Biology subjects

Salinero, A. E.

Publications and source records attributed to Salinero, A. E..

5 recordsLinked to original sources

bioRxiv2024

Effects of High Fat Diet on Metabolic Health Vary by Age of Menopause Onset

Menopause accelerates metabolic dysfunction, including (pre-)diabetes, obesity and visceral adiposity. However, the effects of endocrine vs. chronological aging in this progression are poorly understood. We hypothesize that menopause, especially in the context of middle-age, will exacerbate the metabolic effects of a high fat diet. Using young-adult and middle-aged C57BL/6J female mice, we modeled diet-induce obesity via chronic administration of high fat (HF) diet vs. control diet. We modeled peri-menopause/menopause via injections of 4-vinylcyclohexene diepoxide, which accelerates ovarian failure vs. vehicle. We performed glucose tolerance tests 2.5 and 7 months after diet onset, during the peri-menopausal and menopausal phases, respectively. Peri-menopause increased the severity of glucose intolerance and weight gain in middle-aged, HF-fed mice. Menopause increased weight gain in all mice regardless of age and diet, while chronological aging drove changes in adipose tissue distribution towards more visceral vs. subcutaneous adiposity. These data are in line with clinical data showing that post-menopausal women are more susceptible to metabolic dysfunction and suggest that greater chorological age exacerbates the effects of endocrine aging (menopause). This work highlights the importance of considering both chronological and endocrine aging in studies of metabolic health.

neuroscience↗

bioRxiv2023

Effects of menopause and high fat diet on metabolic outcomes in a mouse model of Alzheimer's disease.

About two-thirds of those with Alzheimers disease (AD) are women, most of whom are post-menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of Alzheimers disease. To model menopause, we used an accelerated ovarian failure model (4-vinylcyclohexene diepoxide, VCD). This ovary-intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL-F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). Some metabolic effects of menopause may be centrally mediated, as menopause altered the expression of hypothalamic genes related to energy balance and increased microgliosis in the lateral hypothalamic nucleus. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. HighlightsO_LIIn a mouse model of AD, menopause, modeled by accelerated ovarian failure, leads to metabolic impairment. C_LIO_LIMenopause has independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). C_LIO_LIMenopause alters the expression of hypothalamic energy balance related genes. C_LIO_LIMenopause leads to increased microgliosis in the lateral hypothalamic nucleus. C_LI

neuroscience↗

bioRxiv2023

Brain Specific Estrogen Ameliorates Cognitive Effects of Surgical Menopause in Mice

Menopause is a major endocrinological shift that leads to an increased vulnerability to the risk factors for cognitive impairment and dementia. This is thought to be due to the loss of circulating estrogens, which exert many potent neuroprotective effects in the brain. Systemic replacement of estrogen post-menopause has many limitations, including increased risk for estrogen-sensitive cancers. A more promising therapeutic approach therefore might be to deliver estrogen only to the brain thus limiting adverse peripheral side effects. We examined whether we could enhance cognitive performance by delivering estrogen exclusively to the brain in post-menopausal mice. We modeled surgical menopause via bilateral ovariectomy (OVX). We treated mice with the pro-drug 10{beta},17{beta}-dihydroxyestra-1,4-dien-3-one (DHED), which can be administered systemically but is converted to 17{beta}-estradiol only in the brain. Young (2.5-month) and middle-aged (11-month-old) female C57BL/6J mice received ovariectomy and a subcutaneous implant containing vehicle (cholesterol) or DHED. At 3.5 months old (young group) and 14.5 months old (middle-aged group), mice underwent behavior testing to assess memory. DHED did not significantly alter metabolic status in middle-aged, post-menopausal mice. In both young and middle-aged mice, the brain-specific estrogen DHED improved spatial memory. Additional testing in middle-aged mice also showed that DHED improved working and recognition memory. These promising results lay the foundation for future studies aimed at determining if this intervention is as efficacious in models of dementia that have comorbid risk factors.

neuroscience↗

bioRxiv2021

High fat diet exacerbates cognitive decline in mouse models of Alzheimer's disease and mixed dementia in a sex-dependent manner.

Approximately 70% of Alzheimers disease (AD) patients have co-morbid vascular contributions to cognitive impairment and dementia (VCID); this highly prevalent overlap of dementia subtypes is known as mixed dementia (MxD). AD is more prevalent in women, while VCID is slightly more prevalent in men. Sex differences in risk factors may contribute to sex differences in dementia subtypes. Unlike metabolically healthy women, diabetic women are more likely to develop VCID than diabetic men. Prediabetes is 3x more prevalent than diabetes and is linked to earlier onset of dementia in women, but not men. How prediabetes influences underlying pathology and cognitive outcomes across different dementia subtypes is unknown. To fill this gap in knowledge, we investigated the impact of diet-induced prediabetes and biological sex on cognitive function and neuropathology in mouse models of AD and MxD. Male and female 3xTg-AD mice received a sham (AD model) or unilateral common carotid artery occlusion surgery to induce chronic cerebral hypoperfusion (MxD model). Mice were fed a control or high fat (HF; 60% fat) diet for 3 months prior to behavior assessment. In both sexes, HF diet elicited a prediabetic phenotype (impaired glucose tolerance) and weight gain. In females, but not males, metabolic consequences of a HF diet were more severe in AD or MxD mice compared to WT. In both sexes, HF-fed AD or MxD mice displayed deficits in spatial memory in the Morris water maze (MWM). In females, but not males, HF-fed AD and MxD mice also displayed impaired spatial learning in the MWM. In females, but not males, AD or MxD caused deficits in activities of daily living, regardless of diet. Astrogliosis was more severe in AD and MxD females compared to males. Further, HF diet caused greater accumulation of amyloid beta in MxD females compared to MxD males. In females, but not males, more severe glucose intolerance (prediabetes) was correlated with increased hippocampal microgliosis. In conclusion, high fat diet had a wider array of metabolic, cognitive, and neuropathological consequences in AD and MxD females compared to males. These findings shed light on potential underlying mechanisms by which prediabetes may lead to earlier dementia onset in women. HighlightsO_LICreated a mouse model of mixed dementia (MxD) with both AD + VCID pathology. C_LIO_LIHF diet caused greater metabolic impairment in AD and MxD females, compared to males. C_LIO_LIAD and MxD females showed a wider array of cognitive deficits, compared to males. C_LIO_LIAstrogliosis and A{beta} pathology were more severe in AD/MxD females, compared to males. C_LIO_LIMetabolic impairment was more consistently associated with reductions in cognitive function in females. C_LIO_LIMore severe glucose intolerance was associated with worse microgliosis in females only. C_LI

neuroscience↗

bioRxiv2020

Role of sex and high fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer's disease

Hypothalamic dysfunction occurs early in the clinical course of Alzheimers disease (AD), likely contributing to disturbances in feeding behavior and metabolic function that are often observable years prior to the onset of cognitive symptoms. Late-life weight loss and low BMI are associated with increased risk of dementia and faster progression of disease. However, high fat diet and metabolic disease (e.g. obesity, type 2 diabetes), particularly in mid-life, are associated with increased risk of AD, as well as exacerbated AD pathology and behavioral deficits in animal models. In the current study, we explored possible relationships between hypothalamic function, diet/metabolic status, and AD. Considering the sex bias in AD, with women representing two-thirds of AD patients, we sought to determine whether these relationships vary by sex. WT and 3xTg-AD male and female mice were fed a control (10% fat) or high fat (HF; 60% diet) diet from ~3-7 months of age, then tested for metabolic and hypothalamic disturbances. On control diet, male 3xTg-AD mice displayed decreased body weight, reduced fat mass, hypoleptinemia, and mild systemic inflammation, as well as increased expression of gliosis- and inflammation-related genes in the hypothalamus (Iba1, GFAP, TNF-, IL-1{beta}). In contrast, female 3xTg-AD mice on control diet displayed metabolic disturbances opposite that of 3xTg-AD males (increased body and fat mass, impaired glucose tolerance). HF diet resulted in expected metabolic alterations across groups (increased body and fat mass; glucose intolerance; increased plasma insulin and leptin, decreased ghrelin; nonalcoholic fatty liver disease-related pathology). HF diet resulted in the greatest weight gain, adiposity, and glucose intolerance in 3xTg-AD females, which were associated with markedly increased hypothalamic expression of GFAP and IL-1{beta}, as well as GFAP labeling in several hypothalamic nuclei that regulate energy balance. In contrast, HF diet increased diabetes markers and systemic inflammation preferentially in AD males but did not exacerbate hypothalamic inflammation in this group. These findings provide further evidence for the roles of hypothalamic and metabolic dysfunction in AD, which in the 3xTg-AD mouse model appears to be dependent on both sex and diet.

neuroscience↗