Hypothalamic protein kinase C regulates glucose production

Rachel Ross, Penny Y T Wang, Madhu Chari, Carol K L Lam, Liora Caspi, Hiraku Ono, Evan D. Muse, Xiaosong Li, Roger Gutierrez-Juarez, Peter E. Light, Gary J. Schwartz, Luciano Rossetti, Tony K T Lam

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

OBJECTIVE-A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K +(K ATP)channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K ATP channels remain unknown. RESEARCH DESIGN AND METHODS-To examine whether hypothalamic protein kinase C(PKC)mediates the ability of central nervous system lipids to activate K ATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K ATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo. RESULTS-We first reported that direct activation of hypotha-lamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol(OAG)suppressed glucose production. Coadministration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K ATP. channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production. CONCLUSIONS-These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.

Original languageEnglish (US)
Pages (from-to)2061-2065
Number of pages5
JournalDiabetes
Volume57
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

Protein Kinase C
Glucose
Adenosine Triphosphate
Glycerol
Lipids
Lipid Metabolism
Protein C Inhibitor
Glyburide
Protein Kinase Inhibitors
Rodentia
Research Design
Central Nervous System
Liver

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Ross, R., Wang, P. Y. T., Chari, M., Lam, C. K. L., Caspi, L., Ono, H., ... Lam, T. K. T. (2008). Hypothalamic protein kinase C regulates glucose production. Diabetes, 57(8), 2061-2065. https://doi.org/10.2337/db08-0206

Hypothalamic protein kinase C regulates glucose production. / Ross, Rachel; Wang, Penny Y T; Chari, Madhu; Lam, Carol K L; Caspi, Liora; Ono, Hiraku; Muse, Evan D.; Li, Xiaosong; Gutierrez-Juarez, Roger; Light, Peter E.; Schwartz, Gary J.; Rossetti, Luciano; Lam, Tony K T.

In: Diabetes, Vol. 57, No. 8, 08.2008, p. 2061-2065.

Research output: Contribution to journalArticle

Ross, R, Wang, PYT, Chari, M, Lam, CKL, Caspi, L, Ono, H, Muse, ED, Li, X, Gutierrez-Juarez, R, Light, PE, Schwartz, GJ, Rossetti, L & Lam, TKT 2008, 'Hypothalamic protein kinase C regulates glucose production', Diabetes, vol. 57, no. 8, pp. 2061-2065. https://doi.org/10.2337/db08-0206
Ross R, Wang PYT, Chari M, Lam CKL, Caspi L, Ono H et al. Hypothalamic protein kinase C regulates glucose production. Diabetes. 2008 Aug;57(8):2061-2065. https://doi.org/10.2337/db08-0206
Ross, Rachel ; Wang, Penny Y T ; Chari, Madhu ; Lam, Carol K L ; Caspi, Liora ; Ono, Hiraku ; Muse, Evan D. ; Li, Xiaosong ; Gutierrez-Juarez, Roger ; Light, Peter E. ; Schwartz, Gary J. ; Rossetti, Luciano ; Lam, Tony K T. / Hypothalamic protein kinase C regulates glucose production. In: Diabetes. 2008 ; Vol. 57, No. 8. pp. 2061-2065.
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abstract = "OBJECTIVE-A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K +(K ATP)channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K ATP channels remain unknown. RESEARCH DESIGN AND METHODS-To examine whether hypothalamic protein kinase C(PKC)mediates the ability of central nervous system lipids to activate K ATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K ATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo. RESULTS-We first reported that direct activation of hypotha-lamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol(OAG)suppressed glucose production. Coadministration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K ATP. channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production. CONCLUSIONS-These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.",
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AU - Wang, Penny Y T

AU - Chari, Madhu

AU - Lam, Carol K L

AU - Caspi, Liora

AU - Ono, Hiraku

AU - Muse, Evan D.

AU - Li, Xiaosong

AU - Gutierrez-Juarez, Roger

AU - Light, Peter E.

AU - Schwartz, Gary J.

AU - Rossetti, Luciano

AU - Lam, Tony K T

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N2 - OBJECTIVE-A selective rise in hypothalamic lipid metabolism and the subsequent activation of SUR1/Kir6.2 ATP-sensitive K +(K ATP)channels inhibit hepatic glucose production. The mechanisms that link the ability of hypothalamic lipid metabolism to the activation of K ATP channels remain unknown. RESEARCH DESIGN AND METHODS-To examine whether hypothalamic protein kinase C(PKC)mediates the ability of central nervous system lipids to activate K ATP channels and regulate glucose production in normal rodents, we first activated hypothalamic PKC in the absence or presence of K ATP channel inhibition. We then inhibited hypothalamic PKC in the presence of lipids. Tracer-dilution methodology in combination with the pancreatic clamp technique was used to assess the effect of hypothalamic administrations on glucose metabolism in vivo. RESULTS-We first reported that direct activation of hypotha-lamic PKC via direct hypothalamic delivery of PKC activator 1-oleoyl-2-acetyl-sn-glycerol(OAG)suppressed glucose production. Coadministration of hypothalamic PKC-δ inhibitor rottlerin with OAG prevented the ability of OAG to activate PKC-δ and lower glucose production. Furthermore, hypothalamic dominant-negative Kir6.2 expression or the delivery of the K ATP. channel blocker glibenclamide abolished the glucose production-lowering effects of OAG. Finally, inhibition of hypothalamic PKC eliminated the ability of lipids to lower glucose production. CONCLUSIONS-These studies indicate that hypothalamic PKC activation is sufficient and necessary for lowering glucose production.

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