RESUMO
Recent evidence in humans and animals indicates an association between maternal obesity and offspring behavioral outcomes. In humans, increased maternal body mass index has been linked to an increased risk of children receiving a diagnosis of early-emerging neurodevelopmental disorders such as Attention Deficit/Hyperactivity Disorder (ADHD) and/or Autism Spectrum Disorder (ASD). However, a limited number of preclinical studies have examined associations between maternal Western-Style Diet (mWSD) exposure and offspring social behavior. To our knowledge, this is the first study to investigate relationships between mWSD exposure and social behavior in non-human primates. Since aberrant social behavior is a diagnostic criterion for several neurodevelopmental disorders, the current study focuses on examining the influence of maternal nutrition and metabolic state on offspring social behavior in Japanese macaques (Macaca fuscata). We found that mWSD offspring initiated less affiliative social behaviors as well as proximity to a peer. Using path analysis, we found that the association between mWSD consumption and reduced offspring social engagement was statistically mediated by increased maternal interleukin (IL)-12 during the third trimester of pregnancy. Additionally, mWSD offspring displayed increased idiosyncratic behavior, which was related to alterations in maternal adiposity and leptin in the third trimester. Together, these results suggest that NHP offspring exposed to mWSD exhibit behavioral phenotypes similar to what is described in some early-emerging neurodevelopmental disorders. These results provide evidence that mWSD exposure during gestation may be linked to increased risk of neurodevelopmental disorders and provides targets for prevention and intervention efforts.
Assuntos
Transtorno do Espectro Autista , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta Ocidental/efeitos adversos , Feminino , Humanos , Macaca fuscata , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Participação SocialRESUMO
OBJECTIVE: Anhedonia, which in part involves the lack of pleasure in consuming palatable food, is a long-lasting symptom observed in patients both when acutely ill and when long term recovered from Anorexia Nervosa. The neurocircuitry underlying this phenomenon is not well understood. Here we use the preclinical activity-based anorexia (ABA) model in adolescent female rats to assess the impact of excessive exercise, limited food intake and acute weight loss, on adolescent female rat orofacial responding to intraoral sucrose, as measured by the taste reactivity test (TRT). Animals were identified as either prone or resistant to this paradigm based on a weight loss criterion. Measures of food intake, running wheel activity, taste reactivity and medial prefrontal cortex astrocyte expression were compared across groups. METHODS: Adolescent female rats implanted with an intraoral catheter were given a TRT using 1 M (M) sucrose at baseline, max weight loss (25% weight loss from start of ABA or 7 full days on the paradigm) or 10 days recovered from the ABA paradigm. Animals were sacrificed after the final TRT and astrocyte density was measured via immunohistochemistry. RESULTS: Animals resistant to the ABA paradigm ran less than prone animals during the ABA period. Additionally, we found that resistant animals displayed more cumulative 'liking' responses to sucrose compared to prone animals at maximum weight loss. Finally, we found prone animals 10-days recovered from ABA had reduced medial prefrontal cortex astrocyte density compared to levels in resistant animals. DISCUSSION: Rats presented with the physiological challenge of the ABA paradigm either adapt their behavior to stabilize their body weight (i.e. resistant), or rapidly lose weight (i.e. prone). Furthermore, we found that prone animals have reduced orofacial responding to 1 M sucrose at maximum weight loss compared to responses in resistant animals, and this anhedonia-like behavior may be a result of reduced astrocyte density that affects cortical function.
Assuntos
Anorexia Nervosa , Anorexia , Animais , Astrócitos , Modelos Animais de Doenças , Feminino , Humanos , Ratos , Redução de PesoRESUMO
The maternal environment during pregnancy is critical for fetal development and perinatal perturbations can prime offspring disease risk. Here, we briefly review evidence linking two well-characterized maternal stressors - psychosocial stress and infection - to increased neuropsychiatric risk in offspring. In the current climate of increasing obesity and globalization of the Western-style diet, maternal overnutrition emerges as a pressing public health concern. We focus our attention on recent epidemiological and animal model evidence showing that, like psychosocial stress and infection, maternal overnutrition can also increase offspring neuropsychiatric risk. Using lessons learned from the psychosocial stress and infection literature, we discuss how altered maternal and placental physiology in the setting of overnutrition may contribute to abnormal fetal development and resulting neuropsychiatric outcomes. A better understanding of converging pathophysiological pathways shared between stressors may enable development of interventions against neuropsychiatric illnesses that may be beneficial across stressors.
Assuntos
Sintomas Afetivos/etiologia , Transtornos Mentais/etiologia , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Animais , Disfunção Cognitiva/etiologia , Meio Ambiente , Feminino , Desenvolvimento Fetal , Humanos , Hipernutrição/complicações , Hipernutrição/fisiopatologia , Placenta/fisiopatologia , Gravidez , Complicações na Gravidez/imunologia , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Fatores de Risco , Estresse Psicológico/imunologia , Estresse Psicológico/psicologiaRESUMO
Maternal stressors during the prenatal and perinatal periods are associated with increased susceptibility for and severity of chronic disease phenotypes in adult offspring. In this study, we used a rat model of maternal high-fat diet (HFD) exposure during pregnancy and lactation to investigate the impact on skeletal homeostasis in offspring. In the distal femur, young male and female offspring (up to 3 weeks of age) from dams fed a HFD exhibited marked increases in trabecular bone volume relative to offspring from dams fed a chow diet, but this was followed by sustained bone loss. By 15 weeks of age, male offspring of HFD fed dams exhibited a 33% reduction in trabecular bone volume fraction that histomorphometric analyses revealed was due to a nearly threefold increase in the abundance of bone-resorbing osteoclasts, while there were no differences between female control and HFD offspring by 15 weeks of age. The osteoblastic differentiation of male offspring-derived bone marrow stromal cells was not affected by maternal diet. However, osteoclastic precursors isolated from the male offspring of HFD fed dams exhibited enhanced differentiation in vitro, forming larger osteoclasts with higher expression of the fusion marker DC-STAMP. This effect appears to be mediated by a cell autonomous increase in the sensitivity of precursors to RANKL. Taken together, these results suggest that maternal stressors like HFD exposure have persistent consequences for the skeletal health of offspring that may ultimately lead to a predisposition for osteopenia/osteoporosis.
Assuntos
Dieta Hiperlipídica , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta Hiperlipídica/efeitos adversos , Feminino , Lactação , Masculino , Osteogênese , Gravidez , RatosRESUMO
Children born to women who experience stress during pregnancy have an increased risk of cancer in later life, but no previous animal studies have tested such a link. We questioned whether prenatal stress (PS) in A/J mice affected the development of lung tumors after postnatal response to tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Timed-bred A/J mice were randomly assigned on gestation day 12.5 to PS by restraint for 5 consecutive days or control (no restraint). Adult offspring of control and stressed pregnancies were all treated with three NNK injections (50 mg/kg every other day) and euthanized 16 weeks later to examine their lungs. Compared with controls, PS dams exhibited significantly increased levels of plasma corticosterone, increased adrenal weights and decreased fetus weights without fetal loss. Prenatally stressed litters had a significantly higher neonatal death rate within first week of life, and surviving male and female offspring developed lung epithelial proliferations with increase multiplicity, increased area and aggressive morphology. PS also induced more advanced atypical adenomatous hyperplasia lesions. We found no difference in lung NNK-derived methyl DNA adducts, but PS did significantly enhance CD3+ T cell and Foxp3+ T cell tumor infiltration. PS significantly increases multiplicity, area of NNK-induced lung tumors and advanced morphology. PS did not affect production of NNK-derived methyl DNA adducts but did increase lymphocytic infiltration of lung tumors. To our knowledge, this is the first animal model of PS with evaluation of cancer development in offspring.
Assuntos
Neoplasias Pulmonares/patologia , Nitrosaminas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estresse Psicológico , Animais , Feminino , Neoplasias Pulmonares/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos A , Gravidez , Restrição FísicaRESUMO
Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism.
Assuntos
Endocanabinoides/metabolismo , Glucocorticoides/efeitos adversos , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , Animais , Corticosterona/farmacologia , Dislipidemias/metabolismo , Endocanabinoides/administração & dosagem , Endocanabinoides/farmacologia , Fígado/metabolismo , Síndrome Metabólica/patologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Especificidade de Órgãos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
There is growing interest in the therapeutic potential of psilocybin for the treatment of a wide variety of medical problems, and even for the promotion of wellbeing among healthy individuals. Interestingly, among the many proposed indications, both obesity and anorexia nervosa (AN) have been discussed. However, the effect of psilocybin on appetitive behavior and metabolism is not well known. Here, we report the effects of psilocybin on body weight, intake and output, body composition, and metabolic function among lean male and female wild-type mice. In the days immediately following treatment, both male and female mice receiving a single intraperitoneal dose of psilocybin were consistently heavier than saline controls, with no effect of psilocybin on intake or output. Co-administration of the 5-HT2A/2C receptor antagonist ketanserin had no effect on this outcome. Body composition analysis revealed that psilocybin significantly increased lean and water mass among males, with a similar trend among females. A metabolic panel revealed increased creatine kinase (CK), aspartate aminotransferase (AST), and chloride among male and female psilocybin treated mice. Together, these findings begin to investigate the potential mechanisms of psilocybin's effects on body weight and metabolic measures. Such understanding will be critical for the safe, efficacious, and well-informed use of psilocybin in clinical and non-clinical settings.
Assuntos
Composição Corporal , Peso Corporal , Psilocibina , Animais , Feminino , Masculino , Camundongos , Composição Corporal/efeitos dos fármacos , Psilocibina/farmacologia , Peso Corporal/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Alucinógenos/farmacologia , Ketanserina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Caracteres SexuaisRESUMO
BACKGROUND: Genome-wide tiling array experiments are increasingly used for the analysis of DNA methylation. Because DNA methylation patterns are tissue and cell type specific, the detection of differentially methylated regions (DMRs) with small effect size is a necessary feature of tiling microarray 'peak' finding algorithms, as cellular heterogeneity within a studied tissue may lead to a dilution of the phenotypically relevant effects. Additionally, the ability to detect short length DMRs is necessary as biologically relevant signal may occur in focused regions throughout the genome. RESULTS: We present a free open-source Perl application, Binding Intensity Only Tile array analysis or "BioTile", for the identification of differentially enriched regions (DERs) in tiling array data. The application of BioTile to non-smoothed data allows for the identification of shorter length and smaller effect-size DERs, while correcting for probe specific variation by inversely weighting on probe variance through a permutation corrected meta-analysis procedure employed at identified regions. BioTile exhibits higher power to identify significant DERs of low effect size and across shorter genomic stretches as compared to other peak finding algorithms, while not sacrificing power to detect longer DERs. CONCLUSION: BioTile represents an easy to use analysis option applicable to multiple microarray platforms, allowing for its integration into the analysis workflow of array data analysis.
Assuntos
Metilação de DNA , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Software , Algoritmos , GenomaRESUMO
Maternal high-fat (HF) diet has long-term consequences on the metabolic phenotype of the offspring. Here, we determined the effects of postweaning exercise in offspring of rat dams fed HF diet during gestation and lactation. Pregnant Sprague-Dawley rats were maintained on chow or HF diet throughout gestation and lactation. All pups were weaned onto chow diet on postnatal day (PND) 21. At 4 wk of age, male pups were given free access to running wheels (RW) or remained sedentary (SED) for 3 wk, after which all rats remained sedentary, resulting in four groups: CHOW-SED, CHOW-RW, HF-SED, and HF-RW. Male HF offspring gained more body weight by PND7 compared with CHOW pups and maintained this weight difference through the entire experiment. Three weeks of postweaning exercise did not affect body weight gain in either CHOW or HF offspring, but reduced adiposity in HF offspring. Plasma leptin was decreased at the end of the 3-wk running period in HF-RW rats but was not different from HF-SED 9 wk after the exercise period ended. At 14 wk of age, intracerebroventricular injection of leptin suppressed food intake in CHOW-SED, CHOW-RW, and HF-RW, while it did not affect food intake in HF-SED group. At death, HF-RW rats also had higher leptin-induced phospho-STAT3 level in the arcuate nucleus than HF-SED rats. Both maternal HF diet and postweaning exercise had effects on hypothalamic neuropeptide and receptor mRNA expression in adult offspring. Our data suggest that postweaning exercise improves central leptin sensitivity and signaling in this model.
Assuntos
Fenômenos Fisiológicos da Nutrição Animal , Encéfalo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Lactação/metabolismo , Leptina/sangue , Fenômenos Fisiológicos da Nutrição Materna , Obesidade/prevenção & controle , Esforço Físico , Efeitos Tardios da Exposição Pré-Natal , Adiposidade , Animais , Glicemia/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Ingestão de Alimentos , Feminino , Regulação da Expressão Gênica , Teste de Tolerância a Glucose , Injeções Intraventriculares , Insulina/sangue , Leptina/administração & dosagem , Masculino , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/fisiopatologia , Fosforilação , Gravidez , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Neuropeptídeos/genética , Receptores de Neuropeptídeos/metabolismo , Fator de Transcrição STAT3/metabolismo , Comportamento Sedentário , Transdução de Sinais , Desmame , Aumento de PesoRESUMO
Anorexia Nervosa (AN) is associated with a high rate of morbidity and mortality as well as a high rate of relapse. The molecular mechanisms underlying the progression of the disorder or the relapses are largely unknown. Patients with AN have been shown to have increased oxidative stress, but its involvement in the development in the disease is unknown. We have previously shown that adolescent female rats undergoing the activity-based anorexia (ABA) paradigm also show signs of oxidative stress. Due to their role in the release of reactive oxygen species (ROS), mitochondria are of high interest in diseases exhibiting oxidative stress. In this study, the impact of ABA on brain mitochondrial dynamics was examined. We found transient changes in the medial prefrontal cortex, hypothalamus, and hippocampus following 25% weight loss and changes in the amygdala at a 10-day weight recovery timepoint. These changes point towards damage in the mitochondria contributing to the oxidative stress.
Assuntos
Anorexia Nervosa , Anorexia , Ratos , Feminino , Animais , Dinâmica Mitocondrial , Hipocampo , EncéfaloRESUMO
Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are satiation factors secreted by the small intestine in response to lipid meals. Apo AIV and CCK-8 has an additive effect to suppress food intake relative to apo AIV or CCK-8 alone. In this study, we determined whether CCK-8 (1, 3, or 5 µg/kg ip) reduces food intake in fasted apo AIV knockout (KO) mice as effectively as in fasted wild-type (WT) mice. Food intake was monitored by the DietMax food system. Apo AIV KO mice had significantly reduced 30-min food intake following all doses of CCK-8, whereas WT mice had reduced food intake only at doses of 3 µg/kg and above. Post hoc analysis revealed that the reduction of 10-min and 30-min food intake elicited by each dose of CCK-8 was significantly larger in the apo AIV KO mice than in the WT mice. Peripheral CCK 1 receptor (CCK1R) gene expression (mRNA) in the duodenum and gallbladder of the fasted apo AIV KO mice was comparable to that in WT mice. In contrast, CCK1R mRNA in nodose ganglia of the apo AIV KO mice was upregulated relative to WT animals. Similarly, upregulated CCK1R gene expression was found in the brain stem of apo AIV KO mice by in situ hybridization. Although it is possible that the increased satiating potency of CCK in apo AIV KO mice is mediated by upregulation of CCK 1R in the nodose ganglia and nucleus tractus solitarius, additional experiments are required to confirm such a mechanism.
Assuntos
Apolipoproteínas A/metabolismo , Colecistocinina/farmacologia , Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Saciação/efeitos dos fármacos , Animais , Apolipoproteínas A/genética , Duodeno/metabolismo , Ingestão de Alimentos/genética , Comportamento Alimentar/fisiologia , Vesícula Biliar/metabolismo , Masculino , Camundongos , Camundongos Knockout , Gânglio Nodoso/metabolismo , Receptores da Colecistocinina/genética , Receptores da Colecistocinina/metabolismo , Saciação/fisiologiaRESUMO
In rodents, early-life exposure to environmental stress or antidepressant medication treatment has been shown to induce similar long-term consequences on memory- and depression-related behavior in adulthood. To expand on this line of work, we evaluated how juvenile exposure to chronic variable stress (CVS) or the selective serotonin reuptake inhibitor fluoxetine (FLX) influences conditioned taste aversion (CTA) learning in adulthood. To do this, in Experiment 1, we examined how adolescent CVS alone (postnatal day [PND] 35-48), or with prenatal stress (PNS) history (PNS + CVS), influenced the acquisition and extinction of CTA in adult male Sprague Dawley rats. Specifically, at PND70+ (adulthood), rats were presented with 0.15 % saccharin followed by an intraperitoneal (i.p.) injection of lithium chloride (LiCl) to induce visceral malaise. A total of four saccharin (conditioned stimulus) and LiCl (unconditioned stimulus) pairings occurred across the CTA acquisition phase. Next, saccharin was presented without aversive consequences, and intake was measured across consecutive days of the extinction phase. No differences in body weight gain across the experimental days, rate of CTA acquisition, or extinction of CTA, were observed among the experimental groups (control, n = 7; CVS, n = 12; PNS + CVS, n = 9). In Experiment 2, we evaluated if early-life FLX exposure alters CTA learning in adulthood. Specifically, adolescent stress naïve male and female rats received FLX (0 or 20 mg/kg/i.p) once daily for 15 consecutive days (PND35-49). During antidepressant exposure, FLX decreased body weight gain in both male (n = 7) and female rats (n = 7), when compared to respective controls (male control, n = 8; female control, n = 8). However, juvenile FLX exposure decreased body weight-gain in adult male, but not female, rats. Lastly, adolescent FLX history had no effect on CTA acquisition or extinction in adulthood (PND70), in neither male nor female rats. Together, the data indicate that juvenile FLX exposure results in a long-term decrease of body weight-gain in a male-specific manner. Yet, independent of sex, neither early-life stress nor FLX exposure alters CTA learning in adulthood.
Assuntos
Fluoxetina , Estresse Psicológico , Animais , Masculino , Ratos , Aprendizagem da Esquiva , Peso Corporal , Fluoxetina/farmacologia , Cloreto de Lítio/farmacologia , Ratos Sprague-Dawley , Sacarina , Paladar , Feminino , Efeitos Tardios da Exposição Pré-NatalRESUMO
Mammalian cloning using somatic cells has been accomplished successfully in several species, and its potential basic, clinical and therapeutic applications are being pursued on many fronts. Determining the long-term effects of cloning on offspring is crucial for consideration of future application of the technique. Although full-term development of animals cloned from adult somatic cells has been reported, problems in the resulting progeny indicate that the cloning procedure may not produce animals that are phenotypically identical to their cell donor. We used a mouse model to take advantage of its short generation time and lifespan. Here we report that the increased body weight of cloned B6C3F1 female mice reflects an increase of body fat in addition to a larger body size, and that these mice share many characteristics consistent with obesity. We also show that the obese phenotype is not transmitted to offspring generated by mating male and female cloned mice.
Assuntos
Peso Corporal , Clonagem de Organismos , Obesidade/genética , alfa-MSH/análogos & derivados , Tecido Adiposo , Animais , Composição Corporal , Corticosterona/sangue , Cruzamentos Genéticos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Privação de Alimentos , Insulina/sangue , Leptina/sangue , Leptina/farmacologia , Masculino , Camundongos , Obesidade/fisiopatologia , Fenótipo , Gravidez , alfa-MSH/farmacologiaRESUMO
The adverse effects of stress on brain and behavior have long been known and well-studied, with abundant evidence linking stress to, among other things, mood and anxiety disorders. Likewise, many have investigated potential treatments for stress-related mood and anxiety phenotypes and demonstrated good response to standard antidepressant medications like selective serotonin reuptake inhibitors (SSRIs), as well as environmental manipulations like exercise or enrichment. However, the extent to which stress and various treatments act on overlapping pathways in the brain is less well understood. Here, we used a widely studied social defeat stress paradigm to induce a robust depression- and anxiety-like phenotype and chronic corticosterone elevation that persisted for at least 4 weeks in wild type male mice. When mice were treated with either the SSRI fluoxetine or an enriched environment, both led to similar behavioral recovery from social defeat. We then focused on the amygdala and assessed the effects of social defeat, fluoxetine, and enrichment on 168 genes broadly related to synaptic plasticity or oxidative stress. We found 24 differentially expressed genes in response to social defeat stress. Interestingly, fluoxetine led to broad normalization of the stress-induced expression pattern while enrichment led to expression changes in a separate set of genes. Together, this study provides additional insight into the chronic effects of social defeat stress on behavior and gene expression in the amygdala. The findings also suggest that, for a subset of genes assessed, fluoxetine and environmental enrichment have strikingly divergent effects on expression in the amygdala, despite leading to similar behavioral outcomes.
RESUMO
The ANK3 locus has been repeatedly found to confer an increased risk for bipolar disorder. ANK3 codes for Ankyrin-G (Ank-G), a scaffold protein concentrated at axon initial segments, nodes of Ranvier, and dendritic spines, where it organizes voltage-gated sodium and potassium channels and cytoskeletal proteins. Mice with homozygous conditional knockout of Ank-G in the adult forebrain display hyperactivity and reduced anxiety-like behaviors, responsive to mood stabilizers. Their behavior switches to a depression-like phenotype when exposed to chronic social defeat stress (SDS), and then spontaneously reverts to baseline hyperactivity. Ank-G heterozygous conditional knockouts (Ank-G Het cKO) have not previously been characterized. Here, we describe the behavior of Ank-G Het cKO mice compared to littermate controls in the open field, elevated plus maze, and forced swim test, under both unstressed and stressed conditions. We found that Ank-G Het cKO is not significantly different from controls at baseline or after chronic SDS. The chronic stress-induced "depression-like" behavioral phenotype is persistent for at least 28 days and is responsive to fluoxetine. Strikingly, Ank-G Het cKO mice display increased sensitivity to a short duration SDS, which does not affect controls. The heterozygous Ank-G genetic model may provide novel insights into the role of Ank-G in the pathophysiology of stress sensitivity and "depression-like" phenotypes and could be useful for studying Ank-G-related gene-environment interactions.
RESUMO
We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Hepatócitos/metabolismo , Lipogênese , Fígado/metabolismo , MicroRNAs/metabolismo , Obesidade , Triglicerídeos , Animais , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética , Obesidade/induzido quimicamente , Obesidade/genética , Obesidade/metabolismo , Triglicerídeos/biossíntese , Triglicerídeos/genéticaRESUMO
Fortunately, the majority of children conceived through assisted reproductive technologies (ARTs) appear healthy; however, metabolic abnormalities, including elevated glucose and increased and altered adipose tissue deposition, have been reported in adolescents. To parse out factors that may be responsible, we investigated the effects of two different ARTs--in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)--as well as somatic cell nuclear transfer (SCNT) on glucose clearance, body weight, and body composition of young adult mice. Female and male mice generated through ART weighed more than control (naturally conceived [STOCK]) mice at birth. No differences in body weight were observed in males up to 8 wk of age. ART females took longer than control mice to clear a glucose bolus, with glucose clearance most impaired in SCNT females. IVF females secreted more insulin and had a higher insulin peak 15 min after glucose injection compared with all other groups. Male mice exhibited no differences in glucose clearance, but IVF males required more insulin to do so. SCNT females weighed more than IVF, ICSI, and STOCK females, and they had higher fat content than ICSI females and higher leptin levels than all other groups. These results show that glucose parameters are altered in young adult mice conceived through techniques associated with ART before onset of obesity and may be responsible for its development later in life. The present study suggests that more investigation regarding the long-term effects of manipulations associated with ART is warranted.
Assuntos
Glucose/metabolismo , Técnicas de Transferência Nuclear/efeitos adversos , Técnicas de Reprodução Assistida/efeitos adversos , Adiposidade , Animais , Glicemia/análise , Composição Corporal , Peso Corporal , Feminino , Fertilização in vitro/efeitos adversos , Teste de Tolerância a Glucose , Insulina/sangue , Leptina/sangue , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Gravidez , Fatores Sexuais , Injeções de Esperma Intracitoplásmicas/efeitos adversosRESUMO
Consumption of a high-fat diet has long been known to increase risk for obesity, diabetes, and the metabolic syndrome. Further evidence strongly suggests that these same metabolic disorders are associated with an increased risk of cognitive impairment later in life. Now faced with an expanding global burden of obesity and increasing prevalence of dementia due to an aging population, understanding the effects of high-fat diet consumption on cognition is of increasingly critical importance. Further, the developmental origins of many adult onset neuropsychiatric disorders have become increasingly clear, indicating a need to investigate effects of various risk factors, including diet, across the lifespan. Here, we use a rat model to assess the effects of maternal diet during pregnancy and lactation on cognition and hippocampal gene expression of offspring. Behaviorally, adult male offspring of high-fat fed dams had impaired object recognition memory and impaired spatial memory compared to offspring of chow-fed dams. In hippocampus, we found decreased expression of Insr, Lepr, and Slc2a1 (GLUT1) among offspring of high-fat fed dams at postnatal day 21. The decreased expression of Insr and Lepr persisted at postnatal day 150. Together, these data provide additional evidence to suggest that maternal exposure to high-fat diet during pregnancy and lactation can have lasting effects on the brain, behavior, and cognition on adult offspring.
Assuntos
Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Hipocampo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Pré-Natal/fisiologia , Animais , Disfunção Cognitiva/metabolismo , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , TranscriptomaRESUMO
As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these animal models. The rat is one particular model animal where an epigenetic tool can complement many pharmacological and behavioral studies to provide insightful mechanistic information. To this end, we adapted the SureSelect Target Capture System (referred to as Methyl-Seq) for the rat, which can assess DNA methylation levels across the rat genome. The rat design targeted promoters, CpG islands, island shores, and GC-rich regions from all RefSeq genes. To implement the platform on a rat experiment, male Sprague Dawley rats were exposed to chronic variable stress for 3 weeks, after which blood samples were collected for genomic DNA extraction. Methyl-Seq libraries were constructed from the rat DNA samples by shearing, adapter ligation, target enrichment, bisulfite conversion, and multiplexing. Libraries were sequenced on a next-generation sequencing platform and the sequenced reads were analyzed to identify DMRs between DNA of stressed and unstressed rats. Top candidate DMRs were independently validated by bisulfite pyrosequencing to confirm the robustness of the platform. Results demonstrate that the rat Methyl-Seq platform is a useful epigenetic tool that can capture methylation changes induced by exposure to stress.
Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Estresse Psicológico/genética , Animais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/patologiaRESUMO
The visible burrow system (VBS) is a model used to study chronic social stress in colony-housed rats. A hierarchy develops among the males resulting in dominant (DOM) and subordinate (SUB) animals. Hierarchy-associated changes in body weight, body composition, behavior, and neuroendocrine measures have been observed. After 14 d of VBS housing, SUB animals have decreased body weight, elevated corticosterone, and decreased testosterone (T), compared with DOM animals and controls, placing SUB animals in an ideal endocrine state to regain lost body weight as adipose tissue. It is hypothesized that maintaining constant androgen concentrations in SUB males during stress will prevent body weight loss by maintaining more lean body mass. To test this, animals were gonadectomized and implanted with SILASTIC implants containing T, 5alpha-dihydrotestosterone (DHT), or cholesterol. Implants maintained constant physiological levels of T. Standard intact, T, and DHT implant colonies formed hierarchies, whereas cholesterol colonies did not. Androgen manipulations significantly altered offensive and defensive behaviors only on the first day of VBS housing. After VBS stress, intact, T, and DHT SUB animals weighed less and lost more adipose and lean tissue than DOM and control males, whereas DOM animals primarily lost adipose tissue. However, on recovery, DHT SUB animals maintained more lean tissue than intact SUB animals. Oral glucose tolerance tests revealed that glucose clears faster in stressed T-implanted males that have increased adipose tissue. Overall, these data suggest that constant androgen concentrations in SUB animals do not prevent weight loss and changes in body composition during stress but do so during recovery.