Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Uranga, Romina María; Bruce‐Keller, Annadora J.; Morrison, Christopher D.; Fernandez-Kim, Sun Ok; Ebenezer, Philip J.; Zhang, Le; Dasuri, Kalavathi; Keller, Jeffrey N.

doi:10.1111/j.1471-4159.2010.06803.x

Cited by 77 publications

(64 citation statements)

References 305 publications

(254 reference statements)

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“…Studies from our laboratory and others' have demonstrated that HFDs exacerbate tissue dysfunction in aging animals (11,29,46,68,76). Additionally, studies from our laboratory and others' have shown that HFDs promote much greater amounts of adipose gain, and presumably adipose tissue dysfunction, compared with younger animals (46,50,66). These data point to important, and as yet unknown, interactions between obesity and aging.…”

Section: Discussionmentioning

confidence: 67%

“…Because of the potential for age-related changes in adipose function to modulate overall health and promote metabolic disease, there is a growing interest in studying aging adipose tissue. White adipose tissue is recognized as an important modulator of multiple physiological processes and is strongly linked to the development of multiple morbidities (8,16,46,66,76). The ability of adipose tissue to exert these effects comes from alterations in the endocrine functions of adipose (22,52,71) as well as the contributions of adipose tissue to glucose and lipid homeostasis (10,26,37,75).…”

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confidence: 99%

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Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Zhang

Ebenezer

Dasuri

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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As a part of aging there are known to be numerous alterations which occur in multiple tissues of the body, and the focus of this study was to determine the extent to which oxidative stress and hypoxia occur during adipose tissue aging. In our studies we demonstrate for the first time that aging is associated with both hypoxia (38% reduction in oxygen levels, Po2 21.7 mmHg) and increases reactive oxygen species in visceral fat depots of aging male C57Bl/6 mice. Interestingly, aging visceral fat depots were observed to have significantly less change in the expression of genes involved in redox regulation compared with aging subcutaneous fat tissue. Exposure of 3T3-L1 adipocytes to the levels of hypoxia observed in aging adipose tissue was sufficient to alter multiple aspects of adipose biology inducing increased levels of in insulin-stimulated glucose uptake and decreased lipid content. Taken together, these data demonstrate that hypoxia and increased levels of reactive oxygen species occur in aging adipose tissue, highlighting the potential for these two stressors as potential modulators of adipose dysfunction during aging.

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Section: Discussionmentioning

confidence: 67%

mentioning

confidence: 99%

Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Zhang

Ebenezer

Dasuri

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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“…Increased inflammatory signaling, adipokine levels, oxidative or nitrostative stress, mitochondrial dysfunction, and lipid metabolism have all been shown to occur with HF feeding (13,27, reviewed in Ref. 52). Some of these peripheral effects, such as oxidative stress, also occur in the brain following HF feeding (21,40,58), and HF feeding increases cognitive impairment, tau deposition, MPTP vulnerability, and inflammation in the brain (15,38,44,45).…”

Section: Discussionmentioning

confidence: 99%

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

Morris

Bomhoff

Stanford

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

127

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(PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-fat diet for 5 wk before infusing 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. Our goal was to determine whether a high-fat diet and the resulting peripheral insulin resistance would exacerbate 6-OHDA-induced nigrostriatal DA depletion. Prior to 6-OHDA infusion, animals on the high-fat diet exhibited greater body weight, increased adiposity, and impaired glucose tolerance. Two weeks after 6-OHDA, locomotor activity was tested, and brain and muscle tissue was harvested. Locomotor activity did not differ between the groups nor did cholesterol levels or measures of muscle atrophy. High-fat-fed animals exhibited higher homeostatic model assessment of insulin resistance (HOMA-IR) values and attenuated insulin-stimulated glucose uptake in fast-twitch muscle, indicating decreased insulin sensitivity. Animals in the high-fat group also exhibited greater DA depletion in the substantia nigra and the striatum, which correlated with HOMA-IR and adiposity. Decreased phosphorylation of HSP27 and degradation of IB␣ in the substantia nigra indicate increased tissue oxidative stress. These findings support the hypothesis that a diet high in fat and the resulting insulin resistance may lower the threshold for developing PD, at least following DA-specific toxin exposure. dopamine; diabetes; substantia nigra; striatum; insulin resistance CLINICAL STUDIES SUGGEST A LINK between type 2 diabetes (T2D) and Parkinson's disease (PD) (30,46), and between fat intake or adiposity and PD (1, 31, 34). Moreover, it was reported over 40 years ago that greater than 50% of PD patients exhibit abnormal glucose tolerance (4, 10) or diabetes (36). Despite this information, very little is known regarding the relationship of these diseases and the impact of comorbidity on their pathogenesis. By 2025, T2D is estimated to impact 300 million individuals (47), with the elderly at greatest risk (54), the population also at greatest risk for neurodegenerative diseases like PD. For these reasons, understanding the potential for T2D, obesity, high dietary fat intake, and insulin resistance to contribute to PD is critical. Although the exact cause of PD is unknown, various environmental factors such as aging, diet, and environmental toxin exposure have been implicated in contributing to its development (29, 34, 51). The idea that "multiple hits" play a role in PD degeneration is supported by the fact that 80% of dopamine (DA)-producing neurons must be lost for symptoms to appear (50). While diabetes and PD do not invariably coincide, several studies suggest that obesity may potentiate neuronal dysfunction or even neurodegeneration (reviewed in Ref. 11). High-f...

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“…3,4 In addition metabolic disorders, such as dyslipidaemia and hyperinsulinaemia, increase with age. 5 Thus, when investigating the metabolic impact of dietary or other interventions using experimental animal models, it is essential to take into consideration the age of the animals in order to interpret the results. 6 The aim of this study was to test the impact of age on the changes in lipid and glucose homeostasis in young and middle-aged mice receiving a high-fat diet (HFD).…”

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confidence: 99%

The effect of biological age on the metabolic responsiveness of mice fed a high-fat diet

et al. 2013

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Mice are widely used in studies investigating the effect of diet on metabolic risk factors, such as lipid profiles and plasma glucose levels. An important factor that is usually not taken into account is the biological age of the experimental models. The up-to-date identified experimental confounders do not cover all the parameters that may affect the results of animal studies. The aim of this study was to investigate the effects of a high-fat diet on the metabolic profile, hepatic and renal function in mice of differing ages. For this purpose two groups of male C57BL/6J mice were used, consisting of 10-week-old mice and 54-week-old mice in each group. Both groups followed identical high-fat diets for 12 weeks. The younger mice showed smaller increases in body weight, serum total cholesterol, glucose and urea levels while they had higher increases in high-density lipoprotein cholesterol levels than the older mice. Our results indicate the necessity to consider an experimental animal's age as a confounding factor when researching or interpreting metabolic studies. Age adjustment is warranted in all animal research while a uniform approach regarding the age of the animal models should be applied in experimental studies.

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Intersection between metabolic dysfunction, high fat diet consumption, and brain aging

Cited by 77 publications

References 305 publications

Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Aging is associated with hypoxia and oxidative stress in adipose tissue: implications for adipose function

Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

The effect of biological age on the metabolic responsiveness of mice fed a high-fat diet

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