Resveratrol stimulates AMP kinase activity in neurons

Abstract

Resveratrol is a polyphenol produced by plants that has multiple beneficial activities similar to those associated with caloric restriction (CR), such as increased life span and delay in the onset of diseases associated with aging. CR improves neuronal health, and the global beneficial effects of CR have been postulated to be mediated by the nervous system. One key enzyme thought to be activated during CR is the AMP-activated kinase (AMPK), a sensor of cellular energy levels. AMPK is activated by increases in the cellular AMP:ATP ratio, whereupon it functions to help preserve cellular energy. In this regard, the regulation of dietary food intake by hypothalamic neurons is mediated by AMPK. The suppression of nonessential energy expenditure by activated AMPK along with the CR mimetic and neuroprotective properties of resveratrol led us to hypothesize that neuronal activation of AMPK could be an important component of resveratrol activity. Here, we show that resveratrol activated AMPK in Neuro2a cells and primary neurons in vitro as well as in the brain. Resveratrol and the AMPK-activating compound 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR) promoted robust neurite outgrowth in Neuro2a cells, which was blocked by genetic and pharmacologic inhibition of AMPK. Resveratrol also stimulated mitochondrial biogenesis in an AMPK-dependent manner. Resveratrol-stimulated AMPK activity in neurons depended on LKB1 activity but did not require the NAD-dependent protein deacetylase SIRT1 during this time frame. These findings suggest that neuronal activation of AMPK by resveratrol could affect neuronal energy homeostasis and contribute to the neuroprotective effects of resveratrol.caloric restriction ͉ neuronal energy ͉ neuronal protection

Low Sirt1 expression, which is upregulated by fasting, in human adipose tissue from obese women

“…4 Sirt1 is also associated with another intracellular nutrient-sensing pathway, the AMPactivated protein kinase (AMPK enzyme). 13 AMPK plays important roles for the increased insulin sensitivity caused by exercise. 14 Until now, no reports on this system have been described in human adipose tissue, and therefore, we wanted, in this initial study, to report whether human adipose tissue expresses Sirt1 mRNA in any significant amount and whether this amount can be modulated by stimuli previously reported to change Sirt1 expression in rodents.…”

Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats

“…Its cardiovascular properties, including inhibition of platelet aggregation and promotion of vasodilation by enhancing the production of NO [19] have also been described [15,20] and recent studies have reported its beneficial effects against ageing and metabolic diseases [21][22][23][24]. Resveratrol has been described as a potent activator of AMPK in several tissues and cell lines, i.e, HepG2 [24], C2C12 myotubes [25] neuronal cell lines and neurons [26].…”

Proenergetic effects of resveratrol in the murine neuronal cell line Neuro2a

“…Numerous studies in the literature also reported resveratrol protected cells from mitochondrial dysfunction [45][46][47]. Interestingly, resveratrol was found to increase the number of mitochondria in various cell lines and tissues, such as in Neuro2a cells [28], endothelial cells [56] and muscle [45]. In cultured human coronary arterial endothelial cells, resveratrol up-regulated protein expression of electron transport chain components, enhanced mitochondrial DNA content and mitochondrial mass, activated mitochondrial biogenesis factors (peroxisome proliferator-activated receptor- coactivator-1α PGC-1α, nuclear respiratory factor-1 NRF-1, mitochondrial transcription factor-A mtTF-A) [56].…”

“…In neurons, however, resveratrol stimulated mitochondrial biogenesis in an AMPK-dependent manner through its upstream LKB1 pathway, but independent of SIRT1 [28]. AMPK activation facilitates not only the generation of new mitochondria, but also the destruction of defective mitochondria [57].…”

“…Resveratrol has been found to activate AMPK in neuroblastoma cells and primary neurons in vitro as well as in the brain by activating calcium/CaMKKβ/AMPK signaling pathways [28,29].…”