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 ( CNFoxO1 POMC or Δ256FoxO1 POMC). POMCPdk1−/− mice showed increased food intake and body weight accompanied by decreased expression of Pomc gene. The CNFoxO1 POMC 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.

Cellular insulin resistance disrupts hypothalamic mHypoA-POMC/GFP neuronal signaling pathways

“…Insulin pretreatment in mHypoA-POMC/GFP-1 cells abolished the increase in POMC and decrease in Ir gene expression observed after insulin treatment in non-resistant cells. The dysregulation of POMC expression is particularly significant, as mice exhibiting lower Pomc gene expression due to disturbances in the PI3K pathway become obese and hyperphagic (Belgardt et al 2008, Iskandar et al 2010. Additionally, after the induction of insulin resistance, the mHypoA-POMC/GFP cell lines showed reduced phosphorylation of second-messenger proteins in the insulin signal transduction pathway, such as Akt and FOXO1.…”

“…The failure of Akt to phosphorylate FOXO1 is a possible cause of the dysregulation of Pomc expression. The PI3K-FOXO1 pathway is essential to POMC neuronal function as disturbance or inhibition of key components of the PI3K pathway lead to an increased body weight associated with hyperphagia (Niswender et al 2003, Belgardt et al 2008, Iskandar et al 2010. Furthermore, all four mHypoA-POMC/GFP cell lines exhibited repressed IR protein levels after prolonged exposure to insulin, contributing to the onset of the insulin-resistant phenotype.…”

Hormonal Signaling Systems of the Brain in Diabetes Mellitus

“…Abbreviations: IRS, insulin receptor substrate proteins; GRB2, growthfactor-receptor-bound protein-2; mSOS, mammalian son of sevenless nucleotide exchange factor; Ras, small G protein of Ras family; c-Raf, cytoplasmic serine/threonine-specific protein kinase Raf; MEK, mitogene-activated protein kinase; ERK1/2, extracellular signalregulated kinases 1 and 2; p85/p110 PI 3K, heterodimeric p85/p110 phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homologue; PDK1, phosphoinositide-dependent kinase 1; PKC, protein kinase C; AKT, protein kinase B; mTOR, mammalian target of rapamycin; GSK3, glycogen synthase kinase 3; FoxO1, forkhead box O1 protein; JAK2, Janus kinase-2; STAT3, signal transducer and activator of transcription of the type 3; PIP 2 and PIP 3 , phosphatidylinositol 3,4-diphosphate and phosphatidylinositol 3,4,5-triphosphate, respectively differentiation and the other processes in neuronal cells. The activation of PI 3-kinase leads to phosphorylation and activation of AKT kinase that regulates the metabolism and cell survival via numerous downstream proteins in the peripheral insulin-sensitive tissues as well as in the CNS, primarily in hypothalamic neurons (Iskandar et al, 2010). AKT kinase partly facilitates signal transduction via phosphorylation and cytoplasmic sequestering of forkhead-box protein O1, a negative regulator of insulin signaling, whose nuclear translocation is associated with obesity and hyperphagia (Kitamura et al, 2006).…”

The anorexigenic cytokine ciliary neurotrophic factor stimulates POMC gene expression via receptors localized in the nucleus of arcuate neurons

“…This hypothesis is reinforced by the fact that Akt can be activated directly in the cell nucleus in different cellular models (60). Moreover, POMC gene transcription is known to be regulated by signaling pathways, including JAK2 and Akt (7,31). The role of STAT3 cannot be totally excluded since CNTF induced its phosphorylation in two out of 10 animals.…”