The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake

Plum, Leona; Lin, Hua; Dutia, Roxanne; Tanaka, Jun; Aizawa, Kumiko; Matsumoto, Michihiro; Kim, Andrea J.; Cawley, Niamh X.; Paik, Ji Hye; Loh, Y. Peng; DePinho, Ronald A.; Wardlaw, Sharon L.; Accili, Domenico

doi:10.1038/nm.2026

Cited by 150 publications

(128 citation statements)

References 55 publications

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“…The present study supports the previous reports in which CNFoxO1 expressed in the hypothalamic ARC by stereotactic adenoviral delivery inhibited Pomc gene expression (13) and confirms that FoxO1 in POMC neurons regulates Pomc gene expression. During the revision of this manuscript, Plum et al (26) reported that FoxO1 ablation in POMC neurons increased ␣-melanocyte-stimulating hormone (␣-MSH) due to increased expression of carboxypeptidase E and decreased food intake. We could not exclude the possibility that FoxO1 affected ␣-MSH protein level directly.…”

Section: Discussionmentioning

confidence: 99%

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

Iskandar

Cao

Hayashi

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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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.

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Section: Discussionmentioning

confidence: 99%

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

Iskandar

Cao

Hayashi

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…These data suggest that defective processing of proinsulin or immature beta cells may be present in these patients and that rapamycin treatment could restore the correct function. It has also been shown that the transcription factor, forkhead box O1 (FOXO1), affects carboxypeptidase E processing of hormone in the hypothalamus and that the mechanistic target of rapamycin (mTOR) pathway affects this process [29]. It would, therefore, be interesting to determine the effects of rapamycin on FOXO1 translocation and carboxypeptidase levels in the beta cell.…”

Section: Discussionmentioning

confidence: 99%

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

Piemonti¹,

Maffi²,

Monti³

et al. 2010

Diabetologia

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Aims/hypothesis Type 1 diabetes is considered nonreversible at end-stage disease when there is no measurable insulin production. However, there are indications that insulin-producing beta cells could be present or return if autoimmunity could be controlled. We therefore sought to determine whether immunosuppression therapy can reinstate beta cell function in patients with long-term type 1 diabetes. Methods We examined pancreatic beta cell function in 22 patients with long-term type 1 diabetes (median disease duration 27 years), who had been receiving rapamycin monotherapy (0.1 mg/kg; target trough levels 8-10 ng/ml; 26-314 days) as pre-conditioning for islet transplantation. As control, beta cell function was measured in 14 patients (median disease duration 17 years) who were waiting for an islet transplant without rapamycin pre-conditioning.

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“…Thus, leptin and insulin promote pFOXO1 and prevent its translocation to the nucleus (Kim et al 2006). This results in increased expression of Pomc (Belgardt et al 2008, Ernst et al 2009, Plum et al 2009) and decreased expression of Agrp (Kitamura et al 2006). Quite opposite to leptin and insulin, we demonstrated that central ghrelin administration increased both hypothalamic FOXO1 and pFOXO1 to a similar extent.…”

Section: Ghs-r 1amentioning

confidence: 99%

Ghrelin and lipid metabolism: key partners in energy balance

Varela¹,

Vázquez²,

Cordido³

et al. 2010

Journal of Molecular Endocrinology

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Ghrelin, the endogenous ligand of the GH secretagogue receptor, has a pleiotropic role in the modulation of energy balance. Recent evidence has demonstrated that besides its orexigenic role, ghrelin regulates central and peripheral lipid metabolism through specific control of hypothalamic AMP-activated protein kinase (AMPK), a critical metabolic gauge regulating both cellular and whole-body energy homeostasis. In this review, we summarize the new milestones of ghrelin's actions on energy balance, with particular focus on its molecular interaction with hypothalamic AMPK and fatty acid metabolism. Understanding this new metabolic pathway can provide new therapeutic targets for the treatment of obesity and the metabolic syndrome.

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The obesity susceptibility gene Cpe links FoxO1 signaling in hypothalamic pro-opiomelanocortin neurons with regulation of food intake

Cited by 150 publications

References 55 publications

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

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

Beta cell function during rapamycin monotherapy in long-term type 1 diabetes

Ghrelin and lipid metabolism: key partners in energy balance

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