PDK1 deficiency in POMC-expressing cells reveals FOXO1-dependent and -independent pathways in control of energy homeostasis and stress response.
Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(DeltaPOMC) mice). PDK1(DeltaPOMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(DeltaPOMC) mice exhibit progressive, severe hypocortisolism caused by loss of POMC-expressing corticotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POMC cells is sufficient to ameliorate positive energy balance in PDK1(DeltaPOMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.
Belgardt
Bengt F
BF
Institute for Genetics, Department of Mouse Genetics and Metabolism, Center for Molecular Medicine Cologne (CMMC), University of Cologne, D-50674 Cologne, Germany.
Husch
Andreas
A
Rother
Eva
E
Ernst
Marianne B
MB
Wunderlich
F Thomas
FT
Hampel
Brigitte
B
Klöckener
Tim
T
Alessi
Dario
D
Kloppenburg
Peter
P
Brüning
Jens C
JC
D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone / Q000378:metabolism / Q000494:pharmacology; D004734:Energy Metabolism; D005260:Female; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006963:Hyperphagia / Q000235:genetics; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010902:Pituitary Gland / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D007328:Insulin; D011333:Pro-Opiomelanocortin; D064413:3-Phosphoinositide-Dependent Protein Kinases; C578564:Pdpk1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D003345:Corticosterone