Coordinate expression of the PDK4 gene: a means of regulating fuel selection in a hibernating mammal

Buck, Michael; Squire, Teresa L.; Andrews, Matthew T.

doi:10.1152/physiolgenomics.00076.2001

Cited by 142 publications

(136 citation statements)

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“…PDK4 inhibits pyruvate dehydrogenase and thus minimizes carbohydrate oxidation by preventing the flow of glycolytic products into the tricarboxylic acid cycle (44). We observed a dramatic down-regulation (8.5 fold) of PDK4, suggesting a metabolic shift toward glycolysis in the aging heart.…”

Section: Aging Results In a Transcriptional Shift Toward Carbohydratementioning

confidence: 67%

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Lee

Allison

Brand

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

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To provide a global analysis of gene expression in the aging heart, we monitored the expression of 9,977 genes simultaneously in 5-and 30-month-old male B6C3F1 mice by using high-density oligonucleotide microarrays and several statistical techniques. Aging was associated with transcriptional alterations consistent with a metabolic shift from fatty acid to carbohydrate metabolism, increased expression of extracellular matrix genes, and reduced protein synthesis. Caloric restriction (CR) started at 14 months of age resulted in a 19% global inhibition of age-related changes in gene expression. Interestingly, CR also resulted in alterations in gene expression consistent with preserved fatty acid metabolism, reduced endogenous DNA damage, decreased innate immune activity, apoptosis modulation, and a marked cytoskeletal reorganization. These observations provide evidence that aging of the heart is associated with specific transcriptional alterations, and that CR initiated in middle age may retard heart aging by inducing a profound transcriptional reprogramming.W hen started either early in life or at middle age, caloric restriction (CR) increases average and maximum lifespan, and reduces the incidence and delays the onset of spontaneous cancers and several other age-related diseases (1). Additionally, CR reduces the age-associated increase in reactive oxygen species (ROS)-induced molecular damage (2-5). Previously, we have used high-density oligonucleotide arrays to define aging and CR-related transcriptional alterations in mouse skeletal muscle (6) and brain (7). These reports provided evidence for an age-associated stress response characterized by the induction of heat-shock factors and other oxidative stress-induced transcripts. CR prevented these age-related alterations completely or partially. Both studies provided further support for the concept that oxidative stress may be an important, and perhaps underlying cause of the aging process of postmitotic tissues.The cardiac myocyte is the most energy demanding cell in the body, contracting constantly, 3 billion times or more in the average human lifespan (8), requiring large supplies of high-energy phosphates (9). Age-related changes in human and rodent hearts include a reduction in the number of myocytes (10, 11), myocyte hypertrophy (11, 12), cardiac fibrosis (13), lipofuscin pigment accumulation (14), a reduction in calcium transport across sarcoplasmic reticulum membrane (15), and alterations in the response to ␤-adrenergic stimulation (16). Collectively, these alterations likely contribute to age-related heart diseases being the leading cause of mortality in the U.S. (17). CR reduces the severity of spontaneous cardiomyopathy in male Sprague-Dawley rats (18) and prevents age-associated alterations in late diastolic function in B6D2F 1 mice (19). At the molecular level, CR reduces the concentration of both 8-hydroxydeoxyguanosine in DNA (20) and dityrosine cross-linking of proteins (21) in the heart of aging mice, and prevents somatic mitochondrial genomic rear...

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Section: Aging Results In a Transcriptional Shift Toward Carbohydratementioning

confidence: 67%

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Lee

Allison

Brand

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

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“…Both genetics and proteomics will be key to a full understanding of this association. Genes in the human have been identified that are homologous to hibernation genes in true hibernating animals [23,49]. It will be intriguing to find out whether manipulation of this group of genes holds the key to the prevention of both type 2 diabetes and cardiovascular disease in man.…”

Section: Discussionmentioning

confidence: 99%

“…During the longer summer days, pineal melatonin secretion is suppressed [21] and food intake maximised, leading to fat loading of the adipocyte in anticipation of winter. This leads to suppression of the phosphatidylinositol 3-kinase/protein kinase B insulin signalling pathway [22,23] and the development of insulin resistance [24]. This is associated with hyperleptinaemia and suppression of adiponectin [25] together with a proinflammatory [26,27] and prothrombotic phenotype [28] as the mammal enters winter.…”

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

“…One might hypothesise that, in the seasonal animal, the suppression of adiponectin and increased leptin secretion are co-ordinated to develop insulin resistance and suppress appetite as food availability diminishes. During long winter nights, melatonin secretion is increased, enhancing adipocyte insulin sensitivity and energy availability whilst the animal is dormant [23,29], leading to an animal that is lean and insulin sensitive once more on re-awakening in spring [23,24]. The seasonally responsive mammal cycles obesity and insulin resistance in response to food availability and photoperiod to generate energy conservation.…”

Section: Seasonal and Circadian Responses In Mammalsmentioning

confidence: 99%

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Neel revisited: the adipocyte, seasonality and type 2 diabetes

Scott

Grant

2006

Diabetologia

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The modern epidemic of obesity and insulin resistance with cardiovascular risk factor clustering is related to the development of type 2 diabetes and cardiovascular disease. Over 40 years ago, Neel postulated that insulin resistance should confer survival benefit. Extrapolating Neel's hypothesis, we propose that the cluster of associated abnormalities also confers survival benefit and is related to metabolic responses seen in seasonally responsive animals. Weight gain in preparation for winter is accompanied by a range of acute metabolic changes virtually identical to the long-term changes seen in type 2 diabetes. In seasonal animals the responses are acute, physiological and protective. In man, similar responses that would once have conferred survival benefit have become chronic, pathological and harmful in modern life. We hypothesise that type 2 diabetes and cardiovascular disease in man are the result of chronic and inappropriate pinealhypothalamic-adipocyte interactions biologically related to seasonal change.Keywords Adipocyte . Cardiovascular disease . Circadian and circannual rhythm . Clock genes . Hypothalamus . Inflammation . Insulin resistance . Melatonin . Metabolic syndrome . Seasonality . Type 2 diabetes Neel revisitedThe world is currently in the midst of an epidemic of type 2 diabetes, and around 300 million individuals are predicted to develop this disorder by the year 2025 [1]. The close biological relationship between diabetes and cardiovascular disease has focused attention on the common genetic and environmental antecedents of these conditions-the common soil hypothesis [2]-but the pathophysiological basis of these associations remains obscure. In 1962, Neel proposed the thrifty genotype hypothesis, which postulated that insulin overproduction must at one time have had a beneficial effect, in that it would provide 'an important energy conserving mechanism when food intake was irregular and obesity rare' [3]. Although Neel recognised insulin antagonism rather than insulin resistance, he hypothesised that the combination of obesity with increased insulin (or the presence of insulin antagonists) would lead to the development of diabetes. With hindsight, Neel was essentially speculating on the potential metabolic benefits of insulin resistance. The recognition in the last 20 years of an insulin resistance risk cluster [4] indicates that, under certain circumstances, elements of the risk cluster should also be beneficial to the survival of the organism, a response that, by analogy with Neel's original hypothesis, may coincidentally lead to the development of cardiovascular disease in times of plenty. The development of both insulin resistance and inflammation are physiological responses to increasing adiposity that, by definition, should be beneficial to the survival of the organism. The observation that the chronic metabolic milieu associated with type 2 diabetes is harmful raises the possibility that the adipocyte response to fat loading is beneficial when acute and short-lived, as is o...

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“…A candidate for substance A is the enzyme pyruvate dehydrogenase kinase 4 (PDK4) (Andrews, 2004) and therefore candidate B is the pyruvate dehydrogenase (PDH) complex. We have shown that levels of PDK4 mRNA and protein increase at the onset of hibernation in heart, skeletal muscle and white adipose tissue of thirteen-lined ground squirrels (Buck et al, 2002). Regulated long-term inhibition of PDH activity is the result of phosphorylation of the PDH complex (conversion of substance B to B p ) by the activity of various isoenzymes of the PDK family (substance A).…”

Section: Discussionmentioning

confidence: 99%

A simple molecular mathematical model of mammalian hibernation

Hampton

Andrews

2007

Journal of Theoretical Biology

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A simple model of the dynamics of the body temperature of a hibernating mammal is presented. Our model provides a good match to experimental data, showing the interruption of lowtemperature torpor bouts with periodic interbout arousals (IBAs). In this paper we present a mathematical model of the molecules that participate in the initiation, regulation and maintenance of the hibernating state. This model can be used to describe the role of regulatory molecules, signal transducers, downstream target enzymes, structural proteins or metabolites. Because many of the biochemical mechanisms are unknown, this is a preliminary and largely phenomenological model that we hope will inspire further investigation.

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Coordinate expression of the PDK4 gene: a means of regulating fuel selection in a hibernating mammal

Cited by 142 publications

References 31 publications

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Neel revisited: the adipocyte, seasonality and type 2 diabetes

A simple molecular mathematical model of mammalian hibernation

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