Abstract
Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1-which modulates ageing in several species-controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1α at specific lysine residues in an NAD +-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 113-118 |
| Number of pages | 6 |
| Journal | Nature |
| Volume | 434 |
| Issue number | 7029 |
| DOIs | |
| State | Published - Mar 3 2005 |
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Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. / Rodgers, Joseph T.; Lerin, Carlos; Haas, Wilhelm; Gygi, Steven P.; Spiegelman, Bruce M.; Puigserver, Pere.
In: Nature, Vol. 434, No. 7029, 03.03.2005, p. 113-118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1
AU - Rodgers, Joseph T.
AU - Lerin, Carlos
AU - Haas, Wilhelm
AU - Gygi, Steven P.
AU - Spiegelman, Bruce M.
AU - Puigserver, Pere
PY - 2005/3/3
Y1 - 2005/3/3
N2 - Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1-which modulates ageing in several species-controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1α at specific lysine residues in an NAD +-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
AB - Homeostatic mechanisms in mammals respond to hormones and nutrients to maintain blood glucose levels within a narrow range. Caloric restriction causes many changes in glucose metabolism and extends lifespan; however, how this metabolism is connected to the ageing process is largely unknown. We show here that the Sir2 homologue, SIRT1-which modulates ageing in several species-controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α. A nutrient signalling response that is mediated by pyruvate induces SIRT1 protein in liver during fasting. We find that once SIRT1 is induced, it interacts with and deacetylates PGC-1α at specific lysine residues in an NAD +-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1α, but does not regulate the effects of PGC-1α on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1α repression of glycolytic genes in response to fasting and pyruvate. Thus, we have identified a molecular mechanism whereby SIRT1 functions in glucose homeostasis as a modulator of PGC-1α. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.
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UR - http://www.scopus.com/inward/citedby.url?scp=14544282413&partnerID=8YFLogxK
U2 - 10.1038/nature03354
DO - 10.1038/nature03354
M3 - Article
C2 - 15744310
AN - SCOPUS:14544282413
VL - 434
SP - 113
EP - 118
JO - Nature
JF - Nature
SN - 0028-0836
IS - 7029
ER -