Abstract
Both insulin and leptin signaling converge on phosphatidylinositol 3-OH kinase [PI(3)K]/3-phosphoinositide-dependent protein kinase-1 (PDK-1)/protein kinase B (PKB, also known as Akt) in proopiomelanocortin (POMC) neurons. Forkhead box-containing protein-O1 (FoxO1) is inactivated in a PI(3)K-dependent manner. However, the interrelationship between PI(3)K/PDK-1/Akt and FoxO1, and the chronic effects of the overexpression of FoxO1 in POMC neurons on energy homeostasis has not been elucidated. To determine the extent to which PDK-1 and FoxO1 signaling in POMC neurons was responsible for energy homeostasis, we generated POMC neuron-specific Pdk1 knockout mice (POMCPdk1-/-) and mice selectively expressing a constitutively nuclear (CN)FoxO1 or transactivation-defective (Δ256)FoxO1 in POMC neurons (CNFoxO1 POMC or Δ256FoxO1POMC). POMCPdk1-/- mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1POMC mice exhibited mild obesity and hyperphagia compared with POMCPdk1-/- mice. Although expression of the CNFoxO1 made POMCPdk1-/- mice more obese due to excessive suppression of Pomc gene, overexpression of Δ256FoxO1 in POMC neurons had no effects on metabolic phenotypes and Pomc expression levels of POMCPdk1 -/- mice. These data suggest a requirement for PDK-1 and FoxO1 in transcriptional regulation of Pomc and food intake.
Original language | English (US) |
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Pages (from-to) | E787-E798 |
Journal | American Journal of Physiology - Endocrinology and Metabolism |
Volume | 298 |
Issue number | 4 |
DOIs | |
State | Published - Apr 2010 |
Keywords
- Food intake
- Forkhead box-containing protein O1
- Phosphoinositide-dependent protein kinase-1
- Pomc
- Proopiomelanocortin neurons
ASJC Scopus subject areas
- Endocrinology, Diabetes and Metabolism
- Physiology
- Physiology (medical)