PDK-1/FoxO1 pathway in POMC neurons regulatesPomcexpression and food intake

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 ( CNFoxO1POMCor Δ256FoxO1POMC). POMCPdk1−/−mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1POMCmice 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.