A5059860261- Metabolism, Diabetes, and Cancer
- Pancreatic function and diabetes
- Caveolin-1 and cellular processes
- Adipose Tissue and Metabolism
- Cellular transport and secretion
- Receptor Mechanisms and Signaling
- Protein Kinase Regulation and GTPase Signaling
- Lipid metabolism and biosynthesis
- Lipid metabolism and disorders
- Biotin and Related Studies
- Peroxisome Proliferator-Activated Receptors
- Lipid Membrane Structure and Behavior
- Growth Hormone and Insulin-like Growth Factors
- Erythrocyte Function and Pathophysiology
- Muscle Physiology and Disorders
- PI3K/AKT/mTOR signaling in cancer
- RNA Research and Splicing
- Adipokines, Inflammation, and Metabolic Diseases
- Endoplasmic Reticulum Stress and Disease
- Glycosylation and Glycoproteins Research
- Monoclonal and Polyclonal Antibodies Research
- Cancer, Hypoxia, and Metabolism
- Muscle metabolism and nutrition
- Drug Transport and Resistance Mechanisms
- Diet and metabolism studies
Boston University
2010-2020
University School
1997-2020
Boston Medical Center
1989-2013
Institute of Molecular Medicine
2010
University Medical Center
1989-2009
AdipoGenix (United States)
2003
State University of New York
1980-1997
Harvard University
1986-1997
Joslin Diabetes Center
1993-1997
Stony Brook University
1980-1997
A number of studies have demonstrated that tumor necrosis factor-α (TNF-α) is associated with profound insulin resistance in adipocytes and may also play a critical role the obesity non-insulin-dependent diabetes mellitus. Reports on mechanism TNF-α action been somewhat contradictory. GLUT4 down-regulation has implicated as possible cause reduced kinase function receptor. Here we examine effects factor protein components thought to be involved insulin-stimulated glucose transport adipocytes,...
Complementary DNA clones encoding a facilitative glucose transporter-like protein have been isolated from human small intestine and muscle cDNA libraries. This 509-amino acid has 65.3, 54.3, 57.5% identity with the previously described erythrocyte/HepG2, liver, fetal transporter/transporter-like proteins, respectively. RNA blotting studies indicate that transcripts this are very abundant in adult skeletal subcutaneous fat. The was expressed vitro by cDNA-directed transcription cell-free...
Insulins modified either at lysine Bzs with an acetyl group or phenylalanine B1 a phenylthiocarbamoyl were both readily cross-linked to the receptor roughly equal efficiency.It is concluded that terminal amino and groups are accessible for cross-linking of insulin by disuccinimidyl suberate.
Abstract Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early formation mice is conserved, whereas later development strain dependent. Proximal, not distal tibial, lost with 21-day cold exposure. Rat adipocytes from sites have an increased proportion of monounsaturated fatty acids Scd1/Scd2 ,...
Plasma membrane insulin receptors, affinity labeled by covalent crosslinking to receptor-bound 125I-labeled insulin, are shown appear as a heterogeneous population of three major disulfide-linked complexes (Mr 350,000, 320,000, and 290,000) upon electrophoresis in highly porous dodecyl sulfate/polyacrylamide gels the absence reductant. This pattern is consistent all rat human tissues that were analyzed. Upon reduction disulfide bonds, each these receptor structures dissociated two successive...
Although the importance of clathrin- and caveolin-independent endocytic pathways has recently emerged, key aspects these routes remain unknown. Using quantitative ultrastructural approaches, we show that clathrin-independent carriers (CLICs) account for approximately three times volume internalized by clathrin-mediated pathway, forming major pathway involved in uptake fluid bulk membrane fibroblasts. Electron tomographic analysis 3D morphology earliest shows they are multidomain organelles...
Polymerase I and transcript release factor (PTRF)/Cavin is a cytoplasmic protein whose expression obligatory for caveola formation. Using biochemistry fluorescence resonance energy transfer–based approaches, we now show that family of related proteins, PTRF/Cavin-1, serum deprivation response (SDR)/Cavin-2, SDR-related gene product binds to C kinase (SRBC)/Cavin-3, muscle-restricted coiled-coil (MURC)/Cavin-4, forms multiprotein complex associates with caveolae. This can constitutively...
Alzheimer's disease is a neurodegenerative disorder characterized by the extracellular deposition in brain of aggregated beta-amyloid peptide, presumed to play pathogenic role, and preferential loss neurons that express 75-kD neurotrophin receptor (p75NTR). Using rat cortical NIH-3T3 cell line engineered stably p75NTR, we find peptide specifically binds p75NTR. Furthermore, 3T3 cells expressing but not wild-type control lacking receptor, undergo apoptosis presence beta-amyloid. Normal neural...
We have recently described a monoclonal antibody (1F8) that recognizes form of glucose transporter unique to fat and muscle (James, D. E., Brown, R., Navarro, J., Pilch, P. F. (1988) Nature 333, 183–185), tissues respond acutely insulin by markedly increasing their uptake. Here, we report rat adipocytes possess two immunologically distinct glucose-transporters: one recognized 1F8, reactive with antibodies raised against the human erythrocyte transporter. Immunoadsorption experiments indicate...
Cavin (PTRF) has been shown to be a highly abundant protein component of caveolae, but its functional role there is unknown. Here, we confirm that cavin co-localizes with caveolin-1 in adipocytes by confocal microscopy and co-distributes lipid raft fractions sucrose gradient flotation. However, does not directly associate as solubilization caveolae disrupts their interaction. Cholesterol depletion beta-cyclodextrin causes significant down-regulation from plasma membrane fractions....
Expression of a constitutively active, membrane-associated Akt-1 (PKB α) construct in 3T3L1 adipocytes was shown to induce glucose uptake the absence insulin by stimulating Glut4 translocation plasma membrane (Kohn, A. D., Summers, S. A., Birnbaum, M. J., and Roth, R. (1996)J. Biol. Chem. 271, 31372–31378). However, rat fat cell vast majority is cytosolic shows no re-distribution response insulin. On other hand, little work has been done with Akt family members such as Akt-2 β) or Akt-3 γ)....
We examined the effects of insulin and insulin-like growth factor I (IGF-I) on production collagen by cultures human embryonic lung fibroblasts. Insulin at 20 ng/ml increased accumulation 58% total protein formation 18%. At 2 micrograms/ml, 2- to 3-fold 2-fold. The mRNA levels for alpha 1(I) 1(III) chains were elevated compared with untreated control values. IGF-I 10 100 maximally 3-fold. A specific antibody receptor (alpha IR-3) caused a concentration-related decline in insulin-induced...
In the presence of adenosine 5'-[gamma-32P]triphosphate ([gamma-32P]ATP) and a partially purified human placental insulin receptor preparation, stimulates phosphorylation an Mr 94000 protein in time- dose-dependent manner. Half-maximal stimulation 32P incorporation occurs at (2-3) X 10(-9) M insulin, concentration identical with Kd for binding this preparation. Immunoprecipitations monoclonal anti-insulin antibody demonstrate that kinase substrate is component receptor, beta subunit. If...
Adipocyte differentiation is regulated by at least two major transcription factors, CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ). Expression of PPARγ in fibroblasts converts them to fat-laden cells with an adipocyte-like morphology. Here, we investigate the ability confer insulin-sensitive glucose transport a variety murine fibroblast cell lines. When cultured presence ligand, Swiss-3T3 BALB/c-3T3 ectopically expressing accumulate lipid...
Epidermal growth factor (EGF) receptor monomers and noncovalently associated dimers were isolated by sucrose density gradient centrifugation, their respective binding autophosphorylation activities determined. We find that are low-affinity receptors high-affinity receptors. In the absence of EGF, exhibit a 4-fold higher activity than do monomers. Addition EGF increases on an average 4.8-fold but has minimal effect dimers. Furthermore, shifts monomer-dimer equilibrium to dimer form. conclude...
Augmentation of glucose transport into skeletal muscle by GLUT4 translocation to the plasma and T-tubule membranes can be mediated independently insulin contraction/exercise. Available data suggest that separable pools intracellular respond these two stimuli. To identify characterize pools, we fractionated in a discontinuous sucrose density gradient. Fractions 32 36% exhibited highest enrichment were responsive exercise, respectively. The combination stimuli depleted both fractions...
Abstract Innervation is important for normal metabolism in skeletal muscle, including insulin-sensitive glucose uptake. However, the transcription factors that transduce signals from neuromuscular junction to nucleus and affect changes metabolic gene expression are not well defined. We demonstrate here orphan nuclear receptor Nur77 a regulator of linked utilization muscle. In vivo, preferentially expressed glycolytic compared with oxidative muscle responsive β-adrenergic stimulation....
OBJECTIVE Nur77 is an orphan nuclear receptor with pleotropic functions. Previous studies have identified as a transcriptional regulator of glucose utilization genes in skeletal muscle and gluconeogenesis liver. However, the net functional impact these pathways unknown. To examine consequence signaling for metabolism vivo, we challenged null mice high-fat feeding. RESEARCH DESIGN AND METHODS Wild-type were fed diet (60% calories from fat) 3 months. We determined tolerance, tissue-specific...