5-HT4 receptor agonists increase sAPPalpha levels in the cortex and hippocampus of male C57BL/6j mice.
Ontology highlight
ABSTRACT:
SUBMITTER: Cachard-Chastel M
PROVIDER: S-EPMC2013878 | biostudies-other | 2007 Apr
REPOSITORIES: biostudies-other
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Project description:Tarsal joint abnormalities have been observed in aged male mice on a C57BL background. This joint disease consists of calcaneal displacement, inflammation, and proliferation of cartilage and connective tissue, that can progress to ankylosis of the joint. While tarsal pathology has been described previously in C57BL/6N substrains, as well as in STR/ort and B10.BR strain, no current literature describes this disease occurring in C57BL/6J mice. More importantly the behavioral features that may result from such a change to the joint have yet to be evaluated. This condition was observed in older male mice of the C57BL/6J lineage, around the age of 20 weeks or older, at a frequency of 1% of the population. To assess potential phenotypic sequela, this study sought to evaluate body weight, frailty assessment, home cage wheel running, dynamic weight bearing, and mechanical allodynia with and without the presence of pain relief with morphine. Overall mice with tarsal injuries had significantly higher frailty scores (p< 0.05) and weighed less (p<0.01) compared to unaffected mice. Affected mice had greater overall touch sensitivity (p<0.05) and they placed more weight on their forelimbs (p<0.01) compared to their hind limbs. Lastly, when housed with a running wheel, affected mice ran for a shorter length of time (p<0.01) but tended to run a greater distance within the time they did run (p<0.01) compared to unaffected mice. When tested just after being given morphine, the affected mice performed more similarly to unaffected mice, suggesting there is a pain sensation to this disease process. This highlights the importance of further characterizing inbred mouse mutations, as they may impact research programs or specific study goals.
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Project description:The widespread prevalence of obesity has lead to extensive research on white adipose tissue (WAT), which frequently uses the C57BL/6J mouse strain as a model. In many studies, results obtained in one WAT depot are often extrapolated to all WAT. However, functional differences among WAT depots are now becoming apparent. Thus, to identify the molecular mechanisms responsible for WAT depot-specific differences under "normal" conditions, four C57BL/6J mouse WAT depots (inguinal, mesenteric, epididymal, and retroperitoneal) were analyzed. Depot proteomic profiles, along with weights, protein contents, adipocyte sizes and oxidative stress were determined. Mesenteric WAT had almost twice the protein content of the other depots analyzed. Mean adipocyte size was highest in epididymal and lowest in mesenteric and inguinal depots. The proteome of inguinal WAT displayed low levels of enzymes involved in ATP generation, glucose and lipid metabolism, and antioxidant proteins. Higher levels of these proteins were observed in mesenteric and epididymal WAT, with variable levels in the retroperitoneal depot. Some of these proteins showed depot-specific correlations with plasma levels of insulin, leptin, and adiponectin. In agreement with the proteomic data, levels of the antioxidant protein heat shock protein ?1 (HSP?1) also were lower in inguinal WAT when analyzed by western blotting and immunohistochemistry. Also, lipid peroxidation products showed similar trends. Our results are consistent with lower triglyceride turnover and lower oxidative stress in inguinal than mesenteric and epididymal WAT. The observed WAT depot-specific differences provide clues as to the mechanisms leading to these depots' respective diverse functions.
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Project description:The global prevalence of type 2 diabetes (T2D) has doubled since 1980. Human epidemiological studies support arsenic exposure as a risk factor for T2D, although the precise mechanism is unclear. We hypothesized that chronic arsenic ingestion alters glucose homeostasis by impairing adaptive thermogenesis, i.e., body heat production in cold environments. Arsenic is a pervasive environmental contaminant, with more than 200 million people worldwide currently exposed to arsenic-contaminated drinking water. Male C57BL/6J mice exposed to sodium arsenite in drinking water at 300 μg/L for 9 wk experienced significantly decreased metabolic heat production when acclimated to chronic cold tolerance testing, as evidenced by indirect calorimetry, despite no change in physical activity. Arsenic exposure increased total fat mass and subcutaneous inguinal white adipose tissue (iWAT) mass. RNA sequencing analysis of iWAT indicated that arsenic dysregulated mitochondrial processes, including fatty acid metabolism. Western blotting in WAT confirmed that arsenic significantly decreased TOMM20, a correlate of mitochondrial abundance; PGC1A, a master regulator of mitochondrial biogenesis; and, CPT1B, the rate-limiting step of fatty acid oxidation (FAO). Our findings show that chronic arsenic exposure impacts the mitochondrial proteins of thermogenic tissues involved in energy expenditure and substrate regulation, providing novel mechanistic evidence for arsenic's role in T2D development.
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Project description:Olanzapine is a widely prescribed antipsychotic drug. While effective in reducing psychoses, treatment with olanzapine causes rapid increases in blood glucose. We wanted to determine if a single bout of exercise, immediately prior to treatment, would attenuate the olanzapine-induced rise in blood glucose and if this occurred in an IL-6 dependent manner. We found that exhaustive, but not moderate exercise, immediately prior to treatment, prevented olanzapine-induced hyperglycemia and this occurred in parallel with increases in serum IL-6. To determine if IL-6 was involved in the mechanisms through which exhaustive exercise protected against olanzapine-induced hyperglycemia several additional experiments were completed. Treatment with IL-6 (3 ng/g bw, IP) alone did not protect against olanzapine-induced increases in blood glucose. The protective effects of exhaustive exercise against olanzapine-induced increases in blood glucose were intact in whole body IL-6 knockout mice. Similarly, treating mice with an IL-6 neutralizing antibody prior to exhaustive exercise did not negate the protective effect of exercise against olanzapine-induced hyperglycemia. Our findings provide evidence that a single bout of exhaustive exercise protects against acute olanzapine-induced hyperglycemia and that IL-6 is neither sufficient, nor required for exercise to protect against increases in blood glucose with olanzapine treatment.
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Project description:ObjectivesThyronamines are decarboxylated and deiodinated metabolites of thyroid hormones (THs). Of all possible thyronamine variants, only 3-iodothyronamine (3-T1AM) and iodine-free thyronamine (T0AM) have been detected in vivo. While intensive research has been done on the (patho-)physiological action of 3-T1AM, the role of T0AM has been studied less intensively.Study designWe determined whether a single pharmacological dose (50 mg/kg, i.p.) or repeated administration (5 mg/kg/day, i.p., for 7 days) of T0AM affects metabolism, cardiovascular function, or thermoregulation in male C57BL/6J mice. Since selenium (Se) is important for proper TH function and Se metabolism is affected by TH, we additionally analyzed Se concentrations in liver, serum, and kidney using total reflection X-ray analysis.ResultsA single injection of T0AM had no effect on heart rate, temperature, or activity as assessed by radio telemetry. Likewise, daily administration of T0AM did not alter body weight, food or water intake, heart rate, blood pressure, brown adipose tissue thermogenesis, or body temperature, and no significant differences in hepatic glycogen content or mRNA expression of genes involved in cardiovascular function or metabolic control were determined. Also, the X-ray analysis of Se concentrations revealed no significant changes. However, hepatic T0AM was significantly increased in the treated animals.ConclusionsIn summary, our data demonstrate that T0AM elicits no obvious metabolic, cardiovascular, or thermoregulatory activities in mice. As T0AM does also not interfere with TH or Se metabolism, we conclude that the deiodination of 3-T1AM to T0AM constitutes an efficient inactivation mechanism, terminating the actions of the more powerful precursor.
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Project description:The lifelong relationship between microorganisms and hosts has a profound impact on the overall health and physiology of the holobiont. Microbiome composition throughout the life span of a host remains largely understudied. Here, the fecal microbiota of conventionally raised C57BL/6J male mice was characterized throughout almost the entire adult life span, from "maturing" (9 weeks) until "very old" (112 weeks) age. Our results suggest that microbiota changes occur throughout life but are more pronounced in maturing to middle-age mice than in mice later in life. Phylum-level analysis indicates a shift of the Bacteroidota-to-Firmicutes ratio in favor of Firmicutes in old and very old mice. More Firmicutes amplicon sequence variants (ASVs) were transient with varying successional patterns than Bacteroidota ASVs, which varied primarily during maturation. Microbiota configurations from five defined life phases were used as training sets in a Bayesian model, which effectively enabled the prediction of host age. These results suggest that age-associated compositional differences may have considerable implications for the interpretation and comparability of animal model-based microbiome studies. The sensitivity of the age prediction to dietary perturbations was tested by applying this approach to two age-matched groups of C57BL/6J mice that were fed either a standard or western diet. The predicted age for the western diet-fed animals was on average 27 ± 11 (mean ± standard deviation) weeks older than that of standard diet-fed animals. This indicates that the fecal microbiota-based predicted age may be influenced not only by the host age and physiology but also potentially by other factors such as diet. IMPORTANCE The gut microbiome of a host changes with age. Cross-sectional studies demonstrate that microbiota of different age groups are distinct but do not demonstrate the temporal change that a longitudinal study is able to show. Here, we performed a longitudinal study of adult mice for over 2 years. We identified life stages where compositional changes were more dynamic and showed temporal changes for the more abundant species. Using a Bayesian model, we could reliably predict the life stages of the mice. Application of the same training set to mice fed different dietary regimens revealed that life-stage age predictions were possible for mice fed the same diet but less so for mice fed different diets. This study sheds light on the temporal changes that occur within the gut microbiota of laboratory mice over their life span and may inform researchers on the appropriate mouse age for their research.
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Project description:Neuropeptide Y (NPY) signaling via limbic NPY1 and 2 receptors (NPY1R and NPY2R, respectively) is known to modulate binge-like ethanol consumption in rodents. However, the role of NPY signaling in the medial prefrontal cortex (mPFC), which provides top-down modulation of the limbic system, is unknown. Here, we used "drinking-in-the-dark" (DID) procedures in C57BL/6J mice to address this gap in the literature. First, the impact of DID on NPY immunoreactivity (IR) was assessed in the mPFC. Next, the role of NPY1R and NPY2R signaling in the mPFC on ethanol consumption was evaluated through site-directed pharmacology. Chemogenetic inhibition of NPY1R+ neurons in the mPFC was performed to further evaluate the role of this population. To determine the potential role of NPY1R+ neurons projecting from the mPFC to the basolateral amygdala (BLA) this efferent population was selectively silenced. Three, 4-day cycles of DID reduced NPY IR in the mPFC. Intra-mPFC activation of NPY1R and antagonism of NPY2R resulted in decreased binge-like ethanol intake. Silencing of mPFC NPY1R+ neurons overall, and specifically NPY1R+ neurons projecting to the BLA, significantly reduced binge-like ethanol intake. We provide novel evidence that (1) binge-like ethanol intake reduces NPY levels in the mPFC; (2) activation of NPY1R or blockade of NPY2R reduces binge-like ethanol intake; and (3) chemogenetic inhibition of NPY1R+ neurons in the mPFC and NPY1R+ mPFC neurons projecting to the BLA blunts binge-like drinking. These observations provide the first direct evidence that NPY signaling in the mPFC modulates binge-like ethanol consumption.
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