405 research outputs found
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Biguanide therapy for diabetes and cancer & a novel methyltransferase that regulates energy expenditure and adiposity and is elevated in many cancers
Electronic structure of the molecule based magnet Cu PM(NO3)2 (H2O)2
We present density functional calculations on the molecule based S=1/2
antiferromagnetic chain compound Cu PM(NO3)2 (H2O)2; PM = pyrimidine. The
properties of the ferro- and antiferromagnetic state are investigated at the
level of the local density approximation and with the hybrid functional B3LYP.
Spin density maps illustrate the exchange path via the pyrimidine molecule
which mediates the magnetism in the one-dimensional chain. The computed
exchange coupling is antiferromagnetic and in reasonable agreement with the
experiment. It is suggested that the antiferromagnetic coupling is due to the
possibility of stronger delocalization of the charges on the nitrogen atoms,
compared to the ferromagnetic case. In addition, computed isotropic and
anisotropic hyperfine interaction parameters are compared with recent NMR
experiments
p70S6 Kinase Phosphorylates AMPK on Serine 491 to Mediate Leptin's Effect on Food Intake
SummaryThe PI3K-AKT, mTOR-p70S6 kinase and AMPK pathways play distinct and critical roles in metabolic regulation. Each pathway is necessary for leptin's anorexigenic effects in the hypothalamus. Here we show that these pathways converge in an integrated phosphorylation cascade to mediate leptin action in the hypothalamus. We identify serine491 on α2AMPK as the site of convergence and show that p70S6 kinase forms a complex with α2AMPK, resulting in phosphorylation on serine491. Blocking α2AMPK-serine491 phosphorylation increases hypothalamic AMPK activity, food intake, and body weight. Serine491 phosphorylation is necessary for leptin's effects on hypothalamic α2AMPK activity, neuropeptide expression, food intake, and body weight. These results identify an inhibitory AMPK kinase, p70S6 kinase, and demonstrate that AMPK is a substrate for mTOR-p70S6 kinase. This discovery has broad biologic implications since mTOR-p70S6 kinase and AMPK have multiple, fundamental and generally opposing cellular effects that regulate metabolism, cell growth, and development
Exchange Interactions and High-Energy Spin States in Mn_12-acetate
We perform inelastic neutron scattering measurements on the molecular
nanomagnet Mn_12-acetate to measure the excitation spectrum up to 45meV (500K).
We isolate magnetic excitations in two groups at 5-6.5meV (60-75K) and
8-10.5meV (95-120K), with higher levels appearing only at 27meV (310K) and
31meV (360K). From a detailed characterization of the transition peaks we show
that all of the low-energy modes appear to be separate S = 9 excitations above
the S = 10 ground state, with the peak at 27meV (310K) corresponding to the
first S = 11 excitation. We consider a general model for the four exchange
interaction parameters of the molecule. The static susceptibility is computed
by high-temperature series expansion and the energy spectrum, matrix elements
and ground-state spin configuration by exact diagonalization. The theoretical
results are matched with experimental observation by inclusion of cluster
anisotropy parameters, revealing strong constraints on possible parameter sets.
We conclude that only a model with dominant exchange couplings J_1 ~ J_2 ~
5.5meV (65K) and small couplings J_3 ~ J_4 ~ 0.6meV (7K) is consistent with the
experimental data.Comment: 17 pages, 12 figure
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Lessons on Conditional Gene Targeting in Mouse Adipose Tissue
Conditional gene targeting has been extensively used for in vivo analysis of gene function in adipocyte cell biology but often with debate over the tissue specificity and the efficacy of inactivation. To directly compare the specificity and efficacy of different Cre lines in mediating adipocyte specific recombination, transgenic Cre lines driven by the adipocyte protein 2 (aP2) and adiponectin (Adipoq) gene promoters, as well as a tamoxifen-inducible Cre driven by the aP2 gene promoter (iaP2), were bred to the Rosa26R (R26R) reporter. All three Cre lines demonstrated recombination in the brown and white fat pads. Using different floxed loci, the individual Cre lines displayed a range of efficacy to Cre-mediated recombination that ranged from no observable recombination to complete recombination within the fat. The Adipoq-Cre exhibited no observable recombination in any other tissues examined, whereas both aP2-Cre lines resulted in recombination in endothelial cells of the heart and nonendothelial, nonmyocyte cells in the skeletal muscle. In addition, the aP2-Cre line can lead to germline recombination of floxed alleles in ∼2% of spermatozoa. Thus, different “adipocyte-specific” Cre lines display different degrees of efficiency and specificity, illustrating important differences that must be taken into account in their use for studying adipose biology
Application of combined omics platforms to accelerate biomedical discovery in diabesity
Diabesity has become a popular term to describe the specific form of diabetes that develops late in life and is associated with obesity. While there is a correlation between diabetes and obesity, the association is not universally predictive. Defining the metabolic characteristics of obesity that lead to diabetes, and how obese individuals who develop diabetes different from those who do not, are important goals. The use of large-scale omics analyses (e.g., metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity may help to identify new targets to treat these conditions. This report discusses how various types of omics data can be integrated to shed light on the changes in metabolism that occur in obesity and diabetes
PTP1B Regulates Leptin Signal Transduction In Vivo
AbstractMice lacking the protein-tyrosine phosphatase PTP1B are hypersensitive to insulin and resistant to obesity. However, the molecular basis for resistance to obesity has been unclear. Here we show that PTP1B regulates leptin signaling. In transfection studies, PTP1B dephosphorylates the leptin receptor-associated kinase, Jak2. PTP1B is expressed in hypothalamic regions harboring leptin-responsive neurons. Compared to wild-type littermates, PTP1B−/− mice have decreased leptin/body fat ratios, leptin hypersensitivity, and enhanced leptin-induced hypothalamic Stat3 tyrosyl phosphorylation. Gold thioglucose treatment, which ablates leptin-responsive hypothalamic neurons, partially overcomes resistance to obesity in PTP1B−/− mice. Our data indicate that PTP1B regulates leptin signaling in vivo, likely by targeting Jak2. PTP1B may be a novel target to treat leptin resistance in obesity
Insulin Resistance Is Not Sustained Following Denervation in Glycolytic Skeletal Muscle
Denervation rapidly induces insulin resistance (i.e., impairments in insulin-stimulated glucose uptake and signaling proteins) in skeletal muscle. Surprisingly, whether this metabolic derangement is long-lasting is presently not clear. The main goal of this study was to determine if insulin resistance is sustained in both oxidative soleus and glycolytic extensor digitorum longus (EDL) muscles following long-term (28 days) denervation. Mouse hindlimb muscles were denervated via unilateral sciatic nerve resection. Both soleus and EDL muscles atrophied ~40%. Strikingly, while denervation impaired submaximal insulin-stimulated [3H]-2-deoxyglucose uptake ~30% in the soleus, it enhanced submaximal (~120%) and maximal (~160%) insulin-stimulated glucose uptake in the EDL. To assess possible mechanism(s), immunoblots were performed. Denervation did not consistently alter insulin signaling (e.g., p-Akt (Thr308):Akt; p-TBC1D1 [phospho-Akt substrate (PAS)]:TBC1D1; or p-TBC1D4 (PAS):TBC1D4) in either muscle. However, denervation decreased glucose transporter 4 (GLUT4) levels ~65% in the soleus but increased them ~90% in the EDL. To assess the contribution of GLUT4 to the enhanced EDL muscle glucose uptake, muscle-specific GLUT4 knockout mice were examined. Loss of GLUT4 prevented the denervation-induced increase in insulin-stimulated glucose uptake. In conclusion, the denervation results sustained insulin resistance in the soleus but enhanced insulin sensitivity in the EDL due to increased GLUT4 protein levels
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