PGC‐1a integrates a metabolism and growth network linked to caloric restriction (original) (raw)
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Proceedings of the National Academy of Sciences of the United States of America, 2012
Calorie restriction (CR) is a dietary intervention that extends lifespan and healthspan in a variety of organisms. CR improves mitochondrial energy production, fuel oxidation, and reactive oxygen species (ROS) scavenging in skeletal muscle and other tissues, and these processes are thought to be critical to the benefits of CR. PGC-1α is a transcriptional coactivator that regulates mitochondrial function and is induced by CR. Consequently, many of the mitochondrial and metabolic benefits of CR are attributed to increased PGC-1α activity. To test this model, we examined the metabolic and mitochondrial response to CR in mice lacking skeletal muscle PGC-1α (MKO). Surprisingly, MKO mice demonstrated a normal improvement in glucose homeostasis in response to CR, indicating that skeletal muscle PGC-1α is dispensable for the whole-body benefits of CR. In contrast, gene expression profiling and electron microscopy (EM) demonstrated that PGC-1α is required for the full CR-induced increases in...
Aging Cell, 2008
There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-γ γ γ γ co-activator 1α α α α (PGC-1α α α α ). We demonstrate that PGC-1α α α α subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1α α α α activity is regulated by glycogen synthase kinase beta (GSK3β β β β ), which targets PGC-1α α α α for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1α α α α activation to be independently controlled. We provide evidence that this pathway of PGC-1α α α α regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2018
Calorie restriction (CR) exerts remarkable, beneficial effects on glucose homeostasis by mechanisms that are not fully understood. Given the relevance of white adipose tissue (WAT) in glucose homeostasis, we aimed at identifying the main cellular processes regulated in WAT in response to CR in a pathologic context of obesity. For this, a gene-expression profiling study was first conducted in mice fed ad libitum or subjected to 40% CR. We found that the gene network related to mitochondria was the most highly upregulated in WAT by CR. To study the role that increased mitochondrial biogenesis plays on glucose homeostasis following CR, we generated a mouse model devoid of the coactivators peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)α and PGC-1β specifically in adipocytes. Our results show that mice lacking PGC-1s in adipocytes are unable to increase mitochondrial biogenesis in WAT upon CR. Despite a blunted induction of mitochondrial biogenesis in response to ...
Aging Cell, 2013
Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR-induced dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation. Furthermore, our data identifies promising pathways for therapeutic targets to combat age-related diseases and promote health in humans.
Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency
Proceedings of the National Academy of Sciences, 2006
Age-related accumulation of cellular damage and death has been linked to oxidative stress. Calorie restriction (CR) is the most robust, nongenetic intervention that increases lifespan and reduces the rate of aging in a variety of species. Mechanisms responsible for the antiaging effects of CR remain uncertain, but reduction of oxidative stress within mitochondria remains a major focus of research. CR is hypothesized to decrease mitochondrial electron flow and proton leaks to attenuate damage caused by reactive oxygen species. We have focused our research on a related, but different, antiaging mechanism of CR. Specifically, using both in vivo and in vitro analyses, we report that CR reduces oxidative stress at the same time that it stimulates the proliferation of mitochondria through a peroxisome proliferation-activated receptor coactivator 1␣ signaling pathway. Moreover, mitochondria under CR conditions show less oxygen consumption, reduce membrane potential, and generate less reactive oxygen species than controls, but remarkably they are able to maintain their critical ATP production. In effect, CR can induce a peroxisome proliferationactivated receptor coactivator 1␣-dependent increase in mitochondria capable of efficient and balanced bioenergetics to reduce oxidative stress and attenuate age-dependent endogenous oxidative damage.
The biochemistry and cell biology of aging: metabolic regulation through mitochondrial signaling
AJP: Endocrinology and Metabolism, 2014
Cellular and organ metabolism affects organismal lifespan. Aging is characterized by increased risks for metabolic disorders, with age-associated degenerative diseases exhibiting varying degrees of mitochondrial dysfunction. The traditional view of the role of mitochondria generated reactive oxygen species (ROS) in cellular aging, assumed to be causative and simply detrimental for a long time now, is in need of reassessment. While there is little doubt that high levels of ROS are detrimental, mounting evidence points toward a lifespan extension effect exerted by mild to moderate ROS elevation. Dietary caloric restriction, inhibition of insulin-like growth factor-I signaling, and inhibition of the nutrient-sensing mechanistic target of rapamycin are robust longevity-promoting interventions. All of these appear to elicit mitochondrial retrograde signaling processes (defined as signaling from the mitochondria to the rest of the cell, for example, the mitochondrial unfolded protein resp...
AJP: Endocrinology and Metabolism, 2014
Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-␥ coactivator-1␣ (Pgc-1␣) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1␣ and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1␣ knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1␣ expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1␣ in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1␣ and Pgc-1 expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1␣ expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1␣ expression and decreased mitochondrial oxidative capacity contribute to worsening glucose tolerance and chronic systemic inflammation associated with aging.
PGC-1α as a Pivotal Factor in Lipid and Metabolic Regulation
International Journal of Molecular Sciences
Traditionally, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), a 91 kDa transcription factor, regulates lipid metabolism and long-chain fatty acid oxidation by upregulating the expression of several genes of the tricarboxylic acid cycle and the mitochondrial fatty acid oxidation pathway. In addition, PGC-1α regulates the expression of mitochondrial genes to control mitochondria DNA replication and cellular oxidative metabolism. Recently, new insights showed that several myokines such as irisin and myostatin are epigenetically regulated by PGC-1α in skeletal muscles, thereby modulating systemic energy balance, with marked expansion of mitochondrial volume density and oxidative capacity in healthy or diseased myocardia. In addition, in our studies evaluating whether PGC-1α overexpression in epicardial adipose tissue can act as a paracrine organ to improve or repair cardiac function, we found that overexpression of hepatic PGC-1α increased hepatic fatty acid oxida...
Transcriptional response to aging and caloric restriction in heart and adipose tissue
Aging Cell, 2007
Sustained caloric restriction (CR) extends lifespan in animal models but the mechanism and primary tissue target(s) have not been identified. Gene expression changes with aging and CR were examined in both heart and white adipose tissue (WAT) of Fischer 344 (F344) male rats using Affymetrix® RAE 230 arrays and validated by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) on 18 genes. As expected, age had a substantial effect on transcription on both tissues, although only 21% of cardiac age-associated genes were also altered in WAT. Gene set enrichment analysis revealed coordinated small magnitude changes in ribosomal, proteasomal, and mitochondrial genes with similarities in aging between heart and WAT. CR had very different effects on these two tissues at the transcriptional level. In heart, very few age-associated expression changes were affected by CR, while in WAT, CR suppressed a substantial subset of the age-associated changes. Genes unaltered by aging but altered by CR were identified in WAT but not heart. Most interestingly, we identified a gene expression signature associated with mammalian target of rapamycin (mTOR) activity that was down-regulated with age but preserved by CR in both WAT and heart. In addition, lipid metabolism genes, particularly those associated with peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ )-mediated adipogenesis were reduced with age but preserved with CR in WAT. These results highlight tissue-specific differences in the gene expression response to CR and support a role for CR-mediated preservation of mTOR activity and adipogenesis in aging WAT.
Diabetes, 2014
This study used mice with muscle-specific overexpression of PGC-1α, a transcriptional co-activator that promotes mitochondrial biogenesis, to determine whether increased oxidative potential facilitates metabolic improvements in response to lifestyle modification. MCK-PGC1α mice and non-transgenic (NT) littermates were fed a high fat diet (HFD) for 10 weeks, followed by stepwise exposures to voluntary wheel running (HFD+Ex) and then 25% caloric restriction with Ex (Ex/CR), each for an additional 10 weeks with continued HFD. Running and CR improved weight and glucose control similarly in MCK-PGC1α and NT mice. Sedentary MCK-PGC1α mice were more susceptible to diet-induced glucose intolerance, and insulin action measured in isolated skeletal muscles remained lower in the transgenic compared to the NT group, even after Ex/CR. Comprehensive profiling of over 200 metabolites and lipid intermediates revealed dramatic group-specific responses to the intervention but did not produce a lead c...