Epidemics of obesity and diabetes are escalating. High-calorie/high-fat food is a major cause for these global health issues, but molecular mechanisms underlying high-fat, diet-induced obesity are ...still not well understood. The aryl hydrocarbon receptor (AhR), a transcription factor that acts as a xenobiotic sensor, mediates environmental toxicant-induced obesity, insulin resistance and development of diabetes. AhR also influences lipid metabolism and diet-induced obesity. The effects of AhR deficiency on diet-induced obesity, hepatic steatosis and insulin resistance were examined.
Male wild-type (WT), AhR null (AhR(-/-)) and AhR heterozygote (AhR(+/-)) mice were fed a normal chow diet (NCD, 10% kcal from fat) or a high-fat diet (HFD, 60% kcal from fat) for up to 14 weeks. Adiposity, adipose and liver morphology, insulin signaling, metabolic parameters and gene profiles were assessed.
AhR deficiency protected against HFD-induced obesity, hepatic steatosis, insulin resistance and inflammation. Moreover, AhR deficiency preserved insulin signaling in major metabolic tissues. These protective effects result from a higher energy expenditure in AhR-deficient mice compared with WT. Levels of transcript for both the thermogenic gene, uncoupling protein 1 (Ucp1), in brown adipose tissue and mitochondrial β-oxidation genes in muscle were significantly higher in AhR(-/-) and AhR(+/-) mice compared with WT.
This work documents a physiologically relevant function for AhR in regulation of body weight, hepatic fat deposition, insulin sensitivity and energy expenditure under HFD exposure, suggesting that AhR signaling may be developed as a potential therapeutic target for treatment of obesity and metabolic disorders.
We construct model wave functions for the half-filled Landau level parametrized by "composite fermion occupation-number configurations" in a two-dimensional momentum space, which correspond to a ...Fermi sea with particle-hole excitations. When these correspond to a weakly excited Fermi sea, they have a large overlap with wave functions obtained by the exact diagonalization of lowest-Landau-level electrons interacting with a Coulomb interaction, allowing exact states to be identified with quasiparticle configurations. We then formulate a many-body version of the single-particle Berry phase for adiabatic transport of a single quasiparticle around a path in momentum space, and evaluate it using a sequence of exact eigenstates in which a single quasiparticle moves incrementally. In this formulation the standard free-particle construction in terms of the overlap between "periodic parts of successive Bloch wave functions" is reinterpreted as the matrix element of a "momentum boost" operator between the full Bloch states, which becomes the matrix elements of a Girvin-MacDonald-Platzman density operator in the many-body context. This allows the computation of the Berry phase for the transport of a single composite fermion around the Fermi surface. In addition to a phase contributed by the density operator, we find a phase of exactly π for this process.
Abstract The fat-derived hormone leptin regulates food intake and body weight in part by modulating the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the hypothalamic ...arcuate nucleus (ARC). To investigate the electrophysiological activity of these neurons and their responses to leptin, we recorded whole-cell calcium currents on NPY and POMC neurons in the ARC of rats, which we identified by morphologic features and immunocytochemical identification at the end of recording. Leptin decreased the peak amplitude of high voltage–activated calcium currents ( IHVA ) in the isolated neurons from ARC, which were subsequently shown to be immunoreactive for NPY. The inhibition was prevented by pretreatment with inhibitors of Janus kinase 2 (JAK2) and mitogen-activated protein kinases (MAPK). In contrast, leptin increased the amplitude of IHVA in POMC-containing neurons. The stimulations of IHVA were inhibited by blockers of JAK2 and phosphatidylino 3-kinase (PI3-k). Both of these effects were counteracted by the L-type calcium channel antagonist nifedipine, suggesting that L-type calcium channels were involved in the regulation induced by leptin. These data indicated that leptin exerted opposite effects on these two classes of neurons. Leptin directly inhibited IHVA in NPY neurons via leptin receptor (LEPR) –JAK2–MAPK pathways, whereas evoked IHVA in POMC neurons by LEPR–JAK2–PI3-k pathways. These neural pathways and intracellular signaling mechanisms may play key roles in regulating NPY and POMC neuron activity, anorectic action of leptin and, thereby, feeding.
Abstract Background To evaluate the literature pertaining to the use of resting-state functional magnetic resonance imaging (fMRI) in Major Depression (MD). Methods A search for papers published in ...English was conducted using MedLine, Embase, PsycINFO, OvidSP, and ScienceDirect with the following words: resting state, depression, MRI, affective, and default-mode. Results The findings from 16 resting-state fMRI studies on MD are tabulated. Some common findings are discussed in further detail. Conclusion The use of resting-state fMRI in MD research has yielded a number of significant findings that provide the basis for understanding the pathophysiology of depressive symptoms. Of particular note and deserving of further research are the roles of the cortico-limbic mood regulating circuit (MRC) and the interaction between task-positive and task-negative networks in MD. There is increasing interest in the use of resting-state fMRI in the study of psychiatric conditions, and continued improvement in technique and methodology will prove valuable in future research.
Hyperactivity of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN) of the hypothalamus is a prominent feature in depression and may be important in the etiology of ...this disease. The activity of the CRF neurons in the stress response is modulated by a number of factors that stimulate or inhibit CRF expression, including (1) corticosteroid receptors and their chaperones, heat shock proteins 70 and 90, (2) sex hormone receptors, (3) CRF receptors 1 (CRFR1) and 2, (4) cytokines interleukin 1-beta and tumor necrosis factor-alpha, (5) neuropeptides and receptors, vasopressin (AVP), AVP receptor 1a (AVPR1A) and oxytocin and (6) transcription factor cAMP-response element-binding protein. We hypothesized that, in depression, the transcript levels of those genes that are involved in the activation of the hypothalamo-pituitary-adrenal (HPA) axis are upregulated, whereas the transcript levels of the genes involved in the inhibition of the HPA axis are downregulated. We performed laser microdissection and real-time PCR in the PVN and as a control in the supraoptic nucleus. Snap-frozen post-mortem hypothalami of seven depressed and seven matched controls were used. We found significantly increased CRF mRNA levels in the PVN of the depressed patients. This was accompanied by a significantly increased expression of four genes that are involved in the activation of CRF neurons, that is, CRFR1, estrogen receptor-alpha, AVPR1A and mineralocorticoid receptor, while the expression of the androgen receptor mRNA involved in the inhibition of CRF neurons was decreased significantly. These findings raise the possibility that a disturbed balance in the production of receptors may contribute to the activation of the HPA axis in depression.
We report Magnetospheric Multiscale observations of macroscopic and electron-scale current layers in asymmetric reconnection. By intercomparing plasma, magnetic, and electric field data at multiple ...crossings of a reconnecting magnetopause on 22 October 2015, when the average interspacecraft separation was approximately 10 km, we demonstrate that the ion and electron moments are sufficiently accurate to provide reliable current density measurements at 30ms cadence. These measurements, which resolve current layers narrower than the interspacecraft separation, reveal electron-scale filamentary Hall currents and electron vorticity within the reconnection exhaust far downstream of the X line and even in the magnetosheath. Slightly downstream of the X line, intense (up to 3 μA/m2) electron currents, a super-Alfvenic outflowing electron jet, and nongyrotropic crescent shape electron distributions were observed deep inside the ion-scale magnetopause current sheet and embedded in the ion diffusion region. These characteristics are similar to those attributed to the electron dissipation/diffusion region around the X line.
Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is proposed to occur by necroptosis, an inflammatory form of regulated cell death. Prior studies implicated necroptosis in ALS based ...on accumulation of necroptotic markers in affected tissues of patients and mouse models, and amelioration of disease in mutant superoxide dismutase 1 (SOD1
) mice with inhibition of the upstream necroptotic mediators, receptor interacting protein kinase 1 (RIPK1), and RIPK3. To definitively address the pathogenic role of necroptosis in ALS, we genetically ablated the critical terminal executioner of necroptosis, mixed lineage kinase domain-like protein (MLKL), in SOD1
mice. Disease onset, progression, and survival were not affected in SOD1
mice lacking MLKL. Motor neuron degeneration and activation of neuroinflammatory cells, astrocytes, and microglia, were independent of MLKL expression in SOD1
mice. While RIPK1 accumulation occurred in spinal cords of SOD1
mice in late stage disease, RIPK3 and MLKL expression levels were not detected in central nervous system tissues from normal or SOD1
mice at any disease stage. These findings demonstrate that necroptosis does not play an important role in motor neuron death in ALS, which may limit the potential of therapeutic targeting of necroptosis in the treatment of neurological disorders.
In an open‐label, 24‐month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced‐dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with ...standard‐dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12‐month composite incidence of biopsy‐proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow‐up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% 97.5% CI: –7.5%, 10.6%) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24‐month mortality was similar (everolimus 1.5 mg 10.6% 30/282, MMF 9.2% 25/271). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12‐month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced‐dose cyclosporine offers similar efficacy to MMF with standard‐dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.
In this study comparing cardiac transplant recipients receiving one of two doses of everolimus with reduced dose cyclosporine to patients receiving mycophenolate mofetil with standard dose cyclosporine, the authors find no effect on acute cellular rejection, modestly reduced renal function, and a reduction in the incidence and severity of lesions defined by intravascular ultrasound. See editorial by Mehra on page 1119.
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