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Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes.

  • Rodríguez-Calvo R
  • Chanda D
  • Oligschlaeger Y
  • Miglianico M
  • Coumans WA
  • Barroso E
  • Tajes M
  • Luiken JJ
  • Glatz JF
  • Vazquez M
  • Neumann D
Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced AKT and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500µM/100nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (~6.2 fold; p0.001) linking to the observed intramyocellular lipid accumulation. SHP overexpressing cells further showed altered expression of genes involved in lipid metabolism, i.e., Acaca, Acadvl or Ucp3, augmented NF-?B DNA-binding activity and induced transcripts of inflammatory genes, i.e., Il6 and Tnf mRNA (~4-fold induction, p0.01). Alterations in metabolism and inflammation found in SHP overexpressing cells were associated with changes in the mRNA levels of Ppara (79% reduction, p0.001) and Pparg (~58-fold induction, p0.001). Finally, co-immunoprecipitation studies showed that SHP overexpression strongly reduced the physical interaction between PPARa and the p65 subunit of NF-?B, suggesting that dissociation of these two proteins is one of the mechanisms by which SHP initiates the inflammatory response in cardiac cells. Overall, our results suggest that SHP upregulation upon high-fat feeding leads to lipid accumulation, insulin resistance and inflammation in cardiomyocytes.

High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents.

  • Petrov D
  • Pedrós I
  • Artiach G
  • Sureda FX
  • Barroso E
  • Pallàs M
  • Casadesús G
  • Beas-Zarate C
  • Carro E
  • Ferrer I
  • Vazquez M
  • Folch J
  • Camins A
Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce ß-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age.

PPARß/d ameliorates fructose-induced insulin resistance in adipocytes by preventing Nrf2 activation.

  • Barroso E
  • Rodríguez-Rodríguez R
  • Chacón MR
  • Maymó-Masip E
  • Ferrer L
  • Salvadó L
  • Salmerón E
  • Wabistch M
  • Palomer FX
  • Vendrell J
  • Wahli W
  • Vazquez M
We studied whether PPARß/d deficiency modifies the effects of high fructose intake (30% fructose in drinking water) on glucose tolerance and adipose tissue dysfunction, focusing on the CD36-dependent pathway that enhances adipose tissue inflammation and impairs insulin signaling. Fructose intake for 8 weeks significantly increased body and liver weight, and hepatic triglyceride accumulation in PPARß/d-deficient mice but not in wild-type mice. Feeding PPARß/d-deficient mice with fructose exacerbated glucose intolerance and led to macrophage infiltration, inflammation, enhanced mRNA and protein levels of CD36, and activation of the JNK pathway in white adipose tissue compared to those of water-fed PPARß/d-deficient mice. Cultured adipocytes exposed to fructose also exhibited increased CD36 protein levels and this increase was prevented by the PPARß/d activator GW501516. Interestingly, the levels of the nuclear factor E2-related factor 2 (Nrf2), a transcription factor reported to up-regulate Cd36 expression and to impair insulin signaling, were increased in fructose-exposed adipocytes whereas co-incubation with GW501516 abolished this increase. In agreement with Nrf2 playing a role in the fructose-induced CD36 protein level increases, the Nrf2 inhibitor trigonelline prevented the increase and the reduction in insulin-stimulated AKT phosphorylation caused by fructose in adipocytes. Protein levels of the well-known Nrf2 target gene

Interrelation of attention and prediction in visual processing: Effects of task-relevance and stimulus probability.

  • Marzecová A
  • Widmann A
  • San-Miguel I
  • Kotz SA
  • Schröger E
The potentially interactive influence of attention and prediction was investigated by measuring event-related potentials (ERPs) in a spatial cueing task with attention (task-relevant) and prediction (probabilistic) cues. We identified distinct processing stages of this interactive influence. Firstly, in line with the attentional gain hypothesis, a larger amplitude response of the contralateral N1, and Nd1 for attended gratings was observed. Secondly, conforming to the attenuation-by-prediction hypothesis, a smaller negativity in the time window directly following the peak of the N1 component for predicted compared to unpredicted gratings was observed. In line with the hypothesis that attention and prediction interface, unpredicted/unattended stimuli elicited a larger negativity at central-parietal sites, presumably reflecting an increased prediction error signal. Thirdly, larger P3 responses to unpredicted stimuli pointed to the updating of an internal model. Attention and prediction can be considered as differentiated mechanisms that may interact at different processing stages to optimise perception.

Early indices of deviance detection in humans and animal models.

  • Grimm S
  • Escera C
  • Nelken I
Detecting unexpected stimuli in the environment is a critical function of the auditory system. Responses to unexpected "deviant" sounds are enhanced compared to responses to expected stimuli. At the human scalp, deviance detection is reflected in the mismatch negativity (MMN) and in an enhancement of the middle-latency response (MLR). Single neurons often respond more strongly to a stimulus when rare than when common, a phenomenon termed stimulus-specific adaptation (SSA). Here we compare stimulus-specific adaptation with scalp-recorded deviance-related responses. We conclude that early markers of deviance detection in the time range of the MLR could be a direct correlate of cortical SSA. Both occur at an early level of cortical activation, both are robust findings with low-probability stimuli, and both show properties of genuine deviance detection. Their causal relation with the later scalp-recorded MMN is a key question in this field.

Phase re-setting of gamma neural oscillations during novelty processing in an appetitive context.

  • Domínguez-Borràs J
  • Garcia-Garcia M
  • Escera C
Based on the previous study where phase-synchronization (PS) of gamma-band responses (GBRs) proved a reliable cerebral correlate of involuntary attention and its enhancement under threat, we measured gamma-PS elicited by novel sounds from human electroencephalogram (EEG) scalp-recordings when participants responded to visual stimuli displaying either highly motivational or neutral sceneries. We then tested the modulatory effect of the emotional conditions on auditory responses. Novel distractor sounds did not affect behavioural accuracy on subjects' visual task performance in neutral context but markedly decreased hit rate in the appetitive one. Similarly, gamma-PS to novel sounds remained intact in neutral context, whereas it showed an increase, within the 35-Hz sub-range, in the appetitive context. These results suggest that a context of processing positive emotional stimuli results into an enhanced processing of task-irrelevant novel auditory events, and, furthermore, that gamma-PS is tuned under conditions that could promote long-term survival.

Ultrafast tracking of sound location changes as revealed by human auditory evoked potentials.

  • Grimm S
  • Recasens M
  • Althen H
  • Escera C
The rapid discrimination of auditory location information enables grouping and selectively attending to specific sound sources. The typical indicator of auditory change detection is the mismatch negativity (MMN) occurring at a latency of about 100-250 ms. However, recent studies have revealed the existence of earlier markers of frequency deviance detection in the middle-latency response (MLR). Here, we measured the MLR and MMN to changes in sound location. Clicks were presented in either the left or right hemifields during oddball (rare 30°-shifts in location), reversed oddball, and control (sounds occurring equiprobably from five locations) conditions. Clicks at deviant locations elicited an MMN and an enhanced Na component of the MLR peaking at 20 ms compared to clicks at standard or control locations. Whereas MMN was not significantly lateralized, the Na effect showed a contralateral dominance. These findings indicate that, also for sound location changes, early detection processes exist upstream of MMN.

A risk variant for alcoholism in the NMDA receptor affects amygdala activity during fear conditioning in humans.

  • Cacciaglia R
  • Nees F
  • Pohlack ST
  • Ruttorf M
  • Winkelmann T
  • Witt SH
  • Nieratschker V
  • Rietschel M
  • Flor H
People at high risk for alcoholism show deficits in aversive learning, as indicated by impaired electrodermal responses during fear conditioning, a basic form of associative learning that depends on the amygdala. A positive family history of alcohol dependence has also been related to decreased amygdala responses during emotional processing. In the present study we report reduced amygdala activity during the acquisition of conditioned fear in healthy carriers of a risk variant for alcoholism (rs2072450) in the NR2A subunit-containing N-methyl-d-aspartate (NMDA)-receptor. These results indicate that rs2072450 might confer risk for alcohol dependence through deficient fear acquisition indexed by a diminished amygdala response during aversive learning, and provide a neural basis for a weak behavioral inhibition previously documented in individuals at high risk for alcohol dependence. Carriers of the risk variant additionally exhibit dampened insula activation, a finding that further strengthens our data, given the importance of this brain region in fear conditioning.

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