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

Marc Claret; Mark A. Smith; Claude Knauf; Hind Al-Qassab; Angela Woods; Amanda Heslegrave; Kaisa Piipari; Julian J. Emmanuel; Andre Colom; Philippe Valet; Patrice D. Cani; Ghazala Begum; Anne White; Phillip Mucket; Marco Peters; Keiko Mizuno; Rachel L. Batterham; K. Peter Giese; Alan Ashworth; Remy Burcelin; Michael L. Ashford; David Carling; Dominic J. Withers

doi:10.2337/db10-1055

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

Marc Claret, Mark A. Smith, Claude Knauf, Hind Al-Qassab, Angela Woods, Amanda Heslegrave, Kaisa Piipari, Julian J. Emmanuel, Andre Colom, Philippe Valet, Patrice D. Cani, Ghazala Begum, Anne White, Phillip Mucket, Marco Peters, Keiko Mizuno, Rachel L. Batterham, K. Peter Giese, Alan Ashworth, Remy BurcelinMichael L. Ashford, David Carling, Dominic J. Withers

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

Abstract

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.

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.

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.

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

Original language	English
Pages (from-to)	735-745
Number of pages	11
Journal	Diabetes
Volume	60
Issue number	3
DOIs	https://doi.org/10.2337/db10-1055
Publication status	Published - Mar 2011

Keywords

ACTIVATED PROTEIN-KINASE
INCREASES INSULIN SENSITIVITY
HEPATIC GLUCOSE
MELANOCORTIN PATHWAYS
RECEPTOR SUBSTRATE-2
UPSTREAM KINASE
ARCUATE NUCLEUS
AGRP NEURONS
SAD KINASES
FOOD-INTAKE

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/db10-1055

Cite this

Claret, M., Smith, M. A., Knauf, C., Al-Qassab, H., Woods, A., Heslegrave, A., Piipari, K., Emmanuel, J. J., Colom, A., Valet, P., Cani, P. D., Begum, G., White, A., Mucket, P., Peters, M., Mizuno, K., Batterham, R. L., Giese, K. P., Ashworth, A., ... Withers, D. J. (2011). Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice. Diabetes, 60(3), 735-745. https://doi.org/10.2337/db10-1055

@article{228e9547087348469e86e271fc6a319b,

title = "Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice",

abstract = "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.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.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.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",

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",

month = mar,

doi = "10.2337/db10-1055",

language = "English",

volume = "60",

pages = "735--745",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

number = "3",

}

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. https://doi.org/10.2337/db10-1055

TY - JOUR

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

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 - 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.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.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.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

AB - 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.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.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.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

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

M3 - Article

SN - 0012-1797

VL - 60

SP - 735

EP - 745

JO - Diabetes

JF - Diabetes

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this