Deletion of Lkb1 in pro-opiomelanocortin neurons impairs peripheral glucose homeostasis in mice.
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.


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.
Laboratory of Diabetes and Obesity, Endocrinology and Nutrition Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic de Barcelona, Barcelona, Spain.
Marc
M
Claret
Mark A
MA
Smith
Claude
C
Knauf
Hind
H
Al-Qassab
Angela
A
Woods
Amanda
A
Heslegrave
Kaisa
K
Piipari
Julian J
JJ
Emmanuel
André
A
Colom
Philippe
P
Valet
Patrice D
PD
Cani
Ghazala
G
Begum
Anne
A
White
Phillip
P
Mucket
Marco
M
Peters
Keiko
K
Mizuno
Rachel L
RL
Batterham
K Peter
KP
Giese
Alan
A
Ashworth
Remy
R
Burcelin
Michael L
ML
Ashford
David
D
Carling
Dominic J
DJ
Withers
D055372:AMP-Activated Protein Kinases; D000704:Analysis of Variance; D000818:Animals; D019540:Area Under Curve; D001835:Body Weight / Q000235:genetics; D002452:Cell Count; D004435:Eating / Q000235:genetics; D004594:Electrophysiology; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006706:Homeostasis / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D018709:Statistics, Nonparametric
D011333:Pro-Opiomelanocortin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; D005947:Glucose
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