Genetic influences on glucose neurotoxicity, aging, and diabetes: A possible role for glucose hysteresis

Mobbs, Charles V.

doi:10.1007/bf01436001

Cited by 17 publications

(15 citation statements)

References 84 publications

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“…2A). A similar hypothesis has been proposed to explain the age-related decrease in insulin sensitivity (54). The desensitization hypothesis is appealing because leptin is a major signal that conveys to the hypothalamus the extent of adipose stores (49).…”

Section: Why Does Obesity Increase With Age?mentioning

confidence: 81%

Obesity Over the Life Course

Mizuno

Shu²,

Makimura³

et al. 2004

Sci. Aging Knowl. Environ.

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Obesity in middle-aged humans is a risk factor for many age-related diseases and decreases life expectancy by about 7 years, which is roughly comparable to the combined effect of all cardiovascular disease and cancer on life span. The prevalence of obesity increases up until late middle age and decreases thereafter. Mechanisms that lead to increased obesity with age are not yet well understood, but current evidence implicates impairments in hypothalamic function, especially impairments in the ability of hypothalamic pro-opiomelanocortin neurons to sense nutritional signals. The rapid increase in the prevalence of obesity at all ages in the past decade suggests that, in the next two or three decades, diseases associated with obesity, especially diabetes, will begin to rise rapidly. Indeed, these trends suggest that for the first time in modern history, the life expectancy of people in developed societies will begin to decrease, unless the rapid increase in the prevalence of obesity can be reversed.

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Section: Why Does Obesity Increase With Age?mentioning

confidence: 81%

Obesity Over the Life Course

Mizuno

Shu²,

Makimura³

et al. 2004

Sci. Aging Knowl. Environ.

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“…( 7 )]. Based on the transcriptional hysteresis of estradiol-regulated genes, it was hypothesized that a similar phenomenon might drive the process of aging ( 6 , 8 ). Initially, it was not obvious how transcriptional hysteresis would drive the process of aging or mechanisms of DR since in contrast to hysteresis in estrogen-regulated genes that drive age-related reproductive impairment, the relevant molecule in aging was not obvious.…”

Section: Transcriptional Hysteresis In Glucose-regulated Genesmentioning

confidence: 99%

“…Other examples of persistent effects on gene expression include those produced by estrogen ( 2 , 3 ). These effects plausibly lead to age-related impairments in female reproductive function due to cumulative and persistent effects of estradiol on neuroendocrine function ( 4 – 6 ).…”

Section: Introductionmentioning

confidence: 99%

Glucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging

Mobbs

2018

Front. Endocrinol.

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During differentiation transient, inducers produce permanent changes in gene expression. A similar phenomenon, transcriptional hysteresis, produced by transient or prolonged exposure to glucose, leads to cumulative, persistent, and largely irreversible effects on glucose-regulated gene expression, and may drive key aspects of metabolic memory, obesity, diabetes, and aging, and explain the protective effects of dietary restriction during aging. The most relevant effects of glucose-induced transcriptional hysteresis are the persistent effects of elevated glucose on genes that control glucose metabolism itself. A key observation is that, as with the lac operon, glucose induces genes that promote glycolysis and inhibits gene expression of alternative metabolic pathways including the pentose pathway, beta oxidation, and the TCA cycle. A similar pattern of metabolic gene expression is observed during aging, suggesting that cumulative exposure to glucose during aging produces this metabolic shift. Conversely, dietary restriction, which increases lifespan and delays age-related impairments, produces the opposite metabolic profile, leading to a shift away from glycolysis and toward the use of alternative substrates, including lipid and ketone metabolisms. The effect of glucose on gene expression leads to a positive feedback loop that leads to metastable persistent expression of genes that promote glycolysis and inhibit alternative pathways, a phenomenon first observed in the regulation of the lac operon. On the other hand, this pattern of gene expression can also be inhibited by activation of peroxisome proliferator activating receptor transcription factors that promote beta oxidation and inhibit metabolism of glucose-derived carbon bonds in the TCA cycle. Several pathological consequences may arise from glucose-induced transcriptional hysteresis. First, elevated glucose induces glycolytic genes in pancreatic beta cells, which induces a semi-stable persistent increase in insulin secretion, which could drive obesity and insulin resistance, and also due to glucose toxicity could eventually lead to beta-cell decompensation and diabetes. Diabetic complications persist even after complete normalization of glucose, a phenomenon known as metabolic memory. This too can be explained by persistent bistable expression of glucose-induced glycolytic genes.

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“…Therefore at 3 mV, the trigger will be either on or off, depending on the history of the circuit. Although not as widely appreciated, gene expression also exhibits hysteresis, also sometimes called 'gene memory' or 'priming' [12][13][14][15][16]. For example, the first time the ovalbumin gene is exposed to estrogen the induction is sluggish and subtle, but subsequent exposures to estrogen produce much more rapid and robust inductions, a phenomenon associated with permanent changes in chromatin structure produced by the initial exposure to estrogen [17].…”

Section: Metabolic Regulation Of Gene Expression Exhibits Hysteresismentioning

confidence: 99%

“…A guiding hypothesis for our research program for almost 20 years has been that longevity is governed in part by a cumulative toxic effect of glucose, particularly on glucose-sensitive neuroendocrine cells in the hypothalamus and pancreas, a phenomenon we referred to as glucose hysteresis [13,14]. Similarly Masoro et al [1] proposed the hypothesis that 'dietary restriction retards the aging processes by altering the characteristics of (glucose) fuel use'.…”

Section: Potential Cumulative Toxic Effect Of Glucose On Neuroendocrimentioning

confidence: 99%

Secrets of the lac Operon

Mobbs¹,

Mastaitis²,

Zhang³

et al. 2006

Interdisciplinary Topics in Gerontology

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Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in ␤-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

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Genetic influences on glucose neurotoxicity, aging, and diabetes: A possible role for glucose hysteresis

Cited by 17 publications

References 84 publications

Obesity Over the Life Course

Obesity Over the Life Course

Glucose-Induced Transcriptional Hysteresis: Role in Obesity, Metabolic Memory, Diabetes, and Aging

Secrets of the lac Operon

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