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; André 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, André 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

Inflammation and Ageing

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

36 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 Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ) 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 Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.

RESULTS: Deletion of Camkkβ 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 α-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.

Original language	English
Pages (from-to)	735-45
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

Analysis of Variance
Animals
Area Under Curve
Body Weight
Cell Count
Eating
Electrophysiology
Energy Metabolism
Female
Glucose
Glucose Clamp Technique
Homeostasis
Hypothalamus
Immunohistochemistry
Insulin Resistance
Male
Mice
Mice, Transgenic
Neurons
Pro-Opiomelanocortin
Protein-Serine-Threonine Kinases
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Statistics, Nonparametric
Journal Article
Research Support, Non-U.S. Gov't

UN SDGs

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

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10.2337/db10-1055

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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), 735-45. https://doi.org/10.2337/db10-1055

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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 Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ) 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 Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS: Deletion of Camkkβ 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 α-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.",

keywords = "Analysis of Variance, Animals, Area Under Curve, Body Weight, Cell Count, Eating, Electrophysiology, Energy Metabolism, Female, Glucose, Glucose Clamp Technique, Homeostasis, Hypothalamus, Immunohistochemistry, Insulin Resistance, Male, Mice, Mice, Transgenic, Neurons, Pro-Opiomelanocortin, Protein-Serine-Threonine Kinases, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Statistics, Nonparametric, Journal Article, Research Support, Non-U.S. Gov't",

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 Andr{\'e} 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--45",

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. 735-45. 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, André

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 Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ) 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 Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS: Deletion of Camkkβ 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 α-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.

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 Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca(2+)-calmodulin-dependent protein kinase kinase β (CaMKKβ) 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 Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.RESULTS: Deletion of Camkkβ 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 α-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.

KW - Analysis of Variance

KW - Animals

KW - Area Under Curve

KW - Body Weight

KW - Cell Count

KW - Eating

KW - Electrophysiology

KW - Energy Metabolism

KW - Female

KW - Glucose

KW - Glucose Clamp Technique

KW - Homeostasis

KW - Hypothalamus

KW - Immunohistochemistry

KW - Insulin Resistance

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Neurons

KW - Pro-Opiomelanocortin

KW - Protein-Serine-Threonine Kinases

KW - Reverse Transcriptase Polymerase Chain Reaction

KW - Signal Transduction

KW - Statistics, Nonparametric

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.2337/db10-1055

DO - 10.2337/db10-1055

M3 - Article

C2 - 21266325

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

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