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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

MBH infusion of resveratrol increases hepatic insulin sensitivity. A: Schematic representation of MBH infusions and insulin clamp protocol. B: Effect of MBH resveratrol on basal glucose and basal insulin levels. C–F: GIR, glucose production, and glucose uptake during basal pancreatic insulin clamp after treatment with vehicle, resveratrol, or SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after resveratrol or SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bars; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars; SIRT1 inhibitor alone, hatched bars.
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Figure 2: MBH infusion of resveratrol increases hepatic insulin sensitivity. A: Schematic representation of MBH infusions and insulin clamp protocol. B: Effect of MBH resveratrol on basal glucose and basal insulin levels. C–F: GIR, glucose production, and glucose uptake during basal pancreatic insulin clamp after treatment with vehicle, resveratrol, or SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after resveratrol or SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bars; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars; SIRT1 inhibitor alone, hatched bars.

Mentions: Given the importance of the MBH on the regulation of glucose homeostasis, we sought to determine its specific role on resveratrol action and the contribution of central SIRT1. Bilateral cannulae were implanted by stereotaxic surgery into the MBH of SD male rats. After adequate postsurgical recovery, vehicle (5% DMSO, CTRL) or resveratrol (RSV, 200 μmol/L) was infused into the MBH of conscious rats during basal pancreatic insulin clamp studies (Fig. 2A). The resveratrol dose selected was used to achieve maximal SIRT1 activation as previously described (36). Central resveratrol treatment significantly decreased the basal plasma glucose and basal insulin levels (Fig. 2B, Supplementary Table 1). In the resveratrol-treated animals, the glucose infusion rate (GIR) required to prevent hypoglycemia was approximately fourfold higher compared with the control group (RSV: 5.0 ± 0.5 vs. CTRL: 1.3 ± 0.6 mg/kg/min; P < 0.005), whereas the endogenous glucose production was significantly lower (RSV: 5.9 ± 0.7 vs. CTRL: 11.1 ± 0.8 mg/kg/min; P < 0.005). Overall, resveratrol suppressed glucose production by 55 ± 5 versus 9 ± 5% in the control group. Peripheral glucose uptake was not different between the two treatment groups, as might be expected in studies performed under basal insulin conditions (Fig. 2C–F). Thus, central resveratrol modulates glucose homeostasis by markedly repressing glucose output from the liver.


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)

MBH infusion of resveratrol increases hepatic insulin sensitivity. A: Schematic representation of MBH infusions and insulin clamp protocol. B: Effect of MBH resveratrol on basal glucose and basal insulin levels. C–F: GIR, glucose production, and glucose uptake during basal pancreatic insulin clamp after treatment with vehicle, resveratrol, or SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after resveratrol or SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bars; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars; SIRT1 inhibitor alone, hatched bars.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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

Figure 2: MBH infusion of resveratrol increases hepatic insulin sensitivity. A: Schematic representation of MBH infusions and insulin clamp protocol. B: Effect of MBH resveratrol on basal glucose and basal insulin levels. C–F: GIR, glucose production, and glucose uptake during basal pancreatic insulin clamp after treatment with vehicle, resveratrol, or SIRT1 inhibitor. G–I: Flux through G6Pase, glycogenolysis, and gluconeogenesis after resveratrol or SIRT1 inhibitor. All values are mean ± SEM. *P < 0.05, **P < 0.005 compared with control. For all studies: control, white bars; resveratrol, black bars; resveratrol and SIRT1 inhibitor, striped bars; SIRT1 inhibitor alone, hatched bars.
Mentions: Given the importance of the MBH on the regulation of glucose homeostasis, we sought to determine its specific role on resveratrol action and the contribution of central SIRT1. Bilateral cannulae were implanted by stereotaxic surgery into the MBH of SD male rats. After adequate postsurgical recovery, vehicle (5% DMSO, CTRL) or resveratrol (RSV, 200 μmol/L) was infused into the MBH of conscious rats during basal pancreatic insulin clamp studies (Fig. 2A). The resveratrol dose selected was used to achieve maximal SIRT1 activation as previously described (36). Central resveratrol treatment significantly decreased the basal plasma glucose and basal insulin levels (Fig. 2B, Supplementary Table 1). In the resveratrol-treated animals, the glucose infusion rate (GIR) required to prevent hypoglycemia was approximately fourfold higher compared with the control group (RSV: 5.0 ± 0.5 vs. CTRL: 1.3 ± 0.6 mg/kg/min; P < 0.005), whereas the endogenous glucose production was significantly lower (RSV: 5.9 ± 0.7 vs. CTRL: 11.1 ± 0.8 mg/kg/min; P < 0.005). Overall, resveratrol suppressed glucose production by 55 ± 5 versus 9 ± 5% in the control group. Peripheral glucose uptake was not different between the two treatment groups, as might be expected in studies performed under basal insulin conditions (Fig. 2C–F). Thus, central resveratrol modulates glucose homeostasis by markedly repressing glucose output from the liver.

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