Obesity and type 2 diabetes mellitus (T2DM)--disorders of energy homeostasis and glucose homeostasis, respectively--are tightly linked and the incidences of both conditions are increasing in ...parallel. The CNS integrates information regarding peripheral nutrient and hormonal changes and processes this information to regulate energy homeostasis. Recent findings indicate that some of the neural circuits and mechanisms underlying energy balance are also essential for the regulation of glucose homeostasis. We propose that disruption of these overlapping pathways links the metabolic disturbances associated with obesity and T2DM. A better understanding of these converging mechanisms may lead to therapeutic strategies that target both T2DM and obesity.
Targeted therapies against cancer have improved both survival and quality of life of patients. However, metabolic rewiring evokes cellular mechanisms that reduce therapeutic mightiness. Resistant ...cells generate more glutathione, elicit nuclear factor erythroid 2-related factor 2 (NRF2) activation, and overexpress many anti-oxidative genes such as superoxide dismutase, catalase, glutathione peroxidase, and thioredoxin reductase, providing stronger antioxidant capacity to survive in a more oxidative environment due to the sharp rise in oxidative metabolism and reactive oxygen species generation. These changes dramatically alter tumour microenvironment and cellular metabolism itself. A rational design of therapeutic combination strategies is needed to flatten cellular homeostasis and accomplish a drop in cancer development. Context-dependent glutaminase isoenzymes show oncogenic and tumour suppressor properties, being mainly associated to MYC and p53, respectively. Glutaminases catalyze glutaminolysis in mitochondria, regulating oxidative phosphorylation, redox status and cell metabolism for tumour growth. In addition, the substrate and product of glutaminase reaction, glutamine and glutamate, respectively, can work as signalling molecules moderating redox and bioenergetic pathways in cancer. Novel synergistic approaches combining glutaminase inhibition and redox-dependent modulation are described in this review. Pharmacological or genetic glutaminase regulation along with oxidative chemotherapy can help to improve the design of combination strategies that escalate the rate of therapeutic success in cancer patients.
The fundamental limits currently faced by traditional computing devices necessitate the exploration of ways to store, compute, and transmit information going beyond the current CMOS-based ...technologies. Here, we propose a three-dimensional (3D) magnetic interconnector that exploits geometry-driven automotion of domain walls (DWs), for the transfer of magnetic information between functional magnetic planes. By combining state-of-the-art 3D nanoprinting and standard physical vapor deposition, we prototype 3D helical DW conduits. We observe the automotion of DWs by imaging their magnetic state under different field sequences using X-ray microscopy, observing a robust unidirectional motion of DWs from the bottom to the top of the spirals. From experiments and micromagnetic simulations, we determine that the large thickness gradients present in the structure are the main mechanism for 3D DW automotion. We obtain direct evidence of how this tailorable magnetic energy gradient is imprinted in the devices, and how it competes with pinning effects that are due to local changes in the energy landscape. Our work also predicts how this effect could lead to high DW velocities, reaching the Walker limit during automotion. This work demonstrates a possible mechanism for efficient transfer of magnetic information in three dimensions.
Obesity is one of the leading health concerns in the United States. Studies from human and rodent models suggest that inherent differences in the function of brain motivation centers, including the ...nucleus accumbens (NAc), contribute to overeating and thus obesity. For example, there are basal enhancements in the excitability of NAc GABAergic medium spiny neurons (MSN) and reductions in basal expression of AMPA‐type glutamate receptors in obesity‐prone vs obesity‐resistant rats. However, very little is known about the regulation of extracellular glutamate and GABA within the NAc of these models. Here we gave obesity‐prone and obesity‐resistant rats stable isotope‐labeled glucose (13C6‐glucose) and used liquid chromatography mass spectrometry (LC–MS) analysis of NAc dialysate to examine the real‐time incorporation of 13C6‐glucose into glutamate, glutamine, and GABA. This novel approach allowed us to identify differences in glucose utilization for neurotransmitter production between these selectively bred lines. We found that voluntarily ingested or gastrically infused 13C6‐glucose rapidly enters the NAc and is incorporated into 13C2‐glutamine, 13C2‐glutamate, and 13C2‐GABA in both groups within minutes. However, the magnitude of increases in NAc 13C2‐glutamine and 13C2‐GABA were lower in obesity‐prone than in obesity‐resistant rats, while basal levels of glutamate were elevated. This suggested that there may be differences in the astrocytic regulation of these analytes. Thus, we next examined NAc glutamine synthetase, GAD67, and GLT‐1 protein expression. Consistent with reduced 13C2‐glutamine and 13C2‐GABA, NAc glutamine synthetase and GLT‐1 protein expression were reduced in obesity‐prone vs obesity‐resistant groups. Taken together, these data show that NAc glucose utilization differs dramatically between obesity‐prone and obesity‐resistant rats, favoring glutamate over GABA production in obesity‐prone rats and that reductions in NAc astrocytic recycling of glutamate contribute to these differences. These data are discussed in light of established differences in NAc function between these models and the role of the NAc in feeding behavior.
We propose that differences in extracellular glutamate and GABA levels between obesity‐prone and obesity‐resistant rats are influenced by changes in astrocyte protein expression. Using microdialysis, we observed decreases in de novo extracellular glutamine and GABA and increases in glutamate in obesity‐prone rats. Decreases in astrocytic proteins GLT‐1 (glutamate transporter) and glutamine synthetase are consistent with elevated glutamate and decreased glutamine, respectively. This work highlights the need to examine the role of glial dysfunction in obesity and furthers evidence that astrocytes may serve as a useful target for future therapeutics.
A deep knowledge of micromechanical properties of each constitutive phase of cemented carbides is crucial to improve their performance on the basis of microstructural design optimization. In the ...present work, a systematic experimental procedure has been followed to determine the intrinsic hardness of individual WC and (W,Ti,Ta,Nb)C particles, as well as that of the metallic binder, within a WC-Co composite containing a solid solution of mixed carbide as a third phase. In doing so, massive nanoindentation and statistical analysis of the gathered data are combined. Results showed that (W,Ti,Ta,Nb)C particles are significantly harder than WC ones, independent of the hardness anisotropy exhibited by the latter. Hardness assessment for the metallic binder required further analysis, including data deconvolution using thin film models and consideration of substrate effects. The attained hardness values are then used for estimation of effective flow stress of the metallic phase by means of Tabor's equation, yielding values ranging between 1.3 and 2.0 GPa. These high constraining-related values are finally validated by experimental assessment of stress levels at which strain bursts are identified in stress-strain curves obtained by uniaxial compression of micropillars.
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•Hardness for cubic mixed carbide in a cemented carbide composite is isotropic.•Surrounding carbides strongly affect hardness value for the constraint binder.•Constraint degree of binder is elevated and affects its flow stress.•Flow stress for constrained binder is validated by compression of micropillars.
In the pursuit of integrated scheduling and control frameworks for chemical processes, it is important to develop accurate integrated models and computational strategies such that optimal decisions ...can be made in a dynamic environment. In this study, a recently developed switched system formulation that integrates scheduling and control decisions is extended to closed‐loop operation embedded with nonlinear model predictive control (NMPC). The resulting framework is a nested online scheduling and control loop that allows to obtain fast and accurate solutions as no model reduction is needed and no integer variables are involved in the formulations. In the outer loop, the integrated model is solved to calculate an optimal product switching sequence such that the process economics is optimized, whereas in the inner loop, an NMPC implements the scheduling decisions. The proposed scheme was tested on two multi‐product continuous systems. Unexpected large disturbances and rush orders were handled effectively.
Asymmetric hydrogenation of acetophenone with trans-RuH(η1-BH4)(S)-tolbinap(S,S)-dpen (TolBINAP = 2,2‘-bis(di-4-tolylphosphino)-1,1‘-binaphthyl; DPEN = 1,2-diphenylethylenediamine) in 2-propanol ...gives (R)-phenylethanol in 82% ee. The reaction proceeds smoothly even at an atmospheric pressure of H2 at room temperature and is further accelerated by addition of an alkaline base or a strong organic base. Most importantly, the hydrogenation rate is initially increased to a great extent with an increase in base molarity but subsequently decreases. Without a base, the rate is independent of H2 pressure in the range of 1−16 atm, while in the presence of a base, the reaction is accelerated with increasing H2 pressure. The extent of enantioselection is unaffected by hydrogen pressure, the presence or absence of base, the kind of base and coexisting metallic or organic cations, the nature of the solvent, or the substrate concentrations. The reaction with H2/(CH3)2CHOH proceeds 50 times faster than that with D2/(CD3)2CDOD in the absence of base, but the rate differs only by a factor of 2 in the presence of KO-t-C4H9. These findings indicate that dual mechanisms are in operation, both of which are dependent on reaction conditions and involve heterolytic cleavage of H2 to form a common reactive intermediate. The key RuH(diphosphine)(diamine)+ and its solvate complex have been detected by ESI-TOFMS and NMR spectroscopy. The hydrogenation of ketones is proposed to occur via a nonclassical metal−ligand bifunctional mechanism involving a chiral RuH2(diphosphine)(diamine), where a hydride on Ru and a proton of the NH2 ligand are simultaneously transferred to the CO function via a six-membered pericyclic transition state. The NH2 unit in the diamine ligand plays a pivotal role in the catalysis. The reaction occurs in the outer coordination sphere of the 18e RuH2 complex without CO/metal interaction. The enantiofaces of prochiral aromatic ketones are kinetically differentiated on the molecular surface of the coordinatively saturated chiral RuH2 intermediate rather than in a coordinatively unsaturated Ru template.
Arcuate Glucagon-Like Peptide 1 Receptors Regulate Glucose Homeostasis but Not Food Intake
Darleen A. Sandoval 1 ,
Didier Bagnol 2 ,
Stephen C. Woods 1 ,
David A. D'Alessio 1 and
Randy J. Seeley 1
1 ...Departments of Psychiatry and Medicine, University of Cincinnati, Cincinnati, Ohio
2 Arena Pharmaceuticals, San Diego, California
Corresponding author: Dr. Darleen Sandoval, darleen.sandoval{at}uc.edu
Abstract
OBJECTIVE— Glucagon-like peptide-1 (GLP-1) promotes glucose homeostasis through regulation of islet hormone secretion, as well as hepatic
and gastric function. Because GLP-1 is also synthesized in the brain, where it regulates food intake, we hypothesized that
the central GLP-1 system regulates glucose tolerance as well.
RESEARCH DESIGN AND METHODS— We used glucose tolerance tests and hyperinsulinemic-euglycemic clamps to assess the role of the central GLP-1 system on glucose
tolerance, insulin secretion, and hepatic and peripheral insulin sensitivity. Finally, in situ hybridization was used to examine
colocalization of GLP-1 receptors with neuropeptide tyrosine and pro-opiomelanocortin neurons.
RESULTS— We found that central, but not peripheral, administration of low doses of a GLP-1 receptor antagonist caused relative hyperglycemia
during a glucose tolerance test, suggesting that activation of central GLP-1 receptors regulates key processes involved in
the maintenance of glucose homeostasis. Central administration of GLP-1 augmented glucose-stimulated insulin secretion, and
direct administration of GLP-1 into the arcuate, but not the paraventricular, nucleus of the hypothalamus reduced hepatic
glucose production. Consistent with a role for GLP-1 receptors in the arcuate, GLP-1 receptor mRNA was found to be expressed
in 68.1% of arcuate neurons that expressed pro-opiomelanocortin mRNA but was not significantly coexpressed with neuropeptide
tyrosine.
CONCLUSIONS— These data suggest that the arcuate GLP-1 receptors are a key component of the GLP-1 system for improving glucose homeostasis
by regulating both insulin secretion and glucose production.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 16 May 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted May 8, 2008.
Received January 2, 2008.
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