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Mediobasal hypothalamic SIRT1 is essential for resveratrol's effects on insulin action in rats.

Knight CM, Gutierrez-Juarez R, Lam TK, Arrieta-Cruz I, Huang L, Schwartz G, Barzilai N, Rossetti L - Diabetes (2011)

Bottom Line: Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production.Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production.In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Diabetes Research Center, Albert EinsteinCollege of Medicine, Bronx, New York, USA. colette.knight@einstein.yu.edu

ABSTRACT

Objective: Sirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.

Research design and methods: Sprague Dawley (SD) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (K(ATP)) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.

Results: Our studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.

Conclusions: Taken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action.

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Related in: MedlinePlus

Central SIRT1 is required to regulate the effects of systemic resveratrol. A: Experimental protocol for basal insulin clamp. B: Effect of systemic resveratrol on plasma basal insulin and basal glucose levels. C–F: GIR, glucose production, or glucose uptake after systemic infusion of vehicle or resveratrol with or without IH SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after treatment with vehicle, resveratrol, or IH SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bar; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars.
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Figure 5: Central SIRT1 is required to regulate the effects of systemic resveratrol. A: Experimental protocol for basal insulin clamp. B: Effect of systemic resveratrol on plasma basal insulin and basal glucose levels. C–F: GIR, glucose production, or glucose uptake after systemic infusion of vehicle or resveratrol with or without IH SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after treatment with vehicle, resveratrol, or IH SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bar; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars.

Mentions: The previous studies have revealed the effect of hypothalamic resveratrol on glucose metabolism and the importance of central SIRT1. Recent reports have shown that chronic oral administration of resveratrol increases insulin sensitivity and reduces hyperglycemia (8–10). We investigated whether acute systemic infusion of resveratrol could recapitulate the metabolic findings of the chronic resveratrol studies and determined the involvement of central SIRT1 to the actions of systemic resveratrol. To this end, we infused vehicle (5% DMSO) or resveratrol (10 μmol/kg) systemically while vehicle (5% DMSO) or the SIRT1 inhibitor was infused IH into chronically catheterized SD male rats during pancreatic insulin-clamp studies (Fig. 5A). Systemic resveratrol significantly lowered plasma insulin levels, whereas basal glucose levels were unchanged (Fig. 5B). During the insulin clamp, the GIR required to maintain euglycemia was more than two times higher in the resveratrol-treated group compared with controls (RSV: 7.0 ± 0.7 vs. CTRL: 2.7 ± 0.6 mg/kg/min; P < 0.005). The need to infuse more glucose was mainly due to a reduction in hepatic glucose production in the resveratrol group compared with the vehicle-treated group (RSV: 5.3 ± 0.9 vs. CTRL: 9.6 ± 0.8 mg/kg/min; P < 0.05). Overall, the percent suppression of hepatic glucose production was 55 ± 5% with resveratrol treatment compared with 26 ± 6% with control. At the same time, no significant change was noted in peripheral glucose uptake between groups (Fig. 5C–F). These results indicate that acute systemic infusion of resveratrol is sufficient to increase insulin sensitivity. More important, after central inhibition of SIRT1, the effect of systemic resveratrol on glucose production was completely reversed.


Mediobasal hypothalamic SIRT1 is essential for resveratrol's effects on insulin action in rats.

Knight CM, Gutierrez-Juarez R, Lam TK, Arrieta-Cruz I, Huang L, Schwartz G, Barzilai N, Rossetti L - Diabetes (2011)

Central SIRT1 is required to regulate the effects of systemic resveratrol. A: Experimental protocol for basal insulin clamp. B: Effect of systemic resveratrol on plasma basal insulin and basal glucose levels. C–F: GIR, glucose production, or glucose uptake after systemic infusion of vehicle or resveratrol with or without IH SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after treatment with vehicle, resveratrol, or IH SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bar; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198094&req=5

Figure 5: Central SIRT1 is required to regulate the effects of systemic resveratrol. A: Experimental protocol for basal insulin clamp. B: Effect of systemic resveratrol on plasma basal insulin and basal glucose levels. C–F: GIR, glucose production, or glucose uptake after systemic infusion of vehicle or resveratrol with or without IH SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after treatment with vehicle, resveratrol, or IH SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bar; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars.
Mentions: The previous studies have revealed the effect of hypothalamic resveratrol on glucose metabolism and the importance of central SIRT1. Recent reports have shown that chronic oral administration of resveratrol increases insulin sensitivity and reduces hyperglycemia (8–10). We investigated whether acute systemic infusion of resveratrol could recapitulate the metabolic findings of the chronic resveratrol studies and determined the involvement of central SIRT1 to the actions of systemic resveratrol. To this end, we infused vehicle (5% DMSO) or resveratrol (10 μmol/kg) systemically while vehicle (5% DMSO) or the SIRT1 inhibitor was infused IH into chronically catheterized SD male rats during pancreatic insulin-clamp studies (Fig. 5A). Systemic resveratrol significantly lowered plasma insulin levels, whereas basal glucose levels were unchanged (Fig. 5B). During the insulin clamp, the GIR required to maintain euglycemia was more than two times higher in the resveratrol-treated group compared with controls (RSV: 7.0 ± 0.7 vs. CTRL: 2.7 ± 0.6 mg/kg/min; P < 0.005). The need to infuse more glucose was mainly due to a reduction in hepatic glucose production in the resveratrol group compared with the vehicle-treated group (RSV: 5.3 ± 0.9 vs. CTRL: 9.6 ± 0.8 mg/kg/min; P < 0.05). Overall, the percent suppression of hepatic glucose production was 55 ± 5% with resveratrol treatment compared with 26 ± 6% with control. At the same time, no significant change was noted in peripheral glucose uptake between groups (Fig. 5C–F). These results indicate that acute systemic infusion of resveratrol is sufficient to increase insulin sensitivity. More important, after central inhibition of SIRT1, the effect of systemic resveratrol on glucose production was completely reversed.

Bottom Line: Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production.Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production.In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Diabetes Research Center, Albert EinsteinCollege of Medicine, Bronx, New York, USA. colette.knight@einstein.yu.edu

ABSTRACT

Objective: Sirtuin 1 (SIRT1) and its activator resveratrol are emerging as major regulators of metabolic processes. We investigate the site of resveratrol action on glucose metabolism and the contribution of SIRT1 to these effects. Because the arcuate nucleus in the mediobasal hypothalamus (MBH) plays a pivotal role in integrating peripheral metabolic responses to nutrients and hormones, we examined whether the actions of resveratrol are mediated at the MBH.

Research design and methods: Sprague Dawley (SD) male rats received acute central (MBH) or systemic injections of vehicle, resveratrol, or SIRT1 inhibitor during basal pancreatic insulin clamp studies. To delineate the pathway(s) by which MBH resveratrol modulates hepatic glucose production, we silenced hypothalamic SIRT1 expression using a short hairpin RNA (shRNA) inhibited the hypothalamic ATP-sensitive potassium (K(ATP)) channel with glibenclamide, or selectively transected the hepatic branch of the vagus nerve while infusing resveratrol centrally.

Results: Our studies show that marked improvement in insulin sensitivity can be elicited by acute administration of resveratrol to the MBH or during acute systemic administration. Selective inhibition of hypothalamic SIRT1 using a cell-permeable SIRT1 inhibitor or SIRT1-shRNA negated the effect of central and peripheral resveratrol on glucose production. Blockade of the K(ATP) channel and hepatic vagotomy significantly attenuated the effect of central resveratrol on hepatic glucose production. In addition, we found no evidence for hypothalamic AMPK activation after MBH resveratrol administration.

Conclusions: Taken together, these studies demonstrate that resveratrol improves glucose homeostasis mainly through a central SIRT1-dependent pathway and that the MBH is a major site of resveratrol action.

Show MeSH
Related in: MedlinePlus