FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake

Ren, Hongxia; Orozco, Ian J.; Su, Ya; Suyama, Shigetomo; Gutiérrez‐Juárez, Roger; Horváth, Tamas L.; Wardlaw, Sharon L.; Plum, Leona; Arancio, Ottavio; Accili, Domenico

doi:10.1016/j.cell.2012.04.032

Cited by 171 publications

(159 citation statements)

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“…1). Thus, FOXO integrate energy intake with energy expenditure in the central nervous system through regulation of neuropeptide processing and signalling [27–29], in liver through glucose and lipid production [17, 30], in adipocytes through NEFA turnover [31], and in the vasculature through nitric oxide production and inflammatory responses [32, 33]. In addition, FOXO carry out seemingly distinct functions in tissue differentiation and lineage stability that are especially evident in pancreatic endocrine cells [9, 10, 21, 34].…”

Section: Foxo and Hormone Regulation Of Gene Expressionmentioning

confidence: 99%

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The new biology of diabetes

Pajvani

Accili

2015

Diabetologia

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Until recently, type 2 diabetes was seen as a disease caused by an impaired ability of insulin to promote the uptake and utilisation of glucose. Work on forkhead box protein O (FOXO) transcription factors revealed new aspects of insulin action that have led us to articulate a liver- and beta cell-centric narrative of diabetes pathophysiology and treatment. FOXO integrate a surprisingly diverse subset of biological functions to promote metabolic flexibility. In the liver, they controls the glucokinase/glucose-6-phosphatase switch and bile acid pool composition, directing carbons to glucose or lipid utilisation, thus providing a unifying mechanism for the two abnormalities of the diabetic liver: excessive glucose production and increased lipid synthesis and secretion. Moreover, FOXO are necessary to maintain beta cell differentiation, and diabetes development is associated with a gradual loss of FOXO function that brings about beta cell dedifferentiation. We proposed that dedifferentiation is the main cause of beta cell failure and conversion into non-beta endocrine cells, and that treatment should restore beta cell differentiation. Our studies investigating these proposals have revealed new dimensions to the pathophysiology of diabetes that can be leveraged to design new therapies.

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Section: Foxo and Hormone Regulation Of Gene Expressionmentioning

confidence: 99%

“…First, insulin receptor signalling in hepatocytes is necessary, but not sufficient, to confer on insulin the ability to suppress HGP [92, 93]. Second, the central nervous system plays an important role in rodents to modulate insulin sensitivity of HGP [29, 94, 95]. Whether the same is true in humans is not known [96].…”

Section: What Remains To Be Discoveredmentioning

confidence: 99%

The new biology of diabetes

Pajvani

Accili

2015

Diabetologia

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“…FoxO1 activity in ARC AgRP-expressing neurons regulates locomotor activity, oxygen consumption, food intake, glucose homeostasis, and ghrelin sensitivity (Cao et al, 2011; Kim et al, 2012; Ren et al, 2012). Interestingly, Foxo1 expression in the ARC was not affected by fasting despite an increase in plasma ghrelin.…”

Section: Discussionmentioning

confidence: 99%

“…Of the three types of CPT-1, hypothalamic neurons express CPT-1c, which does not have acyltransferase activity, while hypothalamic astroyctes express CPT-1a, which does have acyltransferase activity (Wolfgang et al, 2006). FoxO1 is a transcription factor that negatively regulates adipogenesis, mediates insulin-induced gluconeogenesis, and is an effector of Npy / Agrp gene expression (Cao et al, 2011; Ren et al, 2012). …”

Section: Introductionmentioning

confidence: 99%

Differential gene regulation of GHSR signaling pathway in the arcuate nucleus and NPY neurons by fasting, diet-induced obesity, and 17β-estradiol

Yasrebi

Hsieh

Mamounis

et al. 2016

Molecular and Cellular Endocrinology

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Ghrelin’s receptor, growth hormone secretagogue receptor (GHSR), is highly expressed in the arcuate nucleus (ARC) and in neuropeptide Y (NPY) neurons. Fasting, diet-induced obesity (DIO), and 17β-estradiol (E2) influence ARC Ghsr expression. It is unknown if these effects occur in NPY neurons. Therefore, we examined the expression of Npy, Agrp, and GHSR signaling pathway genes after fasting, DIO, and E2 replacement in ARC and pools of NPY neurons. In males, fasting increased ARC Ghsr and NPY Foxo1 but decreased NPY Ucp2. In males, DIO decreased ARC and NPY Ghsr and Cpt1c. In fed females, E2 increased Agrp, Ghsr, Cpt1c, and Foxo1 in ARC. In NPY pools, E2 decreased Foxo1 in fed females but increased Foxo1 in fasted females. DIO in females suppressed Agrp and augmented Cpt1c in NPY neurons. In summary, genes involved in GHSR signaling are differentially regulated between the ARC and NPY neurons in a sex-dependent manner.

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“…Our reporter assay (Fig. 5d) also suggests that VPA inhibits GPR17 expression by likely regulating transcription factors that activate the GPR17 promoter, such as Olig1 or FoxO1 [18,23,44,45], thus disrupting the balance between oligodendroglial commitment and stemcellness.…”

Section: Valproic Acid Fosters the Neuronal Commitment Of Opcs And Momentioning

confidence: 97%

A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro

Boccazzi

Lecca

Marangon

et al. 2016

Purinergic Signalling

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Oligodendrocyte precursor cells (OPCs, also called NG2 cells) are scattered throughout brain parenchyma, where they function as a reservoir to replace lost or damaged oligodendrocytes, the myelin-forming cells. The hypothesis that, under some circumstances, OPCs can actually behave as multipotent cells, thus generating astrocytes and neurons as well, has arisen from some in vitro and in vivo evidence, but the molecular pathways controlling this alternative fate of OPCs are not fully understood. Their identification would open new opportunities for neuronal replace strategies, by fostering the intrinsic ability of the brain to regenerate. Here, we show that the anti-epileptic epigenetic modulator valproic acid (VPA) can promote the generation of new neurons from NG2 + OPCs under neurogenic protocols in vitro, through their initial de-differentiation to a stem cell-like phenotype that then evolves to Bhybrid^cell population, showing OPC morphology but expressing the neuronal marker βIII-tubulin and the GPR17 receptor, a key determinant in driving OPC transition towards myelinating oligodendrocytes. Under these conditions, the pharmacological blockade of the P2Y-like receptor GPR17 by cangrelor, a drug recently approved for human use, partially mimics the effects mediated by VPA thus accelerating cells' neurogenic conversion. These data show a co-localization between neuronal markers and GPR17 in vitro, and suggest that, besides its involvement in oligodendrogenesis, GPR17 can drive the fate of neural precursor cells by instructing precursors towards the neuronal lineage. Being a membrane receptor, GPR17 represents an ideal Bdruggable^target to be exploited for innovative regenerative approaches to acute and chronic brain diseases.

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FoxO1 Target Gpr17 Activates AgRP Neurons to Regulate Food Intake

Cited by 171 publications

References 52 publications

The new biology of diabetes

The new biology of diabetes

Differential gene regulation of GHSR signaling pathway in the arcuate nucleus and NPY neurons by fasting, diet-induced obesity, and 17β-estradiol

A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro

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