Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons

Al-Qassab, Hind; Smith, Mark A.; Irvine, Elaine E.; Guillermet-Guibert, Julie; Claret, Marc; Choudhury, Agharul I.; Selman, Colin; Piipari, Kaisa; Clements, Melanie; Lingard, Steven; Chandarana, Keval; Bell, Jimmy D.; Barsh, Gregory S.; Smith, Andrew J.H.; Batterham, Rachel L.; Ashford, M. L. J.; Vanhaesebroeck, Bart; Withers, Dominic J.

doi:10.1016/j.cmet.2009.09.008

Cited by 149 publications

(184 citation statements)

References 48 publications

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“…Our findings indicate a dissociated role of distinct PI3K catalytic subunits downstream of leptin signaling, which has also been suggested by studies using chemically defined hypothalamic neurons (14, 20, 21). The metabolic similarities between mice with deletion of PI3K and those with deletion of PTEN in LR cells were intriguing (14,20,21). PTEN is a phosphatase associated with conversion of PIP3 to PIP2, resulting in PI3K inactivation (40).…”

Section: Discussionmentioning

confidence: 99%

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PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano¹,

Borges²,

Donato³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 99%

“…neurons has suggested the existence of dissociated effects of both subunits in energy balance and glucose homeostasis (16,(20)(21)(22), but, again, whether these responses are associated with leptin or insulin signaling has not been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

García-Galiano¹,

Borges²,

Donato³

et al. 2017

JCI Insight

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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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“…In a recent study, the authors generated a mouse model carrying a conditional deletion of p110α or p110β specifically from cells that express POMC or AgRP (52). As opposed to what was previously suggested, these authors showed that the p110β subunit exerts a dominant role over p110α in the regulation of energy homeostasis.…”

Section: The Catalytic Subunits Of Class Ia Pi3ksmentioning

confidence: 88%

“…This study also emphasized the importance of the p110β subunit for the electrophysiological properties of these neurons, although some controversial points were presented. For instance, POMC-specific deletion of p110α (POMCp110α null) created a more hyperpolarized resting membrane potential, compared to intact POMC neurons (52). Apparently, these changes did not interfere with leptin activity, since leptin depolarized POMCp110α null neurons and increased their spike firing frequency, as observed in intact POMC neurons.…”

Section: The Catalytic Subunits Of Class Ia Pi3ksmentioning

confidence: 97%

The PI3K signaling pathway mediates the biological effects of leptin

Donato

Frazão

Elias

2010

Arq Bras Endocrinol Metab

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SUMMARYThe activation of the leptin receptor recruits several intracellular signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway. While some of the leptin-induced signaling pathways, such as the JAK2/STAT3 pathway, induce cellular responses primarily through changes in gene expression, the PI3K pathway affects cellular properties more rapidly, through post-translational changes such as protein phosphorylation. Accordingly, several studies have shown that the PI3K pathway is required for the acute effects of leptin, such as a leptin-induced decrease in food intake. Leptin signaling through PI3K also affects the electrophysiological properties of neurons, including changes in their membrane potential and firing rates. In this review, we summarize the recent advances in our understanding of the role played by the PI3K signaling pathway in controlling food intake and energy balance. In particular, we focus on the importance of the PI3K signaling pathway as a mediator of the effects of leptin on hypothalamic neurons. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Keywords Phosphatidylinositol; phosphatidylinositol 3-kinases; energy balance; insulin; Akt; hypothalamus SUMÁRIO A ativação do receptor de leptina recruta diversas vias de sinalização intracelular, entre elas a via da fosfatidilinositol 3-quinase (PI3K). Enquanto algumas dessas vias, como a sinalização pelo JAK2/ STAT3, induzem respostas celulares por meio de mudanças na transcrição gênica, a via da PI3K altera propriedades celulares de forma rápida, via fosforilação de proteínas. Em concordância, estudos mostraram que a via da PI3K é necessária para que a leptina induza seus efeitos agudos, como redução da ingestão alimentar, após administração de leptina. A ativação da PI3K pela leptina também afeta as propriedades fisiológicas de neurônios, incluindo mudanças no potencial de membrana e no potencial de ação. Nesta revisão, resumimos os recentes avanços na compreensão do papel desempenhado pela via de sinalização da PI3K no controle da ingestão alimentar e do balanço energético. Discutimos, principalmente, como a via da PI3K é importante para mediar os efeitos da leptina sobre os neurônios hipotalâmicos. Arq Bras Endocrinol Metab. 2010;54(7):591-602 Descritores Fosfatidilinositol; fosfatidilinositol 3-quinase; balanço energético; insulina; Akt; hipotálamo review

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Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons

Cited by 149 publications

References 48 publications

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

PI3Kα inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction

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

The PI3K signaling pathway mediates the biological effects of leptin

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