AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons.
Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.
Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London, United Kingdom.
Marc
M
Claret
Mark A
MA
Smith
Rachel L
RL
Batterham
Colin
C
Selman
Agharul I
AI
Choudhury
Lee G D
LG
Fryer
Melanie
M
Clements
Hind
H
Al-Qassab
Helen
H
Heffron
Allison W
AW
Xu
John R
JR
Speakman
Gregory S
GS
Barsh
Benoit
B
Viollet
Sophie
S
Vaulont
Michael L J
ML
Ashford
David
D
Carling
Dominic J
DJ
Withers
D055372:AMP-Activated Protein Kinases; D054369:Agouti-Related Protein; D000818:Animals; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009097:Multienzyme Complexes / Q000172:deficiency / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009097:Multienzyme Complexes; D011333:Pro-Opiomelanocortin; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose