Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake

Kitamura, Tadahiro; Feng, Yun; Kitamura, Yoichi; Chua, Streamson C.; Xu, Allison; Barsh, Gregory S.; Rossetti, Luciano; Accili, Domenico

doi:10.1038/nm1392

Cited by 405 publications

(401 citation statements)

References 41 publications

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“…We have previously shown that SOCS3 expression is Cre-dependent, and its expression is upregulated approximately twofold in Cre-expressing cells upon recombination (6). The Tg.Agrp-Cre mice have been used and validated in a number of independent studies (7,(25)(26)(27)(28)(29)(30)(31). The resultant mutant mice, termed AgRP-SOCS3-OE, were born in Mendelian ratio with no detectable gross abnormalities.…”

Section: Expression Of Socs3 In Agrp Neurons Is Dynamically Modulated Inmentioning

confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

111

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Chronic consumption of a fat-rich diet leads to attenuation of leptin signaling in hypothalamic neurons, a hallmark feature of cellular leptin resistance. To date, little is known about the temporal and spatial dysregulation of neuronal function under conditions of nutrient excess. We show that agouti-related protein (AgRP)-expressing neurons precede proopiomelanocortin neurons in developing diet-induced cellular leptin resistance. High-fat diet-induced up-regulation of suppressor of cytokine signaling-3 (SOCS3) occurs in AgRP neurons before proopiomelanocortin and other hypothalamic neurons. SOCS3 expression in AgRP neurons increases after 2 d of high-fat feeding, but reduces after switching to a low-fat diet for 1 d. Consistently, transgenic overexpression of SOCS3 in AgRP neurons produces metabolic phenotypes resembling those observed after short-term high-fat feeding. We further show that AgRP neurons are the predominant cell type situated outside the blood-brain barrier in the mediobasal hypothalamus. AgRP neurons are more responsive to low levels of circulating leptin, but they are also more prone to development of leptin resistance in response to a small increase in blood leptin concentrations. Collectively, these results suggest that AgRP neurons are able to sense slight changes in plasma metabolic signals, allowing them to serve as first-line responders to fluctuation of energy intake. Furthermore, modulation of SOCS3 expression in AgRP neurons may play a dynamic and physiological role in metabolic fine tuning in response to short-term changes of nutritional status.M ost common forms of obesity, including diet-induced obesity, are associated with hyperleptinemia and impairment of leptin signaling in hypothalamic neurons, the hallmark feature of cellular leptin resistance. Suppressor of cytokine signaling-3 (SOCS3), a direct transcriptional product of STAT3, is up-regulated in the hypothalamus of diet-induced obese animals (1, 2). Mice with heterozygous mutation of the Socs3 gene, neuronal, or proopiomelanocortin (POMC)-specific deletion of the Socs3 gene are hypersensitive to leptin and resistant to diet-induced obesity (3-5). Conversely, up-regulation of SOCS3 in POMC neurons of chow-fed mice leads to increased body adiposity (6). In addition, wide-spread up-regulation of SOCS3 has been shown to be associated with neuronal inflammation in diet-induced obese animals (7). Thus SOCS3, which is up-regulated in chronic obesity, is commonly thought to play a pathophysiological role in obesity-associated leptin resistance.Multiple neuronal subtypes in several regions of the hypothalamus, including the arcuate nucleus, ventromedial hypothalamus, dorsomedial hypothalamus, and lateral hypothalamic area, have been implicated in the regulation of energy balance and leptin action (8,9). A number of hypothalamic neurons and extrahypothalamic neurons express functional leptin receptor (10, 11). Among these neurons, POMC and agouti-related protein (AgRP) neurons are two key arcuate neuronal subtypes. POMC and AgRP neu...

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Section: Expression Of Socs3 In Agrp Neurons Is Dynamically Modulated Inmentioning

confidence: 99%

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Olofsson

Unger

Cheung

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

123

111

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“…Among the targets of activated Akt are mTOR and the forkhead transcription factor FoxO1 (19). Recently, it was reported that FoxO1 in hypothalamus is involved in regulating neuropeptide expression and food intake (13,14). Pomc expression partially depends on the PDK-1-FoxO1 signaling pathway.…”

Section: Loss Of Pdk-1 In Pomc Neurons Blunts Influx Of Ca 2ϩ By Leptinmentioning

confidence: 99%

“…FoxO1 is a downstream element of insulin signaling: it is phosphorylated and inhibited in a PI(3)K -dependent manner (1). Recent FoxO1 studies using adenoviral delivery to the hypothalamus have demonstrated that FoxO1 increased food intake through the activation of AgRP and/or Npy gene expression and the inhibition of Pomc gene expression (13,14). Belgardt et al (4) delineated the importance of pathways downstream of PI(3)K in POMC neurons by using mice in which Pdk1 was inactivated specifically in POMC neurons.…”

mentioning

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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“…Previously, we have identified that forkhead boxcontaining protein 1 (FOXO1) may act at a step downstream of STAT3 phosphorylation to prevent activated STAT3 from interacting with the SP1-Pomc promoter complex, thereby repressing transcriptional activation [10]. FOXO1 may also inhibit phosphorylated STAT3 (pSTAT3) action directly at the promoter level [11,12].…”

Section: Introductionmentioning

confidence: 99%

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

Shi

Wang

et al. 2013

Diabetologia

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Aims/hypothesis While chronic low-grade inflammation is associated with obesity, acute inflammation reduces food intake and leads to negative energy balance. Although both types of inflammation activate nuclear factor κB (NF-κB) signalling, it remains unclear how NF-κB activation results in opposite physiological responses in the two types of inflammation. The goal of this study was to address this question, and to understand the link between inflammation and leptin signalling.Methods We studied the ability of NF-κB to modulate Pomc transcription, and how it impinges on signal transducer and activator of transcription 3 (STAT3)-mediated leptin signalling by using a combination of animal models, biochemical assays and molecular biology. Results We report that suppression of food intake and physical movement with acute inflammation is not dependent on STAT3 activation in pro-opiomelanocortin (POMC) neurons. Under these conditions, activated NF-κB independently leads to increased Pomc transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation (ChIP) experiments reveal that NF-κB v-rel reticuloendotheliosis viral oncogene homologue A (avian) (RELA [also known as p65]) binds to the Pomc promoter region between −138 and −88 bp, which also harbours the trans-acting transcription factor 1 (SP1) binding site. We found significant changes in the methylation pattern at this region and reduced Pomc activation under chronic inflammation induced by a high-fat diet. Furthermore, RELA is unable to bind and activate transcription when the Pomc promoter is methylated. Finally, RELA binds to STAT3 and inhibits STAT3-mediated promoter activity, suggesting that RELA, possibly together with forkhead box-containing protein 1 (FOXO1), may prevent STAT3-mediated leptin activation of the Pomc promoter. Conclusions/interpretation Our study provides a mechanism for the involvement of RELA in the divergent regulation of energy homeostasis in acute and chronic inflammation.

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Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake

Cited by 405 publications

References 41 publications

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

Modulation of AgRP-neuronal function by SOCS3 as an initiating event in diet-induced hypothalamic leptin resistance

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

Nuclear factor κB (NF-κB) suppresses food intake and energy expenditure in mice by directly activating the Pomc promoter

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