Swimming exercise ameliorates insulin resistance and nonalcoholic fatty liver by negatively regulating PPARγ transcriptional network in mice fed high fat diet.

BACKGROUND: Recent findings elucidated hepatic PPARγ functions as a steatogenic-inducer gene that activates de novo lipogenesis, and is involved in regulation of glucose homeostasis, lipid accumulation, and inflammation response. This study delved into a comprehensive analysis of how PPARγ signaling affects the exercise-induced improvement of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD), along with its underlying mechanism. METHODS: Chronic and acute swimming exercise intervention were conducted in each group mice. IR status was assessed by GTT and ITT assays. Serum inflammatory cytokines were detected by Elisa assays. PPARγ and its target genes expression were detected by qPCR assay. Relative protein levels were quantified via Western blotting. ChIP-qPCR assays were used to detect the enrichment of PPARγ on its target genes promoter. RESULTS: Through an exploration of a high-fat diet (HFD)-induced IR and NAFLD model, both chronic and acute swimming exercise training led to significant reductions in body weight and visceral fat mass, as well as hepatic lipid accumulation. The exercise interventions also demonstrated a significant amelioration in IR and the inflammatory response. Meanwhile, swimming exercise significantly inhibited PPARγ and its target genes expression induced by HFD, containing CD36, SCD1 and PLIN2. Furthermore, swimming exercise presented significant modulation on regulatory factors of PPARγ expression and transcriptional activity. CONCLUSION: The findings suggest that swimming exercise can improve lipid metabolism in IR and NAFLD, possibly through PPARγ signaling in the liver of mice.

Top-down influence of areas 21a and 7 differently affects the surround suppression of V1 neurons in cats.

Surround suppression (SS) is a phenomenon whereby a neuron's response to stimuli in its central receptive field (cRF) is suppressed by stimuli extending to its surround receptive field (sRF). Recent evidence show that top-down influence contributed to SS in the primary visual cortex (V1). However, how the top-down influence from different high-level cortical areas affects SS in V1 has not been comparatively observed. The present study applied transcranial direct current stimulation (tDCS) to modulate the neural activity in area 21a (A21a) and area 7 (A7) of cats and examined the changes in the cRF and sRF of V1 neurons. We found that anode-tDCS at A21a reduced V1 neurons' cRF size and increased their response to visual stimuli in cRF, causing an improved SS strength. By contrast, anode-tDCS at A7 increased V1 neurons' sRF size and response to stimuli in cRF, also enhancing the SS. Modeling analysis based on DoG function indicated that the increased SS of V1 neurons after anode-tDCS at A21a could be explained by a center-only mechanism, whereas the improved SS after anode-tDCS at A7 might be mediated through a combined center and surround mechanism. In conclusion, A21a and A7 may affect the SS of V1 neurons through different mechanisms.

Suppression of top-down influence decreases both behavioral and V1 neuronal response sensitivity to stimulus orientations in cats.

How top-down influence affects behavioral detection of visual signals and neuronal response sensitivity in the primary visual cortex (V1) remains poorly understood. This study examined both behavioral performance in stimulus orientation identification and neuronal response sensitivity to stimulus orientations in the V1 of cat before and after top-down influence of area 7 (A7) was modulated by non-invasive transcranial direct current stimulation (tDCS). Our results showed that cathode (c) but not sham (s) tDCS in A7 significantly increased the behavioral threshold in identifying stimulus orientation difference, which effect recovered after the tDCS effect vanished. Consistently, c-tDCS but not s-tDCS in A7 significantly decreased the response selectivity bias of V1 neurons for stimulus orientations, which effect could recover after withdrawal of the tDCS effect. Further analysis showed that c-tDCS induced reduction of V1 neurons in response selectivity was not resulted from alterations of neuronal preferred orientation, nor of spontaneous activity. Instead, c-tDCS in A7 significantly lowered the visually-evoked response, especially the maximum response of V1 neurons, which caused a decrease in response selectivity and signal-to-noise ratio. By contrast, s-tDCS exerted no significant effect on the responses of V1 neurons. These results indicate that top-down influence of A7 may enhance behavioral identification of stimulus orientations by increasing neuronal visually-evoked response and response selectivity in the V1.

Modulation of top-down influence affects trafficking of glutamatergic receptors in the primary visual cortex.

Numerous studies indicate that top-down influence plays critical roles in visual perception by enhancing neuronal excitability in the primary visual cortex (V1). The underlying mechanisms are poorly understood. This study examined changes of excitatory glutamatergic markers in the V1 cortex of cat after top-down influence of cortical area 7 (A7) was modulated by transcranial direct current stimulation (tDCS). Our results showed that the content of glutamate as well as the total cellular protein of glutamatergic receptors, including the key subunit GluA1 of AMPA receptors and subunit NR1 of NMDA receptors, in the V1 cortex had no significant change after anode- and cathode-tDCS relative to sham-tDCS in A7. However, the plasma membrane protein content of GluA1 and NR1 in the V1 was significantly increased after anode-tDCS, but decreased after cathode-tDCS when compared with that after sham-tDCS in A7. Further, the abundance of phosphorylated GluA1 and NR1 in the V1 also elevated significantly after anode-tDCS, but lowered after cathode-tDCS compared with that after sham-tDCS. Additionally, the content of phosphorylated CaMKII (p-CaMKII), a protein kinase preferentially boosting phosphorylation of glutamatergic receptors, in the V1 improved after anode-tDCS although no significant alteration occurred after c-tDCS in A7. Taken together, our results indicate that feedback influence of A7 may facilitate the trafficking of glutamatergic receptors to postsynaptic membrane in the V1 cortex through receptors' phosphorylation process, which could be an important mechanism of high-level cortex in modulating visual information processing in the V1 cortex.

Mechanisms of Surround Suppression Effect on the Contrast Sensitivity of V1 Neurons in Cats.

Surround suppression (SS) is a phenomenon that a neuron's response to visual stimuli within the classical receptive field (cRF) is suppressed by a concurrent stimulation in the surrounding receptive field (sRF) beyond the cRF. Studies show that SS affects neuronal response contrast sensitivity in the primary visual cortex (V1). However, the underlying mechanisms remain unclear. Here, we examined SS effect on the contrast sensitivity of cats' V1 neurons with different preferred SFs using external noise-masked visual stimuli and perceptual template model (PTM) analysis at the system level. The contrast sensitivity was evaluated by the inverted threshold contrast of neurons in response to circular gratings of different contrasts in the cRF with or without an annular grating in the sRF. Our results showed that SS significantly reduced the contrast sensitivity of cats' V1 neurons. The SS-induced reduction of contrast sensitivity was not correlated with SS strength but was dependent on neuron's preferred SF, with a larger reduction for neurons with low preferred SFs than those with high preferred SFs. PTM analysis of threshold versus external noise contrast (TvC) functions indicated that SS decreased contrast sensitivity by increasing both the internal additive noise and impact of external noise for neurons with low preferred SFs, but improving only internal additive noise for neurons with high preferred SFs. Furthermore, the SS effect on the contrast-response function of low- and high-SF neurons also exhibited different mechanisms in contrast gain and response gain. Collectively, these results suggest that the mechanisms of SS effect on neuronal contrast sensitivity may depend on neuronal populations with different SFs.

Exercise ameliorates high-fat diet-induced insulin resistance accompanied by changes in protein levels of hepatic ATF3-related signaling in rats.

PURPOSE: Exercise is an effective way to alleviate insulin resistance (IR). However, the underlying mechanisms remain to be elucidated. Previous studies demonstrated that cardiolipin synthase 1 (CRLS1)/interferon-regulatory factor-2 binding protein 2 (IRF2bp2)-activating transcription factor 3 (ATF3)-adiponectin receptor 2 (AdipoR2)-adaptor protein containing pH domain, PTB domain and leucine zipper motif 1 (APPL1)-protein kinase B (AKT/PKB)-related signaling was closely associated with obesity-induced IR-related diseases, but the correlation between exercise training alleviating obesity-induced IR and the protein levels of hepatic CRLS1/IRF2bp2-ATF3-AdipoR2-APPL1-AKT-related signaling in rats is unknown. Therefore, We want to investigate the effect of exercise training on IR and the protein levels of hepatic CRLS1/IRF2bp2-ATF3-AdipoR2-APPL1-AKT-related signaling in rat. METHODS: The male healthy Sprague-Dawley rats were divided into four groups: normal control group (NCG, n = 10), diet-induced obesity-sedentary group (DIO-SG, n = 10), diet-induced obesity-chronic exercise group (DIOCEG, n = 10) received chronic swim exercise training and diet-induced obesity-acute exercise group (DIO-AEG, n = 10) received acute swim exercise training. We measured the levels of IR-related indicators and the protein levels of hepatic CRLS1/IRF2bp2-ATF3-AdipoR2-APPL1-AKT-related signaling in NCG, DIO-SG, DIOCEG and DIO-AEG. RESULTS: We found that high-fat diet (HFD)-induced obesity decreased insulin sensitivity in rats accompanied by decreased protein levels of hepatic CRLS1, IRF2bp2, AdipoR2, APPL1, p-AKT and increased protein level of hepatic ATF3. The acute exercise and the chronic exercise both increased insulin sensitivity in rats. The chronic exercise decreased hepatic ATF3 protein level and increased CRLS1, IRF2bp2, AdipoR2, APPL1, p-AKT protein levels in HFD-fed rats. The acute exercise decreased hepatic ATF3 protein level and increased hepatic IRF2bp2, APPL1 and p-AKT protein levels in HFD-fed rats. The acute exercise had no significant effect on hepatic CRLS1 and AdipoR2 protein levels in HFD-fed rats. CONCLUSION: Our current findings indicated that exercise alleviated obesity-induced IR accompanied by changes in protein levels of hepatic ATF3-related signaling in rats. Our results are meaningful for exploring the molecular mechanism of exercise alleviating IR symptoms.

Effects of top-down influence suppression on behavioral and V1 neuronal contrast sensitivity functions in cats.

To explore the relative contributions of higher-order and primary visual cortex (V1) to visual perception, we compared cats' behavioral and V1 neuronal contrast sensitivity functions (CSF) and threshold versus external noise contrast (TvC) functions before and after top-down influence of area 7 (A7) was modulated with transcranial direct current stimulation (tDCS). We found that suppressing top-down influence of A7 with cathode-tDCS, but not sham-tDCS, reduced behavioral and neuronal contrast sensitivity in the same range of spatial frequencies and increased behavioral and neuronal contrast thresholds in the same range of external noise levels. The neuronal CSF and TvC functions were highly correlated with their behavioral counterparts both before and after the top-down suppression. Analysis of TvC functions using the Perceptual Template Model (PTM) indicated that top-down influence of A7 increased both behavioral and V1 neuronal contrast sensitivity by reducing internal additive noise and the impact of external noise.

Exercise ameliorates insulin resistance and improves ASK1-mediated insulin signalling in obese rats.

Increasing evidence reveals that physical exercise is an efficient therapeutical approach in the treatment of insulin resistance (IR) and related metabolic diseases. However, the potential beneficial effects of exercise on insulin resistance and its underlying mechanisms remain unclear. Recent findings elucidated the negative role of ASK1 in repressing the glucose uptake through JNK1-IRS1-Akt signalling in liver. Thus, a detailed investigation of the effect of ASK1-mediated insulin signalling on exercise-mediated improvement of insulin sensitivity and its underlying mechanism was implemented in this study. Using a high-fat diet-induced IR rat model of chronic or acute swimming exercise training, we here showed that body weight and visceral fat mass were significantly reduced after chronic exercise. Moreover, chronic exercise reduced serum FFAs levels and hepatic triglyceride content. Both chronic and acute exercise promoted glucose tolerance and insulin sensitivity. Meanwhile, both chronic and acute exercise decreased ASK1 phosphorylation and improved JNK1-IRS1-Akt signalling. Furthermore, exercise training decreased CFLAR, CREG and TRAF1 protein levels in liver of obese rats, which are positive regulator of ASK1 activity. These results suggested that swimming exercise demonstrated to be an effective ameliorator of IR through the regulation of ASK1-mediated insulin signalling and therefore, could present a prospective therapeutic mean towards the treatment of IR and several metabolic diseases based on IR, containing NAFLD and type Ⅱ diabetes.

Suppression of top-down influence decreases neuronal excitability and contrast sensitivity in the V1 cortex of cat.

How top-down influence affects neuronal activity and information encoding in the primary visual cortex (V1) remains elusive. This study examined changes of neuronal excitability and contrast sensitivity in cat V1 cortex after top-down influence of area 7 (A7) was modulated by transcranial direct current stimulation (tDCS). The neuronal excitability in V1 cortex was evaluated by visually evoked field potentials (VEPs), and contrast sensitivity (CS) was assessed by the inverse of threshold contrast of neurons in response to visual stimuli at different performance accuracy. We found that the amplitude of VEPs in V1 cortex lowered after top-down influence suppression with cathode-tDCS in A7, whereas VEPs in V1 did not change after sham-tDCS in A7 and nonvisual cortical area 5 (A5) or cathode-tDCS in A5 and lesioned A7. Moreover, the mean CS of V1 neurons decreased after cathode-tDCS but not sham-tDCS in A7, which could recover after tDCS effect vanished. Comparisons of neuronal contrast-response functions showed that cathode-tDCS increased the stimulus contrast required to generate the half-maximum response, with a weakly-correlated reduction in maximum response but not baseline response. Therefore, top-down influence of A7 enhanced neuronal excitability in V1 cortex and improved neuronal contrast sensitivity by both contrast gain and response gain.

Exercise ameliorates insulin resistance and improves SIRT6-mediated insulin signaling transduction in liver of obese rats.

Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6) - mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR.

Top-down influence affects the response adaptation of V1 neurons in cats.

The visual system lowers its perceptual sensitivity to a prolonged presentation of the same visual signal. This brain plasticity, called visual adaptation, is generally attributed to the response adaptation of neurons in the visual cortex. Although well-studied in the neurons of the primary visual cortex (V1), the contribution of high-level visual cortical regions to the response adaptation of V1 neurons is unclear. In the present study, we measured the response adaptation strength of V1 neurons before and after the top-down influence of the area 21a (A21a), a higher-order visual cortex homologous to the primate V4 area, was modulated with a noninvasive tool of transcranial direct current stimulation (tDCS). Our results showed that the response adaptation of V1 neurons enhanced significantly after applying anode (a-) tDCS in A21a when compared with that before a-tDCS, whereas the response adaptation of V1 neurons weakened after cathode (c-) tDCS relative to before c-tDCS in A21a. By contrast, sham (s-) tDCS in A21a had no significant impact on the response adaptation of V1 neurons. Further analysis indicated that a-tDCS in A21a significantly increased both the initial response (IR) of V1 neurons to the first several (five) trails of visual stimulation and the plateau response (PR) to the prolonged visual stimulation; the increase in PR was lower than in IR, which caused an enhancement in response adaptation. Conversely, c-tDCS significantly decreased both IR and PR of V1 neurons; the reduction in PR was smaller than in IR, which resulted in a weakness in response adaptation. Furthermore, the tDCS-induced changes of V1 neurons in response and response adaptation could recover after tDCS effect vanished, but did not occur after the neuronal activity in A21a was silenced by electrolytic lesions. These results suggest that the top-down influence of A21a may alter the response adaptation of V1 neurons through activation of local inhibitory circuitry, which enhances network inhibition in the V1 area upon an increased top-down input, weakens inhibition upon a decreased top-down input, and thus maintains homeostasis of V1 neurons in response to the long-presenting visual signals.

Anodal and cathodal tDCS modulate neural activity and selectively affect GABA and glutamate syntheses in the visual cortex of cats.

KEY POINTS: The present study showed that anodal and cathodal transcranial direct current stimulation (tDCS) can respectively increase and decrease the amplitude of visually evoked field potentials in the stimulated visual cortex of cats, with the effect lasting for ∼60-70 min. We directly measured tDCS-induced changes in the concentration of inhibitory and excitatory neurotransmitters in the visual cortex using the enzyme-linked immunosorbent assay method and showed that anodal and cathodal tDCS can selectively decrease the concentration of GABA and glutamate in the stimulated cortical area. Anodal and cathodal tDCS can selectively inhibit the synthesis of GABA and glutamate by suppressing the expression of GABA- and glutamate-synthesizing enzymes, respectively. ABSTRACT: Transcranial direct current stimulation (tDCS) evokes long-lasting neuronal excitability in the target brain region. The underlying neural mechanisms remain poorly understood. The present study examined tDCS-induced alterations in neuronal activities, as well as the concentration and synthesis of GABA and glutamate (GLU), in area 21a (A21a) of cat visual cortex. Our analysis showed that anodal and cathodal tDCS respectively enhanced and suppressed neuronal activities in A21a, as indicated by a significantly increased and decreased amplitude of visually evoked field potentials (VEPs). The tDCS-induced effect lasted for ∼60-70 min. By contrast, sham tDCS had no significant impact on the VEPs in A21a. On the other hand, the concentration of GABA, but not that of GLU, in A21a significantly decreased after anodal tDCS relative to sham tDCS, whereas the concentration of GLU, but not that of GABA, in A21a significantly decreased after cathodal tDCS relative to sham tDCS. Furthermore, the expression of GABA-synthesizing enzymes GAD65 and GAD67 in A21a significantly decreased in terms of both mRNA and protein concentrations after anodal tDCS relative to sham tDCS, whereas that of GLU-synthesizing enzyme glutaminase (GLS) did not change significantly after anodal tDCS. By contrast, both mRNA and protein concentrations of GLS in A21a significantly decreased after cathodal tDCS relative to sham tDCS, whereas those of GAD65/GAD67 showed no significant change after cathodal tDCS. Taken together, these results indicate that anodal and cathodal tDCS may selectively reduce GABA and GLU syntheses and thus respectively enhance and suppress neuronal excitability in the stimulated brain area.

Heroin exposure and withdrawal differentially influence expression of NMDA receptor NR2 subunits in the prelimbic region of rat medial prefrontal cortex.

It is widely reported that drug addiction involves the strengthening of specific reward circuits through N-methyl-d-aspartic acid receptor (NMDAR)-dependent synaptic potentiation, and several lines of evidence strongly implicate NMDA receptor 2 (NR2) subunits in drug abuse. To explore the potential mechanism of heroin dependence, this study examined changes in the expression levels of NR2 subunits NR2A-D in the prelimbic (PL) region of the medial prefrontal cortex (mPFC) after repeated heroin administration and subsequent abstinence. The conditioned place preference (CPP) test confirmed successful induction of heroin dependence and withdrawal. Western blotting and qRT-PCR revealed no differences in NR2A subunit expression among heroin-exposure, heroin-withdrawal, and control group rats; in contrast, expression of NR2B was significantly higher in the heroin-exposure group, whereas expression levels of NR2C and NR2D were significantly higher in the heroin-withdrawal group relative to the controls. Further studies are needed to identify the functional significance based on alterations of NR2 subunits.

Characterization of Feedback Neurons in the High-Level Visual Cortical Areas That Project Directly to the Primary Visual Cortex in the Cat.

Previous studies indicate that top-down influence plays a critical role in visual information processing and perceptual detection. However, the substrate that carries top-down influence remains poorly understood. Using a combined technique of retrograde neuronal tracing and immunofluorescent double labeling, we characterized the distribution and cell type of feedback neurons in cat's high-level visual cortical areas that send direct connections to the primary visual cortex (V1: area 17). Our results showed: (1) the high-level visual cortex of area 21a at the ventral stream and PMLS area at the dorsal stream have a similar proportion of feedback neurons back projecting to the V1 area, (2) the distribution of feedback neurons in the higher-order visual area 21a and PMLS was significantly denser than in the intermediate visual cortex of area 19 and 18, (3) feedback neurons in all observed high-level visual cortex were found in layer II-III, IV, V, and VI, with a higher proportion in layer II-III, V, and VI than in layer IV, and (4) most feedback neurons were CaMKII-positive excitatory neurons, and few of them were identified as inhibitory GABAergic neurons. These results may argue against the segregation of ventral and dorsal streams during visual information processing, and support "reverse hierarchy theory" or interactive model proposing that recurrent connections between V1 and higher-order visual areas constitute the functional circuits that mediate visual perception. Also, the corticocortical feedback neurons from high-level visual cortical areas to the V1 area are mostly excitatory in nature.

[Effect of swimming exercise on MEK and ERK1 phosphorylation level in adipose tissue of insulin resistance rats].

OBJECTIVE: To investigate the effect of chronic and acute swimming exercise intervention on the mitogen-activated extracellular signal-regulated kinase(MEK) and extracellular signal-regulated kinase 1(ERK1) phosphorylation level in adipose tissues of obesityinduced insulin resistance rats. METHODS: A total of 100 SD rats were randomly divided into control group(n=10) fed with normal diet and high-fat diet group(n=90) fed with high fat diet. After 8 weeks, one third rats(n=30) with upper weight in high-fat diet group were selected and randomly divided into high-fat diet sedentary group(n=10), chronic exercise group(n=10) and acute exercise group(n=10). Under another 8-week high-fat diet feeding, exercise intervention was performed according to the exercise procedure; control group was fed with normal diet for 8 weeks. After exercise intervention, visceral adipose tissues were separated and MEK and ERK1 phosphorylation level in adipose tissue was detected by Western blot method. RESULTS: Chronic exercise intervention significantly reduced body weight, visceral fat weight and visceral fat weight/body weight ratio(P<0. 01), and acute exercise intervention had no significant effect on body weight, visceral fat weight and visceral fat weight/body weight ratio. Both chronic and acute exercise intervention significantly increased body insulin sensitivity(P<0. 05), as well as significantly decreased MEK and ERK1 phosphorylation level in adipose tissues(P<0. 01). CONCLUSION: The improvement of obesity-induced insulin resistance by exercise might be related to inhibited phosphorylation of MEK and ERK1 in adipose tissues.

Theta-gamma coupling in the prelimbic area is associated with heroin addiction.

The medial prefrontal cortex (mPFC) is implicated in the regulation of drug-seeking behavior, but the specific contributions of the mPFC prelimbic (PL) subdivision and the precise mechanisms underlying heroin abuse remain largely unclear. In the present study, we examined changes in the rhythmic ensemble activity of PL neurons after induction of heroin addiction in rats. Rats were injected daily with saline (control group) or heroin (addiction group) in the light chamber of a light-dark shuttle box, and a video tracking system was used to measure conditioned place preference (CPP) as a sign of addiction. A wireless telemetry system was used to record local field potentials (LFPs) from the PL area during expression of CPP. Before treatment, there was no difference in CPP between groups (P > 0.05). However, rats in the experimental group exhibited significant CPP (P < 0.05) in the light chamber after heroin treatment compared to before treatment and compared to control rats. During CPP, addicted rats demonstrated substantial alterations in relative θ and γ frequency band power (Ps < 0.05); moreover, the θ wave alteration was strongly coupled to γ waves in heat map analyses (P < 0.05). Collectively, these findings implicate heroin-induced alterations in PL area neural activity and θ-γ coupling in heroin addiction.

Exercise ameliorates insulin resistance via regulating TGFß-activated kinase 1 (TAK1)-mediated insulin signaling in liver of high-fat diet-induced obese rats.

Exercise is an effective therapy for insulin resistance. However, the underlying mechanism remains to be elucidated. Previous research demonstrated that TGFß-activated kinase 1 (TAK1)-dependent signaling plays a crucial character in hepatic insulin resistance. Hepatic ubiquitin specific protease 4 (USP4), USP18, and dual-specificity phosphatases 14 (DUSP14) can suppress TAK1 phosphorylation, besides tumor necrosis factor receptor-associated factor 3 (TRAF3) and tripartite motif 8 (TRIM8) promote its phosphorylation. In this study, we tried to verify our hypothesis that exercise improves insulin resistance in high-fat diet (HFD)-induced obese (DIO) rats via regulating the TAK1 dependent signaling and TAK1 regulators in liver. Forty male Sprague-Dawley rats were randomized into four groups (n = 10): standard diet and sedentary as normal control; fed on HFD and DIO-sedentary; fed on HFD and DIO-chronic exercise; and fed on HFD and DIO-acute exercise. HFD feeding resulted in increased body weight, visceral fat mass, serum FFAs and hepatic lipid deposition, but decreased hepatic glycogen content and insulin sensitivity. Moreover, hepatic TRAF3 and TRIM8 protein levels increased, whereas USP4, USP18, and DUSP14 protein levels were decreased under obese status, which resulted in enhanced TAK1 phosphorylation and impaired insulin signaling. Exercise training, containing chronic and acute mode, both ameliorated insulin resistance. Meanwhile, decreased TAK1, c-Jun N-terminal kinase 1 (JNK1), and insulin receptor substrate 1 (IRS1) phosphorylation enhanced Akt phosphorylation in liver. Moreover, exercise enhanced USP4 and DUSP14 protein levels, whereas decreased TRIM8 protein levels in obese rats' liver. These results showed that exercise triggered a crucial modulation in TAK1-dependent signaling and its regulators in obese rats' liver, and distinct improvement in insulin sensitivity, which provide new insights into the mechanism by which physical exercise improves insulin resistance.

Axon initial segment plasticity accompanies enhanced excitation of visual cortical neurons in aged rats.

Recent studies have indicated that the structure of the axon initial segment (AIS) of neurons is highly plastic in response to changes in neuronal activity. Whether an age-related enhancement of neuronal responses in the visual cortex is coupled with plasticity of AISs is unknown. Here, we compare the AIS length and the distribution of Nav1.6, a key Na ion channel in action potential (AP) initiation, along the AIS of layer II/III neurons in the primary visual cortex (V1) of young adult and aged rats, which were examined previously in a single-unit recording study. In that study, we found that V1 neurons in aged rats showed a significantly higher spontaneous activity and stronger visually evoked responses than did neurons in young rats. Our present study shows that the mean AIS length of layer II/III neurons in the V1 area of aged rats was significantly shorter than that of young adult rats. Further, the proportion of AIS with the Nav1.6 distribution was also reduced significantly in aged rats relative to young rats, as indicated by a decrease in the mean Nav1.6 immunofluorescence optical density within AISs and a specific decrease in Nav1.6 immunofluorescence optical density near the proximal region of the AIS. Our results indicate that aging results in both shortening of AISs and reduction of Nav1.6 Na ion channel distribution along AISs, which accompanies enhanced neuronal activity. This age-related morphological plasticity may lower the AP amplitude by reducing Na ion entry during AP initiation, spare ATPs consumed by Na ion pumps during membrane potential restoration, and thus balance the energy expenditure caused by an increased firing rate of cortical neurons during the aging process.