Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation.
The metabolic demands and synthetic capacity of the lactating mammary gland exceed that of any other tissue, thereby providing a useful paradigm for understanding the developmental regulation of cellular metabolism. By evaluating mice bearing targeted deletions in Akt1 or Akt2, we demonstrate that Akt1 is specifically required for lactating mice to synthesize sufficient quantities of milk to support their offspring. Whereas cellular proliferation, differentiation, and apoptosis are unaffected, loss of Akt1 disrupts the coordinate regulation of metabolic pathways that normally occurs at the onset of lactation. This results in a failure to upregulate glucose uptake, Glut1 surface localization, lipid synthesis, and multiple lipogenic enzymes, as well as a failure to downregulate lipid catabolic enzymes. These findings demonstrate that Akt1 is required in an isoform-specific manner for orchestrating many of the developmental changes in cellular metabolism that occur at the onset of lactation and establish a role for Akt1 in glucose metabolism.
Boxer
Robert B
RB
Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Stairs
Douglas B
DB
Dugan
Katherine D
KD
Notarfrancesco
Kathleen L
KL
Portocarrero
Carla P
CP
Keister
Blaine A
BA
Belka
George K
GK
Cho
Han
H
Rathmell
Jeffrey C
JC
Thompson
Craig B
CB
Birnbaum
Morris J
MJ
Chodosh
Lewis A
LA
D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism*; D007527:Isoenzymes / Q000172:deficiency / Q000378:metabolism; D007774:Lactation / Q000235:genetics / Q000378:metabolism*; D008055:Lipids / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000378:metabolism; D021381:Protein Transport / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000172:deficiency / Q000378:metabolism*
D051272:Glucose Transporter Type 1; D007527:Isoenzymes; D008055:Lipids; C495678:Slc2a1 protein, mouse; C514862:Akt1 protein, mouse; C494922:Akt2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose