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Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

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Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. / Claret, Marc; Smith, Mark A.; Knauf, Claude; Al-Qassab, Hind; Woods, Angela; Heslegrave, Amanda; Piipari, Kaisa; Emmanuel, Julian J.; Colom, Andre; Valet, Philippe; Cani, Patrice D.; Begum, Ghazala; White, Anne; Mucket, Phillip; Peters, Marco; Mizuno, Keiko; Batterham, Rachel L.; Giese, K. Peter; Ashworth, Alan; Burcelin, Remy; Ashford, Michael L.; Carling, David; Withers, Dominic J.

In: Diabetes, Vol. 60, No. 3, 03.2011, p. 735-745.

Research output: Contribution to journalArticle

Harvard

Claret, M, Smith, MA, Knauf, C, Al-Qassab, H, Woods, A, Heslegrave, A, Piipari, K, Emmanuel, JJ, Colom, A, Valet, P, Cani, PD, Begum, G, White, A, Mucket, P, Peters, M, Mizuno, K, Batterham, RL, Giese, KP, Ashworth, A, Burcelin, R, Ashford, ML, Carling, D & Withers, DJ 2011, 'Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice' Diabetes, vol 60, no. 3, pp. 735-745., 10.2337/db10-1055

APA

Claret, M., Smith, M. A., Knauf, C., Al-Qassab, H., Woods, A., Heslegrave, A., ... Withers, D. J. (2011). Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. Diabetes, 60(3), 735-745. 10.2337/db10-1055

Vancouver

Claret M, Smith MA, Knauf C, Al-Qassab H, Woods A, Heslegrave A et al. Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. Diabetes. 2011 Mar;60(3):735-745. Available from: 10.2337/db10-1055

Author

Claret, Marc; Smith, Mark A.; Knauf, Claude; Al-Qassab, Hind; Woods, Angela; Heslegrave, Amanda; Piipari, Kaisa; Emmanuel, Julian J.; Colom, Andre; Valet, Philippe; Cani, Patrice D.; Begum, Ghazala; White, Anne; Mucket, Phillip; Peters, Marco; Mizuno, Keiko; Batterham, Rachel L.; Giese, K. Peter; Ashworth, Alan; Burcelin, Remy; Ashford, Michael L.; Carling, David; Withers, Dominic J. / Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice.

In: Diabetes, Vol. 60, No. 3, 03.2011, p. 735-745.

Research output: Contribution to journalArticle

Bibtex - Download

@article{228e9547087348469e86e271fc6a319b,
title = "Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice",
keywords = "ACTIVATED PROTEIN-KINASE, INCREASES INSULIN SENSITIVITY, HEPATIC GLUCOSE, MELANOCORTIN PATHWAYS, RECEPTOR SUBSTRATE-2, UPSTREAM KINASE, ARCUATE NUCLEUS, AGRP NEURONS, SAD KINASES, FOOD-INTAKE",
author = "Marc Claret and Smith, {Mark A.} and Claude Knauf and Hind Al-Qassab and Angela Woods and Amanda Heslegrave and Kaisa Piipari and Emmanuel, {Julian J.} and Andre Colom and Philippe Valet and Cani, {Patrice D.} and Ghazala Begum and Anne White and Phillip Mucket and Marco Peters and Keiko Mizuno and Batterham, {Rachel L.} and Giese, {K. Peter} and Alan Ashworth and Remy Burcelin and Ashford, {Michael L.} and David Carling and Withers, {Dominic J.}",
year = "2011",
doi = "10.2337/db10-1055",
volume = "60",
number = "3",
pages = "735--745",
journal = "Diabetes",
issn = "0012-1797",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice

A1 - Claret,Marc

A1 - Smith,Mark A.

A1 - Knauf,Claude

A1 - Al-Qassab,Hind

A1 - Woods,Angela

A1 - Heslegrave,Amanda

A1 - Piipari,Kaisa

A1 - Emmanuel,Julian J.

A1 - Colom,Andre

A1 - Valet,Philippe

A1 - Cani,Patrice D.

A1 - Begum,Ghazala

A1 - White,Anne

A1 - Mucket,Phillip

A1 - Peters,Marco

A1 - Mizuno,Keiko

A1 - Batterham,Rachel L.

A1 - Giese,K. Peter

A1 - Ashworth,Alan

A1 - Burcelin,Remy

A1 - Ashford,Michael L.

A1 - Carling,David

A1 - Withers,Dominic J.

AU - Claret,Marc

AU - Smith,Mark A.

AU - Knauf,Claude

AU - Al-Qassab,Hind

AU - Woods,Angela

AU - Heslegrave,Amanda

AU - Piipari,Kaisa

AU - Emmanuel,Julian J.

AU - Colom,Andre

AU - Valet,Philippe

AU - Cani,Patrice D.

AU - Begum,Ghazala

AU - White,Anne

AU - Mucket,Phillip

AU - Peters,Marco

AU - Mizuno,Keiko

AU - Batterham,Rachel L.

AU - Giese,K. Peter

AU - Ashworth,Alan

AU - Burcelin,Remy

AU - Ashford,Michael L.

AU - Carling,David

AU - Withers,Dominic J.

PY - 2011/3

Y1 - 2011/3

N2 - <p>OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.</p><p>RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.</p><p>RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.</p><p>CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011</p>

AB - <p>OBJECTIVE AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampk alpha 2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin-dependent protein kinase kinase beta (CaMKK beta) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.</p><p>RESEARCH DESIGN AND METHODS Mice lacking either Camkk beta or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.</p><p>RESULTS Deletion of Camkk beta in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased alpha-melanocyte-stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.</p><p>CONCLUSIONS Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons. Diabetes 60:735-745, 2011</p>

KW - ACTIVATED PROTEIN-KINASE

KW - INCREASES INSULIN SENSITIVITY

KW - HEPATIC GLUCOSE

KW - MELANOCORTIN PATHWAYS

KW - RECEPTOR SUBSTRATE-2

KW - UPSTREAM KINASE

KW - ARCUATE NUCLEUS

KW - AGRP NEURONS

KW - SAD KINASES

KW - FOOD-INTAKE

U2 - 10.2337/db10-1055

DO - 10.2337/db10-1055

M1 - Article

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 3

VL - 60

SP - 735

EP - 745

ER -

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