee1 resulted in the clinical-grade inhibitor, AZD1775. However, AZD1775 is burdened by dose-limiting adverse events, and has off-target PLK1 activity. In an attempt to overcome these limitations, we developed Wee1 degraders by conjugating AZD1775 to the cereblon (CRBN)-binding ligand, pomalidomide. The resulting lead compound, ZNL-02-096, degrades Wee1 while sparing PLK1, induces G2/M accumulation at 10-fold lower doses …

The Vimentin Rod Domain Blocks P-Selectin-P-Selectin Glycoprotein Ligand 1 Interactions To Attenuate Leukocyte Adhesion To Inflamed Endothelium, Fong Wilson Lam, Cameron August Brown, Christian Valladolid, Dabel Cynthia Emebo, Timothy Gerald Palzkill, Miguel Angel Cruz

Faculty, Staff and Students Publications

Acute inflammation begins with leukocyte P-selectin glycoprotein ligand-1 (PSGL-1) binding to P-selectin on inflamed endothelium and platelets. In pathologic conditions, this process may contribute to secondary organ damage, like sepsis-induced liver injury. Therefore, developing novel therapies to attenuate inflammation may be beneficial. We previously reported that recombinant human vimentin (rhVim) binds P-selectin to block leukocyte adhesion to endothelium and platelets. In this study, we used SPOT-peptide arrays to identify the rod domain as the active region within rhVim that interacts with P-selectin. Indeed, recombinant human rod domain of vimentin (rhRod) binds to P-selectin with high affinity, with in silico modeling …

Assessment Of Physical Fitness After Bariatric Surgery And Its Association With Protein Intake And Type Of Cholecalciferol Supplementation, Hendrika J M Smelt, Sjaak Pouwels, Alper Celik, Adarsh Gupta, Johannes F Smulders

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Background: Several studies showed that there is a relationship between vitamin and mineral status and muscle strength. In particular this is the case for handgrip strength (HS) and vitamin D deficiency. In bariatric surgery there is a risk of decrease in muscle strength after surgery and also vitamin and mineral deficiencies are not uncommon. The aim of this study is to assess the effect of low vitamin 25 (OH) cholecalciferol levels, high dose cholecalciferol supplementation regime and protein intake on physical fitness, measured using handgrip strength (HS) and the shuttle walk run test (SWRT). Methods: For this retrospective …

In-Hospital Mortality And Post-Surgical Complications Among Cancer Patients With Metabolic Syndrome, Tomi Akinyemiju, Swati Sakhuja, Neomi Vin-Raviv

Epidemiology and Environmental Health Faculty Publications

Background

Metabolic syndrome (MetS) is an important etiologic and prognostic factor for cancer, but few studies have assessed hospitalization outcomes among patients with both conditions.

Methods

Data was obtained from the Healthcare Cost and Utilization project Nationwide Inpatient Sample (HCUP-NIS). Study variables were assessed using ICD-9 codes on adults aged 40 years and over admitted to a US hospital between 2007 and 2011 with primary diagnosis of either breast, colorectal, or prostate cancer. We examined in-hospital mortality, post-surgical complications, and discharge disposition among cancer patients with MetS and compared with non-MetS patients.

Results

Hospitalized breast (OR: 0.31, 95% CI: 0.20–0.46), …

Probing The Metabolic Phenotype Of Breast Cancer Cells By Multiple Tracer Stable Isotope Resolved Metabolomics, Andrew N. Lane, Julie Tan, Yali Wang, Jun Yan, Richard M. Higashi, Teresa W. -M. Fan

Center for Environmental and Systems Biochemistry Faculty Publications

Breast cancers vary by their origin and specific set of genetic lesions, which gives rise to distinct phenotypes and differential response to targeted and untargeted chemotherapies. To explore the functional differences of different breast cell types, we performed Stable Isotope Resolved Metabolomics (SIRM) studies of one primary breast (HMEC) and three breast cancer cells (MCF-7, MDAMB-231, and ZR75-1) having distinct genotypes and growth characteristics, using ¹³C₆-glucose, ¹³C-1+2-glucose, ¹³C₅,¹⁵N₂-Gln, ¹³C₃-glycerol, and ¹³C₈-octanoate as tracers. These tracers were designed to probe the central energy producing …

Cpt1a Methylation Is Associated With Plasma Adiponectin, S. Aslibekyan, A. N. Do, H. Xu, S. Li, M. R. Irvin, D Zhi, H. K. Tiwari, D. M. Absher, A. R. Shuldiner, T. Zhang, W. Chen, K. Tanner, C. Hong, B. D. Mitchell, G. Berenson, Donna K. Arnett

Epidemiology and Environmental Health Faculty Publications

Background and Aims—Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood.

Methods and Results—We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n= 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression …

Association Of Dna Methylation At Cpt1a Locus With Metabolic Syndrome In The Genetics Of Lipid Lowering Drugs And Diet Network (Goldn) Study, Mithun Das, Jin Sha, Bertha Hidalgo, Stella Aslibekyan, Anh N. Do, Degui Zhi, Dianjianyi Sun, Tao Zhang, Shengxu Li, Wei Chen, Sathanur R. Srinivasan, Hemant K. Tiwari, Devin Absher, Jose M. Ordovas, Gerald S. Berenson, Donna K. Arnett, Marguerite R. Irvin

Epidemiology and Environmental Health Faculty Publications

In this study, we conducted an epigenome-wide association study of metabolic syndrome (MetS) among 846 participants of European descent in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN). DNA was isolated from CD4+ T cells and methylation at ~470,000 cytosine-phosphate-guanine dinucleotide (CpG) pairs was assayed using the Illumina Infinium HumanMethylation450 BeadChip. We modeled the percentage methylation at individual CpGs as a function of MetS using linear mixed models. A Bonferroni-corrected P-value of 1.1 x 10⁻⁷ was considered significant. Methylation at two CpG sites in CPT1A on chromosome 11 was significantly associated with MetS (P for cg00574958 = …

The Synergistic Roles Of Cholecystokinin B And Dopamine D5 Receptors On The Regulation Of Renal Sodium Excretion., Xiaoliang Jiang, Wei Chen, Xing Liu, Zihao Wang, Yunpeng Liu, Robin A Felder, John J Gildea, Pedro A. Jose, Chuan Qin, Zhiwei Yang

Medicine Faculty Publications

Renal dopamine D1-like receptors (D1R and D5R) and the gastrin receptor (CCKBR) are involved in the maintenance of sodium homeostasis. The D1R has been found to interact synergistically with CCKBR in renal proximal tubule (RPT) cells to promote natriuresis and diuresis. D5R, which has a higher affinity for dopamine than D1R, has some constitutive activity. Hence, we sought to investigate the interaction between D5R and CCKBR in the regulation of renal sodium excretion. In present study, we found D5R and CCKBR increase each other's expression in a concentration- and time-dependent manner in the HK-2 cell, the specificity of which was …

Ethnic Differences In Maternal Adipokines During Normal Pregnancy, Xinhua Chen, Theresa O Scholl

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Two adipokines (adiponectin and resistin) have opposite relations with insulin resistance and inflammation. Our major focus was to determine whether there were detectable ethnic differences in maternal adipokines during pregnancy. We also explored the correlation of the adipokines with maternal glucose homeostasis, blood pressure and anthropometric parameters. Pregnant women (n = 1634) were from a large prospective cohort study in Camden NJ (African-American 36.8%; Hispanic 47.6%; Caucasian 15.6%). Serum adiponectin and resistin were measured at entry (week 16.8) and the 3rd trimester (week 30.7) using the Luminex xMapTechnology. Significant differences were observed among ethnic groups, controlling for confounding variables. African …

A Truncation Mutation In Tbc1d4 In A Family With Acanthosis Nigricans And Postprandial Hyperinsulinemia, Satya Dash, Hiroyuki Sano, Justin J. Rochford, Robert K. Semple

Dartmouth Scholarship

Tre-2, BUB2, CDC16, 1 domain family member 4 (TBC1D4) (AS160) is a Rab-GTPase activating protein implicated in insulin-stimulated glucose transporter 4 (GLUT4) translocation in adipocytes and myotubes. To determine whether loss-of-function mutations in TBC1D4 might impair GLUT4 translocation and cause insulin resistance in humans, we screened the coding regions of this gene in 156 severely insulin-resistant patients. A female presenting at age 11 years with acanthosis nigricans and extreme postprandial hyperinsulinemia was heterozygous for a premature stop mutation (R363X) in TBC1D4. After demonstrating reduced expression of wild-type TBC1D4 protein and expression of the truncated protein in lymphocytes from the proband, …

Role For Akt3/Protein Kinase Bγ In Attainment Of Normal Brain Size, Rachel M. Easton, Han Cho, Kristin Roovers, Diana W. Shineman

Dartmouth Scholarship

Studies of Drosophila and mammals have revealed the importance of insulin signaling through phosphatidylinositol 3-kinase and the serine/threonine kinase Akt/protein kinase B for the regulation of cell, organ, and organismal growth. In mammals, three highly conserved proteins, Akt1, Akt2, and Akt3, comprise the Akt family, of which the first two are required for normal growth and metabolism, respectively. Here we address the function of Akt3. Like Akt1, Akt3 is not required for the maintenance of normal carbohydrate metabolism but is essential for the attainment of normal organ size. However, in contrast to Akt1^−/− mice, which display a …