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

Colette M. Knight, Roger Gutierrez-Juarez, Tony K T Lam, Isabel Arrieta-Cruz, Loli Huang, Gary J. Schwartz, Nir Barzilai, Luciano Rossetti

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2691-2700
Number of pages10
JournalDiabetes
Volume60
Issue number11
DOIs
StatePublished - Nov 2011

Fingerprint

Sirtuin 1
Insulin
Hypothalamus
Glucose
Liver
Small Interfering RNA
resveratrol
Adenosine Triphosphate
KATP Channels
Arcuate Nucleus of Hypothalamus
AMP-Activated Protein Kinases
Vagus Nerve
Glyburide
Vagotomy

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Knight, C. M., Gutierrez-Juarez, R., Lam, T. K. T., Arrieta-Cruz, I., Huang, L., Schwartz, G. J., ... Rossetti, L. (2011). Mediobasal hypothalamic SIRT1 is essential for Resveratrol's effects on insulin action in rats. Diabetes, 60(11), 2691-2700. https://doi.org/10.2337/db10-0987

Mediobasal hypothalamic SIRT1 is essential for Resveratrol's effects on insulin action in rats. / Knight, Colette M.; Gutierrez-Juarez, Roger; Lam, Tony K T; Arrieta-Cruz, Isabel; Huang, Loli; Schwartz, Gary J.; Barzilai, Nir; Rossetti, Luciano.

In: Diabetes, Vol. 60, No. 11, 11.2011, p. 2691-2700.

Research output: Contribution to journalArticle

Knight, CM, Gutierrez-Juarez, R, Lam, TKT, Arrieta-Cruz, I, Huang, L, Schwartz, GJ, Barzilai, N & Rossetti, L 2011, 'Mediobasal hypothalamic SIRT1 is essential for Resveratrol's effects on insulin action in rats', Diabetes, vol. 60, no. 11, pp. 2691-2700. https://doi.org/10.2337/db10-0987
Knight, Colette M. ; Gutierrez-Juarez, Roger ; Lam, Tony K T ; Arrieta-Cruz, Isabel ; Huang, Loli ; Schwartz, Gary J. ; Barzilai, Nir ; Rossetti, Luciano. / Mediobasal hypothalamic SIRT1 is essential for Resveratrol's effects on insulin action in rats. In: Diabetes. 2011 ; Vol. 60, No. 11. pp. 2691-2700.
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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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AU - Knight, Colette M.

AU - Gutierrez-Juarez, Roger

AU - Lam, Tony K T

AU - Arrieta-Cruz, Isabel

AU - Huang, Loli

AU - Schwartz, Gary J.

AU - Barzilai, Nir

AU - Rossetti, Luciano

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N2 - 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.

AB - 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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