Relationship Between a High-Fat Diet, Reduced Mobility, and Trace Element Overload in the Olfactory Bulbs of C57BL/6J and DBA/2J Mice.

The dysregulation of trace elements in the brain, which can be caused by genetic or environmental factors, has been associated with disease and compromised mobility. Research regarding trace elements and motor function has focused mainly on the basal ganglia, but few studies have examined the olfactory bulb in this context. Diets high in fat have been shown to have consequences of dysregulated iron and manganese in the brain and disrupted motor activity. The aim of our study was to examine the relationship between mobility and trace element disruption in the olfactory bulb in male and female C57BL/6J and DBA/2J mice fed a high-fat diet. Mobility was significantly reduced in male C57BL/6Js, but the correlation between iron and manganese in the olfactory bulb with velocity, distance travelled, and habituation was not statistically significant. However, there appears to be an overall pattern of a high-fat diet having a statistically significant impact individually on elevated iron and manganese in the olfactory bulb, reduced velocity, reduced distance travelled, and reduced habituation mainly in the male C57BL/6J strain. We found similar trends within the scientific literature to suggest that dysregulated trace element status in the olfactory bulb may be related to motor function in both humans and animals and that males may be more susceptible to the negative outcomes. Our findings contribute new information regarding the impact of diet on the brain, behavior, and potential connection between trace element dysregulation in the olfactory bulb with mobility.

Influence of Sex and Strain on Hepatic and Adipose Tissue Trace Element Concentrations and Gene Expression in C57BL/6J and DBA/2J High Fat Diet Models.

The objective of this study was to determine the influence of sex and strain on the dysregulation of trace element concentration and associative gene expression due to diet induced obesity in adipose tissue and the liver. Male and female C57BL/6J (B6J) and DBA/2J (D2J) were randomly assigned to a normal-fat diet (NFD) containing 10% kcal fat/g or a mineral-matched high-fat diet (HFD) containing 60% kcal fat/g for 16 weeks. Liver and adipose tissue were assessed for copper, iron, manganese, and zinc concentrations and related changes in gene expression. Notable findings include three-way interactions of diet, sex, and strain amongst adipose tissue iron concentrations (p = 0.005), adipose hepcidin expression (p = 0.007), and hepatic iron regulatory protein (IRP) expression (p = 0.012). Cd11c to Cd163 ratio was increased in adipose tissue due to HFD amongst all biological groups except B6J females, for which tissue iron concentrations were reduced due to HFD (p = 0.002). Liver divalent metal transporter 1 (DMT-1) expression was increased due to HFD amongst B6J males (p < 0.005) and females (p < 0.004), which coincides with the reduction in hepatic iron concentrations found in these biological groups (p < 0.001). Sex, strain, and diet affected trace element concentration, the expression of genes that regulate trace element homeostasis, and the expression of macrophages that contribute to tissue iron-handling in adipose tissue. These findings suggest that sex and strain may be key factors that influence the adaptive capacity of iron mismanagement in adipose tissue and its subsequent consequences, such as insulin resistance.

Alterations in metal homeostasis occur prior to canonical markers in Huntington disease.

The importance of metal biology in neurodegenerative diseases such as Huntingtin Disease is well documented with evidence of direct interactions between metals such as copper, zinc, iron and manganese and mutant Huntingtin pathobiology. To date, it is unclear whether these interactions are observed in humans, how this impacts other metals, and how mutant Huntington alters homeostatic mechanisms governing levels of copper, zinc, iron and manganese in cerebrospinal fluid and blood in HD patients. Plasma and cerebrospinal fluid from control, pre-manifest, manifest and late manifest HD participants were collected as part of HD-Clarity. Levels of cerebrospinal fluid and plasma copper, zinc, iron and manganese were measured as well as levels of mutant Huntingtin and neurofilament in a sub-set of cerebrospinal fluid samples. We find that elevations in cerebrospinal fluid copper, manganese and zinc levels are altered early in disease prior to alterations in canonical biomarkers of HD although these changes are not present in plasma. We also evidence that CSF iron is elevated in manifest patients. The relationships between plasma and cerebrospinal fluid metal are altered based on disease stage. These findings demonstrate that there are alterations in metal biology selectively in the CSF which occur prior to changes in known canonical biomarkers of disease. Our work indicates that there are pathological changes related to alterations in metal biology in individuals without elevations in neurofilament and mutant Huntingtin.

The impact of a high-fat diet on physical activity and dopamine neurochemistry in the striatum is sex and strain dependent in C57BL/6J and DBA/2J mice.

BACKGROUND: Obesity has been linked to behavioral and biochemical changes, such as reduced physical activity, dysregulated dopamine metabolism, and gene expression alterations in the brain. The impact of a continuous high-fat diet and resulting state of obesity may vary depending on sex and genetics. OBJECTIVE: The aim of this study was to investigate the impact of a high-fat diet on physical activity, gene expression in the striatum, and dopamine neurochemistry using male and female mice from different strains as a model to examine sex and strain influences on dopamine-mediated behavior and neurobiology. METHODS: Male and female mice from the C57BL/6J (B6J) and DBA/2J (D2J) strains were randomly assigned a control low-fat diet with 10% kcal fat or a high-fat diet with 60% kcal fat for 16 weeks. We assessed ambulation and habituation using the open field test; dopamine release and reuptake using ex-vivo fast scan cyclic voltammetry; and striatal mRNA expression of dopamine receptor D2, alpha synuclein, and tyrosine hydroxylase. RESULTS: Mice fed a high-fat diet exhibited reduced motor activity, but only obese B6J male mice displayed reduced habituation. Dopamine clearance in the dorsal striatum was reduced only in obese D2J mice, while dopamine clearance in the nucleus accumbens core was reduced only in male obese D2J mice. Striatal dopamine receptor D2 gene expression was upregulated exclusively in obese male B6J mice. CONCLUSION: Our study provides evidence for important sex and strain influences on the impact of a high-fat diet and obesity-induced behavior alterations and neurobiology dysregulation in the striatum.

YAC128 mouse model of Huntington disease is protected against subtle chronic manganese (Mn)-induced behavioral and neuropathological changes.

Manganese (Mn) is an essential micronutrient but excessive levels induce neurotoxic effects. Increasing evidence suggests a deficit of bioavailable Mn in Huntington disease (HD), an inherited neurodegenerative disease characterized by motor and cognitive disturbances. Previous studies have shown rescue of some molecular HD phenotypes by acute Mn exposure. This study simultaneously examined the potential for chronic Mn exposure to attenuate HD behavioral phenotypes, and for the HD genotype to offer protection against detrimental effects of chronic Mn exposure. In two independent studies a chronic Mn exposure paradigm was implemented in the YAC128 mouse model of HD and behavior was assessed at several timepoints. Study 1 exposed WT and YAC128 mice to twice weekly subcutaneous injections of 0, 5, 15, or 50 mg/kg MnCl[2] tetrahydrate from 12 to 32 weeks of age. A promising protective effect against motor coordination decline in 5 mg/kg MnCl[2] tetrahydrate-treated YAC128 mice was detected. Study 2 thus exposed WT and YAC128 mice to either 0 or 5 mg/kg MnCl[2] tetrahydrate from 12 to 52 weeks of age (with a partial randomized treatment crossover at 31 weeks). The same protective effect was not observed under these conditions at higher statistical power. We report subtle toxicological changes in exploratory behavior and total activity induced by chronic Mn exposure in WT mice only, despite similar total increases in brain Mn in WT and YAC128 mice. Further, chronic Mn treatment resulted in a 10-12 % decrease in striatal NeuN positive cell density in WT mice but not YAC128 mice, despite vehicle cell counts already being reduced compared to WT mice as expected for the HD genotype. The subtle changes observed in specific outcome measures, but not others, following long-term low-level Mn exposure in WT mice delineate the neurobehavioral and neuropathological effects at the threshold of chronic Mn toxicity. We conclude that these chronic low-dose Mn exposures do not significantly rescue behavioral HD phenotypes, but YAC2128 mice are protected against the subtle Mn-induced behavioral changes and decreased striatal neuron density observed in Mn-exposed WT mice.

The influence of sex and strain on trace element dysregulation in the brain due to diet-induced obesity.

BACKGROUND: The objective of this study was to identify interaction effects between diet, sex, and strain on trace element dysregulation and gene expression alterations due to diet-induced obesity (DIO) in the hippocampus, striatum, and midbrain. METHODS: Male and female C57BL/6 J (B6 J) and DBA/2 J (D2 J) mice were fed either a low fat (10 % kcal) diet (LFD) or high fat (60 % kcal) diet (HFD) for 16 weeks, then assessed for trace element concentrations and gene expression patterns in the brain. RESULTS: In the hippocampus, zinc was significantly increased by 48 % in D2 J males but decreased by 44 % in D2 J females, and divalent metal transporter 1 was substantially upregulated in B6 J males due to DIO. In the striatum, iron was significantly elevated in B6 J female mice, and ceruloplasmin was significantly upregulated in D2 J female mice due to DIO. In the midbrain, D2 J males fed a HFD had a 48 % reduction in Cu compared to the LFD group, and D2 J females had a 37 % reduction in Cu compared to the control group. CONCLUSIONS: The alteration of trace element homeostasis and gene expression due to DIO was brain-region dependent and was highly influenced by sex and strain. A significant three-way interaction between diet, sex, and strain was discovered for zinc in the hippocampus (for mice fed a HFD, zinc increased in male D2 Js, decreased in female D2 Js, and had no effect in B6 J mice). A significant diet by sex interaction was observed for iron in the striatum (iron increased only in female mice fed a HFD). A main effect of decreased copper in the midbrain was found for the D2 J strain fed a HFD. These results emphasize the importance of considering sex and genetics as biological factors when investigating potential associations between DIO and neurodegenerative disease.

Diet-Induced Obesity Disrupts Trace Element Homeostasis and Gene Expression in the Olfactory Bulb.

The aim of this study was to determine the impact of diet-induced obesity (DIO) on trace element homeostasis and gene expression in the olfactory bulb and to identify potential interaction effects between diet, sex, and strain. Our study is based on evidence that obesity and olfactory bulb impairments are linked to neurodegenerative processes. Briefly, C57BL/6J (B6J) and DBA/2J (D2J) male and female mice were fed either a low-fat diet or a high-fat diet for 16 weeks. Brain tissue was then evaluated for iron, manganese, copper, and zinc concentrations and mRNA gene expression. There was a statistically significant diet-by-sex interaction for iron and a three-way interaction between diet, sex, and strain for zinc in the olfactory bulb. Obese male B6J mice had a striking 75% increase in iron and a 50% increase in manganese compared with the control. There was an increase in zinc due to DIO in B6J males and D2J females, but a decrease in zinc in B6J females and D2J males. Obese male D2J mice had significantly upregulated mRNA gene expression for divalent metal transporter 1, alpha-synuclein, amyloid precursor protein, dopamine receptor D2, and tyrosine hydroxylase. B6J females with DIO had significantly upregulated brain-derived neurotrophic factor expression. Our results demonstrate that DIO has the potential to disrupt trace element homeostasis and mRNA gene expression in the olfactory bulb, with effects that depend on sex and genetics. We found that DIO led to alterations in iron and manganese predominantly in male B6J mice, and gene expression dysregulation mainly in male D2J mice. These results have important implications for health outcomes related to obesity with possible connections to neurodegenerative disease.

Huntington's disease genotype suppresses global manganese-responsive processes in pre-manifest and manifest YAC128 mice.

Manganese (Mn) is an essential micronutrient required for the proper function of several enzymes. Accumulating evidence demonstrates a selective decrease of bioavailable Mn in vulnerable cell types of Huntington's Disease (HD), an inherited progressive neurodegenerative disorder with no cure. Amelioration of underlying pathophysiology, such as alterations in Mn-dependent biology, may be therapeutic. We therefore sought to investigate global Mn-dependent and Mn-responsive biology following various Mn exposures in a mouse model of HD. YAC128 and wildtype (WT) littermate control mice received one of three different Mn exposure paradigms by subcutaneous injection of 50 mg kg-1 MnCl2·4(H2O) across two distinct HD disease stages. "Pre-manifest" (12-week old mice) mice received either a single (1 injection) or week-long (3 injections) exposure of Mn or vehicle (H2O) and were sacrificed at the pre-manifest stage. "Manifest" (32-week old) mice were sacrificed following either a week-long Mn or vehicle exposure during the manifest stage, or a 20-week-long chronic (2× weekly injections) exposure that began in the pre-manifest stage. Tissue Mn, mRNA, protein, and metabolites were measured in the striatum, the brain region most sensitive to neurodegeneration in HD. Across all Mn exposure paradigms, pre-manifest YAC128 mice exhibited a suppressed response to transcriptional and protein changes and manifest YAC128 mice showed a suppressed metabolic response, despite equivalent elevations in whole striatal Mn. We conclude that YAC128 mice respond differentially to Mn compared to WT as measured by global transcriptional, translational, and metabolomic changes, suggesting an impairment in Mn homeostasis across two different disease stages in YAC128 mice.

Iron and manganese-related CNS toxicity: mechanisms, diagnosis and treatment.

INTRODUCTION: Iron (Fe) and manganese (Mn) are essential nutrients for humans. They act as cofactors for a variety of enzymes. In the central nervous system (CNS), these two metals are involved in diverse neurological activities. Dyshomeostasis may interfere with the critical enzymatic activities, hence altering the neurophysiological status and resulting in neurological diseases. Areas covered: In this review, the authors cover the molecular mechanisms of Fe/Mn-induced toxicity and neurological diseases, as well as the diagnosis and potential treatment. Given that both Fe and Mn are abundant in the earth crust, nutritional deficiency is rare. In this review the authors focus on the neurological disorders associated with Mn and Fe overload. Expert commentary: Oxidative stress and mitochondrial dysfunction are the primary molecular mechanism that mediates Fe/Mn-induced neurotoxicity. Although increased Fe or Mn concentrations have been found in brain of patients, it remains controversial whether the elevated metal amounts are the primary cause or secondary consequence of neurological diseases. Currently, treatments are far from satisfactory, although chelation therapy can significantly decrease brain Fe and Mn levels. Studies to determine the primary cause and establish the molecular mechanism of toxicity may help to adapt more comprehensive and satisfactory treatments in the future.