Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1

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-1alpha. 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-1alpha at specific lysine residues in an NAD(+)-dependent manner. SIRT1 induces gluconeogenic genes and hepatic glucose output through PGC-1alpha, but does not regulate the effects of PGC-1alpha on mitochondrial genes. In addition, SIRT1 modulates the effects of PGC-1alpha 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-1alpha. These findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

“…43 SIRT1 acts as a nutrient sensor and is thought to be a molecular switch relaying the beneficial effects of caloric restriction on a healthy phenotype and longevity. 44 Hence, involvement of SIRT1 in human body weight regulation seems likely.…”

“…56 Gluconeogenic gene expression in liver driven by the best-studied PPAR gamma co-activator family member, PPAR gamma co-activator-1a, is enhanced after deacetylation by sirtuin 1 (SIRT1), a sensor for nutritional status. 44 In a recent publication, KLF5 was identified as a ligand dependant mediator of PPAR repressor activity, by attracting NCOR1 and 2 and co-activation activity through (de)SUMOylation, regulating lipid metabolism in muscle and adipocyte differentiation. 57 Hence, it is tempting to speculate that genetic variations in interacting transcription mediators influence body weight phenotypes through differential expression of nuclear receptor target genes.…”

Nutrition, sirtuins and aging

“…That the NAD + /NADH-ratio can be regulated in a very complex way was shown in the livers of fasted mice where NAD + -levels were increased by fasting and returned to control levels by F F F F Fig. 1 refeeding without significant changes of NADH-levels (Rodgers et al, 2005). Besides changes in energy state associated with altered NAD + -levels, alterations of nicotinamide concentrations are likely to contribute to the physiological regulation of sirtuins.…”

Pathophysiology of the aging kidney and therapeutic interventions

“…78 SIRT1 also deacetylates HIF-2a and has an important role in EPO production, which suggests that SIRT1 may act as a critical modulator of systemic oxygen levels and local oxygen tension. 84 SIRT1 stimulates the activity of the liver-X receptor (LXR) 85 and the farnesoid X receptor (FXR), 86 both of which regulate lipid metabolism. 85,86 SIRT1 activated-LXR and -FXR play preventative roles in the onset and progression of proteinuria and glomerulosclerosis in type 2 diabetes and diet-induced obesity in animal models.…”

“…84 SIRT1 stimulates the activity of the liver-X receptor (LXR) 85 and the farnesoid X receptor (FXR), 86 both of which regulate lipid metabolism. 85,86 SIRT1 activated-LXR and -FXR play preventative roles in the onset and progression of proteinuria and glomerulosclerosis in type 2 diabetes and diet-induced obesity in animal models. [87][88][89][90] Although the beneficial effects of calorie restriction and SIRT1 activation on halting kidney aging and expanding longevity has not yet been reported in humans, the above evidence indicates that calorie restriction and/or SIRT1 activation may provide a potential clue to combat kidney aging.…”