Hypothalamic CaMKK2 contributes to the regulation of energy balance.
Detailed knowledge of the pathways by which ghrelin and leptin signal to AMPK in hypothalamic neurons and lead to regulation of appetite and glucose homeostasis is central to the development of effective means to combat obesity. Here we identify CaMKK2 as a component of one of these pathways, show that it regulates hypothalamic production of the orexigenic hormone NPY, provide evidence that it functions as an AMPKalpha kinase in the hypothalamus, and demonstrate that it forms a unique signaling complex with AMPKalpha and beta. Acute pharmacologic inhibition of CaMKK2 in wild-type mice, but not CaMKK2 null mice, inhibits appetite and promotes weight loss consistent with decreased NPY and AgRP mRNAs. Moreover, the loss of CaMKK2 protects mice from high-fat diet-induced obesity, insulin resistance, and glucose intolerance. These data underscore the potential of targeting CaMKK2 as a therapeutic intervention.
Anderson
Kristin A
KA
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
Ribar
Thomas J
TJ
Lin
Fumin
F
Noeldner
Pamela K
PK
Green
Michelle F
MF
Muehlbauer
Michael J
MJ
Witters
Lee A
LA
Kemp
Bruce E
BE
Means
Anthony R
AR
D000091162:AMP-Activated Protein Kinase Kinases; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001069:Appetite Regulation / Q000502:physiology*; D001562:Benzimidazoles / Q000494:pharmacology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000502:physiology*; D002478:Cells, Cultured; D004036:Diet, Atherogenic; D004734:Energy Metabolism / Q000502:physiology*; D005260:Female; D018149:Glucose Intolerance / Q000209:etiology; D005951:Glucose Tolerance Test; D007031:Hypothalamus / Q000201:enzymology* / Q000473:pathology; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053644:Naphthalimides / Q000494:pharmacology; D009478:Neuropeptide Y / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015431:Weight Loss
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D001562:Benzimidazoles; D007328:Insulin; D053644:Naphthalimides; D009478:Neuropeptide Y; D012333:RNA, Messenger; C458525:STO 609; D011494:Protein Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C517700:Camkk2 protein, mouse; D000091162:AMP-Activated Protein Kinase Kinases; C045073:Cre recombinase; D019426:Integrases; D000103:Acetyl-CoA Carboxylase