Age and Diet Modulate the Insulin-Sensitizing Effects of Exercise: A Tracer-Based Oral Glucose Tolerance Test.

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance and mitochondrial lipid oxidation and also enhances insulin sensitivity (IS). It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests with tracers were conducted in mice ranging from 4 to 21 months of age, fed a low-fat diet (LFD) or high-fat diet (HFD) with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Values for an IS index derived for peripheral tissues (IS-P) and one for the liver (IS-L) were steeply decreased by aging and an HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In young animals fed an LFD, RW access enhanced the IS-P concomitantly with the muscle ß-oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease; however this only occurred in animals fed an LFD. Therefore, this study indicates that endurance exercise can improve the age-dependent decline in organ-specific IS if paired with a healthy diet. ARTICLE HIGHLIGHTS: Exercise is a known strategy to improve insulin sensitivity (IS), whereas aging and a lipid-rich diet decrease IS. Using a tracer-based oral glucose tolerance test, we investigated how exercise, age, and diet interact in the development of tissue-specific insulin resistance. Exercise (voluntary access to a running wheel) mainly improved IS in animals fed a low-fat diet. In these animals, exercise improved peripheral IS only at young age but fully prevented the age-dependent decline of hepatic IS. The prevention of age-dependent decline in IS by exercise is tissue-specific and blunted by a lipid-rich diet.

Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test.

Diet modulates the development of insulin resistance during aging. This includes tissue-specific alterations in insulin signaling and mitochondrial function, which ultimately affect glucose homeostasis. Exercise stimulates glucose clearance, mitochondrial lipid oxidation and enhances insulin sensitivity. It is not well known how exercise interacts with age and diet in the development of insulin resistance. To investigate this, oral glucose tolerance tests (OGTT) with a tracer were conducted in mice ranging from 4 to 21 months of age, fed a low- (LFD) or high-fat diet (HFD), with or without life-long voluntary access to a running wheel (RW). We developed a computational model to derive glucose fluxes, which were commensurate with independent values from steady-state tracer infusions. Both insulin sensitivity indices derived for peripheral tissues and liver (IS-P and IS-L, respectively) were steeply decreased by aging and a HFD. This preceded the age-dependent decline in the mitochondrial capacity to oxidize lipids. In LFD young animals, RW access enhanced the IS-P concomitantly with the muscle ß- oxidation capacity. Surprisingly, RW access completely prevented the age-dependent IS-L decrease, but only in LFD animals. This study indicates, therefore, that endurance exercise can improve the age-dependent decline in organ-specific IS mostly in the context of a healthy diet.

Neuropeptide precursors and neuropeptides in the sea cucumber Apostichopus japonicus: a genomic, transcriptomic and proteomic analysis.

The sea cucumber Apostichopus japonicus is a foodstuff with very high economic value in China, Japan and other countries in south-east Asia. It is at the heart of a multibillion-dollar industry and to meet demand for this product, aquaculture methods and facilities have been established. However, there are challenges associated with optimization of reproduction, feeding and growth in non-natural environments. Therefore, we need to learn more about the biology of A. japonicus, including processes such as aestivation, evisceration, regeneration and albinism. One of the major classes of molecules that regulate physiology and behaviour in animals are neuropeptides, and a few bioactive peptides have already been identified in A. japonicus. To facilitate more comprehensive investigations of neuropeptide function in A. japonicus, here we have analysed genomic and transcriptomic sequence data and proteomic data to identify neuropeptide precursors and neuropeptides in this species. We identified 44 transcripts encoding neuropeptide precursors or putative neuropeptide precursors, and in some instances neuropeptides derived from these precursors were confirmed by mass spectrometry. Furthermore, analysis of genomic sequence data enabled identification of the location of neuropeptide precursor genes on genomic scaffolds and linkage groups (chromosomes) and determination of gene structure. Many of the precursors identified contain homologs of neuropeptides that have been identified in other bilaterian animals. Precursors of neuropeptides that have thus far only been identified in echinoderms were identified, including L- and F-type SALMFamides, AN peptides and others. Precursors of several peptides that act as modulators of neuromuscular activity in A. japonicus were also identified. The discovery of a large repertoire of neuropeptide precursors and neuropeptides provides a basis for experimental studies that investigate the physiological roles of neuropeptide signaling systems in A. japonicus. Looking ahead, some of these neuropeptides may have effects that could be harnessed to enable improvements in the aquaculture of this economically important species.

Bisphenol F has different effects on preadipocytes differentiation and weight gain in adult mice as compared with Bisphenol A and S.

Bisphenol S (2,2-bisulfone, BPS) and Bisphenol F (2,2-bis [4-hydroxyphenol]methane, BPF) are analogs of Bisphenol A (2,2-bis[4-hydroxyphenyl]propane, BPA), a widely used endocrine disrupting compound present in polycarbonate plastics, thermal receipts and epoxy resins that line food cans. Here we examined effects of BPA, BPS, and BPF in low concentrations on differentiation in murine 3T3-L1 preadipocytes. We also fed adult male mice chow with one of three doses of BPF (0, 0.5, 5, 50 mg/kg chow, or approximately 0.044, 0.44 and 4.4 mg/kg body weight per day) for 12 weeks, collected body weights, food intake, and tested for glucose tolerance. The doses of BPF used produced mean concentrations of 0, 6.2, 43.6, and 561 ng/mL in plasma. In 3T3-L1 cells BPS had the greatest effects, along with BPA, both increased expression of several genes required for preadipocyte differentiation over 12 days in culture. In contrast, BPF decreased expression of several genes late in differentiation. This dichotomy was also reflected in lipid accumulation as BPA and BPS treated cells had elevated lipid concentrations compared to controls or cells treated with BPF. Male mice fed either the highest or lowest concentrations of BPF gained less weight than controls with no effects on glucose levels or glucose tolerance. Plasma levels of BPF reflected doses in food with no overlap between doses. In summary, our results suggest that BPS has a strong potential to be obesogenic while effects of BPF are subtler and potentially in the opposite direction.

Testosterone enhancement during pregnancy influences social coping and gene expression of oxytocin and vasopressin in the brain of adult rats.

Steroid hormones are important mediators of prenatal maternal effects and play an important role in fetal programming. The aim of our study was to investigate how testosterone enhancement during pregnancy influences neurobehavioral aspects of social coping of rat offspring in adulthood. Pregnant rat dams were exposed to depot form of testosterone during the last third of pregnancy (i.e., beginning on the 14th day of pregnancy). Their adult offspring were later tested in a social interaction test and expression of oxytocin and arginine-vasopressin mRNA in the hypothalamic nuclei was evaluated. Our research showed that prenatal exposure to higher levels of testosterone activated socio­cohesive and socio­aversive interactions, but only in males. The testosterone­exposed group also showed decreased oxytocin mRNA expression in the supraoptic and paraventricular nuclei of the hypothalamus, and increased arginine-vasopressin mRNA expression in the supraoptic and suprachiasmatic nuclei as compared to controls. However, we did not observe any sex differences in the expression of oxytocin and arginine­vasopressin mRNA in these regions. Our findings show that testosterone enhancement in pregnancy could have long­lasting effects on oxytocin and arginine-vasopressin levels in the brain of adult animals, but lead to changes in behavioral aspects of coping strategies only in males.

Transcriptomic discovery and comparative analysis of neuropeptide precursors in sea cucumbers (Holothuroidea).

Neuropeptides synthesized and released by neuronal cells play important roles in the regulation of many processes, e.g. growth, feeding, reproduction, and behavior. In the past decade, next-generation sequencing technologies have helped to facilitate the identification of multiple neuropeptide genes in a variety of taxa, including arthropods, molluscs and echinoderms. In this study, we extend these studies to Holothuria scabra, a sea cucumber species that is widely cultured for human consumption. In silico analysis of H. scabra neural and gonadal transcriptomes enabled the identification of 28 transcripts that encode a total of 26 bilaterian and echinoderm-specific neuropeptide precursors. Furthermore, publicly available sequence data from another sea cucumber, Holothuria glaberrima, allowed a more in-depth comparative investigation. Interestingly, two isoforms of a calcitonin-type peptide precursor (CTPP) were deduced from the H. scabra transcriptome - HscCTPP-long and HscCTPP-short, likely the result of alternative splicing. We also identified a sea cucumber relaxin-type peptide precursor, which is of interest because relaxin-type peptides have been shown to act as gonadotropic hormones in starfish. Two neuropeptides that appear to be holothurian-specific are GLRFA, and GN-19. In H. scabra, the expression of GLRFA was restricted to neural tissues, while GN-19 expression was additionally found in the longitudinal muscle and intestinal tissues. In conclusion, we have obtained new insights into the neuropeptide signaling systems of holothurians, which will facilitate physiological studies that may enable advances in the aquaculture of sea cucumbers.

Running-wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post-transcriptional mechanism.

Loss of mitochondrial respiratory flux is a hallmark of skeletal muscle aging, contributing to a progressive decline of muscle strength. Endurance exercise alleviates the decrease in respiratory flux, both in humans and in rodents. Here, we dissect the underlying mechanism of mitochondrial flux decline by integrated analysis of the molecular network. Mice were given a lifelong ad libitum low-fat or high-fat sucrose diet and were further divided into sedentary and running-wheel groups. At 6, 12, 18 and 24 months, muscle weight, triglyceride content and mitochondrial respiratory flux were analysed. Subsequently, transcriptome was measured by RNA-Seq and proteome by targeted LC-MS/MS analysis with 13 C-labelled standards. In the sedentary groups, mitochondrial respiratory flux declined with age. Voluntary running protected the mitochondrial respiratory flux until 18 months of age. Beyond this time point, all groups converged. Regulation Analysis of flux, proteome and transcriptome showed that the decline of flux was equally regulated at the proteomic and at the metabolic level, while regulation at the transcriptional level was marginal. Proteomic regulation was most prominent at the beginning and at the end of the pathway, namely at the pyruvate dehydrogenase complex and at the synthesis and transport of ATP. Further proteomic regulation was scattered across the entire pathway, revealing an effective multisite regulation. Finally, reactions regulated at the protein level were highly overlapping between the four experimental groups, suggesting a common, post-transcriptional mechanism of muscle aging.

Animal-Assisted Interventions for Children with Attention Deficit/Hyperactivity Disorder: A Theoretical Review and Consideration of Future Research Directions.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental disorders and is characterized by core symptoms of inattention, impulsivity, and hyperactivity. Given the limitations of the existing treatment strategies, it seems necessary to consider the further exploration of alternative treatment approaches. In this review, the application and complementary use of animal-assisted interventions to the treatment of ADHD were discussed. Several mechanisms including calming, socializing, motivating, and cognitive effects of animal-assisted interventions were explored. Since studies directly investigating these effects on ADHD are scarce, so each of them were examined in terms of how it could benefit the treatment of ADHD. These effects can have a positive effect on several core symptoms of ADHD.

Habituation of exploratory behaviour in VPA rats: animal model of autism.

Autism is a neurodevelopmental disorder with multifactorial aetiology, represented as impairment in social behaviour, communication and the occurrence of repetitive activities, which can be observed in the early life. The core features are frequently accompanied by other manifestations, including limited environmental exploration. The aim of the presented study, realised on an animal model of autism - VPA rats, i.e. animals prenatally affected with valproic acid on gestation day 12.5, was to investigate the habituation process of exploratory activity (manifested by a gradual decrease in the intensity of locomotor activity), which reflects the stage of the central nervous system. VPA rats were tested in open-field in three developmental periods - weaning (postnatal day 21 - PND 21), puberty (PND 42) and adulthood (PND 72). In each period of ontogenesis, the rapidity of habituation was evaluated by using the method of linear regression. Compared to controls, VPA rats showed a significant decrease in the intensity and an increase in the rapidity of exploratory activity habituation during puberty and adulthood. Our results indicate that the animal model of autism, i.e. VPA rats, showed disabilities in the development of the nervous system. These findings can help confirm not only the validity of this animal model of autism but can also help better understand neuronal changes in humans with autism.

Animal models of autism with a particular focus on the neural basis of changes in social behaviour: an update article.

Research on autism has been gaining more and more attention. However, its aetiology is not entirely known and several factors are thought to contribute to the development of this neurodevelopmental disorder. These potential contributing factors range from genetic heritability to environmental effects. A significant number of reviews have already been published on different aspects of autism research as well as focusing on using animal models to help expand current knowledge around its aetiology. However, the diverse range of symptoms and possible causes of autism have resulted in as equally wide variety of animal models of autism. In this update article we focus only on the animal models with neurobehavioural characteristics of social deficit related to autism and present an overview of the animal models with alterations in brain regions, neurotransmitters, or hormones that are involved in a decrease in sociability.

Influence of up-regulated renin-angiotensin system on the exploration, anxiety-related behavior and object recognition.

The renin-angiotensin system (RAS) plays an important role in the development of hypertension and has serious consequences on behaviour. The aim of our study was to investigate the effect of hypertension, induced by up-regulated RAS, on the exploration, anxiety-related behaviour and object recognition in laboratory rats. In the experiment, 12 weeks old normotensive Sprague-Dawley (SD) and hypertensive TGR(mREN2)27 (TGR) male rats with up-regulated RAS were used. In the open-field test, the TGR rats were less active in ambulating, rearing and sniffing and more active in self-grooming and urinating than SD ones. In the elevated plus-maze test, the TGR rats showed lower frequency of total arm entries, closed arm entries and higher frequency of defecation than in controls. In the emergence test, TGR rats did not show significant differences. In the novel object recognition task, the TGR rats spent less time with exploration of both familiar and unfamiliar objects but preferred the novel object over the familiar one and exhibited higher percentage of the total exploring time spent with novel object exploration than SD rats. Our results indicate that the TGR rats are less actively exploring, show some modifications of emotional/anxiety-related behavior and exhibited better recognition abilities.

Testosterone enhancement during pregnancy influences the 2D:4D ratio and open field motor activity of rat siblings in adulthood.

In humans, the relationship between the prenatal testosterone exposure and the ratio of the second and the fourth digits (2D:4D) has been extensively studied. Surprisingly, data on this relationship have thus far been lacking in experimental animals such as rats. We studied the effect of maternal testosterone enhancement during pregnancy on the digit ratio and open field activity of adult progeny in Wistar rats. Elevated levels of maternal testosterone resulted in lower 2D:4D ratios and an elongated 4D on the left and right forepaws in both males and females. We found no sex difference in 2D:4D in control animals. In the open field test, control females were more active than control males and testosterone females, while the activity of testosterone females did not differ from that of control males. We found a positive correlation between motor activity and the right forepaw 2D:4D ratio of control males and females. Prenatal exposure to testosterone resulted in the disappearance of this correlation in both males and females. Our results show that elevated levels of testosterone during the prenatal period can influence forepaw 4D length, 2D:4D ratio, and open field motor activity of rats, and that these variables are positively correlated. Thus, this approach represents a noninvasive and robust method for evaluating the effects of prenatal testosterone enhancement on anatomical and physiological parameters.

Some assessments of the amygdala role in suprahypothalamic neuroendocrine regulation: a minireview.

The amygdala is a complex structure playing primary role in the processing and memorizing of emotional reactions. The amygdalae send impulses to the hypothalamus for activation of the sympathetic nervous system, to the reticular nucleus for increasing reflexes, to the nuclei of the trigeminal nerve and facial nerve for facial expressions of fear, and to the ventral tegmental area, locus coeruleus, and laterodorsal tegmental nucleus for activation of dopamine, norepinephrine and epinephrine release. The amygdala plays a key role in what has been called the "general-purpose defense response control network" and reacts in response to unpleasant sights, sensations, or smells. Anger, avoidance, and defensiveness are emotions activated largely by the amygdale. The amygdala is responsible for activating ancestral signs of distress such as "tense-mouth" and defensive postures such as crouching. Poor functioning of amygdala has also been associated with anxiety, autism, depression, narcolepsy, post-traumatic stress disorder, phobias, frontotemporal dementia, and schizophrenia. Impairment of emotional event memory in patients with Alzheimer's disease also correlates with the intensity of amygdalar damage. All these events speak out for the importance to preserve the normal function of the amygdala which can only be achieved by constant deepening of our knowledge about this unique structure.