mTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability

Mazier, Wilfrid; Saucisse, Nicolas; Simon, Vincent; Cannich, Astrid; Marsicano, Giovanni; Massa, Federico; Cota, Daniela

doi:10.1016/j.molmet.2019.08.005

Cited by 19 publications

(32 citation statements)

References 60 publications

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“…All animals used in experiments involving mutant mice were littermates. We have previously characterized POMC-Rptor-KO mice and POMC-CB1-KO mice (Haissaguerre et al, 2018;Mazier et al, 2019). Effective Cremediated deletion of rictor in POMC neurons was assessed by immunohistochemistry.…”

Section: Animalsmentioning

confidence: 99%

“…Then, by using optogenetics, we evaluated whether the acute inhibition of mTORC1 activity could alter POMC-driven neurotransmission. Among the different brain structures receiving POMC neurons projections, we studied this effect on parvocellular neurons of the PVN, since they are one of the targets of POMC neurons for the control of food intake Mazier et al, 2019).…”

Section: Mtorc1 Activity Oppositely Regulates Pomc/gabaergic and Pomcmentioning

confidence: 99%

“…Differently from a-MSH, hypothalamic endocannabinoids levels are high in fasting and low in refeeding (Kirkham et al, 2002) and CB1R activation counteracts behavioral and neuromodulatory effects of a-MSH (Mazier et al, 2019;Monge-Roffarello et al, 2014;Verty et al, 2004). We therefore reasoned that changes in hypothalamic a-MSH levels induced by the acute blockade of mTORC1 activity could be accompanied by opposite changes in hypothalamic endocannabinoid levels, which could have participated to the observed hyperphagia.…”

Section: Msh and Endocannabinoids Levelsmentioning

confidence: 99%

“…Endocannabinoids modulate food intake by acting onto CB1R (Mazier et al, 2015). To verify whether the hyperphagia induced by RAPA was due to increased endocannabinoid-CB1R signaling at the level of POMC neurons, we evaluated the effect of the mTORC1 inhibitor in mice lacking the expression of CB1 in POMC neurons (POMC-CB1-KO mice) (Mazier et al, 2019). Deletion of CB1 from POMC neurons did not alter per se 24h food intake ( Figure S7A), or the refeeding response ( Figure 6A).…”

Section: Mtorc1-dependent Recruitment Of Cb1r Signaling Restrains Gabmentioning

confidence: 99%

“…Among these, the retrograde suppression of neurotransmitter release through endocannabinoids acting at the presynaptic cannabinoid type 1 receptor (CB1R) is well described (Busquets-Garcia et al, 2018;Castillo et al, 2012). Brain CB1R activation generally stimulates food intake (Mazier et al, 2015) and it offsets a-MSH effects in the PVN (Mazier et al, 2019;Monge-Roffarello et al, 2014;Verty et al, 2004). However, the impact of brain CB1R on food intake is also cell-type specific.…”

Section: Introductionmentioning

confidence: 99%

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POMC neurons functional heterogeneity relies on mTORC1 signaling

Saucisse

Mazier

Simon

et al. 2020

Preprint

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Hypothalamic Pro-opiomelanocortin (POMC) neurons are classically known to trigger satiety. However, they encompass heterogeneous subpopulations whose functions are unknown.Here we show that POMC neurons releasing GABA, glutamate or both neurotransmitters possess distinct spatial distribution, molecular signatures and functions. Functional specificity of these subpopulations relies on the energy sensor mechanistic Target of Rapamycin Complex 1 (mTORC1), since pharmacological blockade of mTORC1, by mimicking a cellular negative energy state, simultaneously inhibited POMC/glutamatergic and activated POMC/GABAergic neurons. Chemogenetics and conditional deletion of mTORC1 then demonstrated that mTORC1 blockade in POMC neurons causes hyperphagia. This is due to decreased POMCderived anorexigenic a-melanocyte-stimulating hormone and the recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Genetic inhibition of glutamate release from POMC neurons also produced hyperphagia, recapitulating the phenotype caused by mTORC1 blockade.Altogether, these findings pinpoint the molecular mechanisms engaged by POMC neurons to oppositely control feeding, thereby challenging conventional views about their functions.

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Section: Animalsmentioning

confidence: 99%

Section: Mtorc1 Activity Oppositely Regulates Pomc/gabaergic and Pomcmentioning

confidence: 99%

Section: Msh and Endocannabinoids Levelsmentioning

confidence: 99%

Section: Mtorc1-dependent Recruitment Of Cb1r Signaling Restrains Gabmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

POMC neurons functional heterogeneity relies on mTORC1 signaling

Saucisse

Mazier

Simon

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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Hypothalamic cannabinoid signaling: Consequences for eating behavior

Lord,

Noble

2024

Pharmacology Res & Perspec

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In parallel to the legalization of cannabis for both medicinal and recreational purposes, cannabinoid use has steadily increased over the last decade in the United States. Cannabinoids, such as tetrahydrocannabinol and anandamide, bind to the central cannabinoid‐1 (CB1) receptor to impact several physiological processes relevant for body weight regulation, including appetite and energy expenditure. The hypothalamus integrates peripheral signals related to energy balance, houses several nuclei that orchestrate eating, and expresses the CB1 receptor. Herein we review literature to date concerning cannabinergic action in the hypothalamus with a specific focus on eating behaviors. We highlight hypothalamic areas wherein researchers have focused their attention, including the lateral, arcuate, paraventricular, and ventromedial hypothalamic nuclei, and interactions with the hormone leptin. This review serves as a comprehensive analysis of what is known about cannabinoid signaling in the hypothalamus, highlights gaps in the literature, and suggests future directions.

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Effects of mammalian target of rapamycin and aryl hydrocarbon receptor‐mediating autophagy signaling on the balance of Th17/Treg cells during perinatal bisphenol A exposure in female offspring mice

Gao

Luo

et al. 2022

Environmental Toxicology

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Bisphenol A (BPA)'s immunotoxic properties have received increasing interest, which can lead to immune dysfunction and related disease development. However, the mechanism is not completely clear. A growing body of evidence suggests that autophagy has important roles in innate immunity, inflammatory response, and adaptive immunity. This study aimed to investigate the possible mechanisms of mammalian target of rapamycin (mTOR), aryl hydrocarbon receptor (AhR), and autophagy in Treg/Th17 imbalance induced by perinatal BPA exposure. Our results showed that the number of Th17 cells in the spleen of offspring female mice significantly increased, while the number of Treg cells decreased significantly, which was consistent with the expression levels of up‐regulation of RORγt protein and a down‐regulation Foxp3 protein. The levels of mTOR, p‐mTOR, P62, and AhR protein expression increased, and LC3 protein decreased in spleen. However, in the thymus, we found that RORγt and Foxp3 proteins changed most significantly in the low‐dose BPA group, and the same as p‐mTOR and P62 protein levels. We conjectured that the potential mechanism of the imbalance of Th17/Treg upon perinatal exposure to BPA was probably associated with autophagy dysfunction. Proper autophagy plays an important role in maintaining the homeostasis of the thymic and spleen immune system.

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mTORC1 and CB1 receptor signaling regulate excitatory glutamatergic inputs onto the hypothalamic paraventricular nucleus in response to energy availability

Cited by 19 publications

References 60 publications

POMC neurons functional heterogeneity relies on mTORC1 signaling

POMC neurons functional heterogeneity relies on mTORC1 signaling

Hypothalamic cannabinoid signaling: Consequences for eating behavior

Effects of mammalian target of rapamycin and aryl hydrocarbon receptor‐mediating autophagy signaling on the balance of Th17/Treg cells during perinatal bisphenol A exposure in female offspring mice

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