mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice

Burke, Luke K.; Darwish, Tamana; Cavanaugh, Althea R.; Virtue, Sam; Roth, Emma; Moro, Joanna; Liu, Shunmei; Xia, Jing; Dalley, Jeffrey W.; Burling, Keith; Chua, Streamson C.; Vidal-Puig, Toni; Schwartz, Gary J.; Blouet, Clémence

doi:10.1101/110544

Cited by 7 publications

(12 citation statements)

References 66 publications

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“…Increased mTORC1 activity is associated with increased intracellular energy availability [20], [21]. We and others have shown that mTORC1 signaling participates in the regulation of energy balance by modulating the function of both POMC and AgRP neurons [22], [23], [24], [25], [26]. mTORC1 activity also regulates oxidative metabolism in POMC neurons, which, in turn, is critical for the appetite suppressant action of the hormone leptin [27].…”

Section: Introductionmentioning

confidence: 99%

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

Mazier

Saucisse

Simon

et al. 2019

Molecular Metabolism

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ObjectiveThe hypothalamic paraventricular nucleus (PVN) is a key target of the melanocortin system, which orchestrates behavioral and metabolic responses depending on energy availability. The mechanistic target of rapamycin complex 1 (mTORC1) and the endocannabinoid type 1 receptor (CB1R) pathways are two key signaling systems involved in the regulation of energy balance whose activity closely depends upon energy availability. Here we tested the hypothesis that modulation of mTORC1 and CB1R signaling regulates excitatory glutamatergic inputs onto the PVN.MethodsPatch-clamp recordings in C57BL/6J mice, in mice lacking the mTORC1 component Rptor or CB1R in pro-opio-melanocortin (POMC) neurons, combined with pharmacology targeting mTORC1, the melanocortin receptor type 4 (MC4R), or the endocannabinoid system under chow or a hypercaloric diet.ResultsAcute pharmacological inhibition of mTORC1 in C57BL/6J mice decreased glutamatergic inputs onto the PVN via a mechanism requiring modulation of MC4R, endocannabinoid 2-AG mobilization by PVN parvocellular neurons, and retrograde activation of presynaptic CB1R. Further electrophysiology studies using mice lacking mTORC1 activity or CB1R in POMC neurons indicated that the observed effects involved mTORC1 and CB1R-dependent regulation of glutamate release from POMC neurons. Finally, energy surfeit caused by hypercaloric high-fat diet feeding, rapidly and time-dependently altered the glutamatergic inputs onto parvocellular neurons and the ability of mTORC1 and CB1R signaling to modulate such excitatory activity.ConclusionsThese findings pinpoint the relationship between mTORC1 and endocannabinoid-CB1R signaling in the regulation of the POMC-mediated glutamatergic inputs onto PVN parvocellular neurons and its rapid alteration in conditions favoring the development of obesity.

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Section: Introductionmentioning

confidence: 99%

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

Mazier

Saucisse

Simon

et al. 2019

Molecular Metabolism

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“…Along this line, the AgRP response to food cues is accompanied by modulation of their physiological outputs. For instance, food sensory exposure in AgRP‐activated mice rapidly increases iBAT temperature to the level of control animals (Burke et al, 2017), revealing that acute sensory inhibition of AgRP neurons is sufficient to initiate whole‐body responses similar to that observed upon refeeding. Food perception also primes post‐prandial hepatic responses through the activation of ARH neurons expressing pro‐opiomelanocortin (POMC) (Brandt et al, 2018).…”

Section: Agrp Neuronal Regulation In the Anticipatory Phasementioning

confidence: 99%

AgRP neuronal activity across feeding‐related behaviours

Gouveia

Beleza

Steculorum

2021

Eur J of Neuroscience

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AgRP neurons trigger one of the most potent orexigenic responses and are both necessary and sufficient for feeding. Recent technical advances for monitoring in vivo neuronal activity have revisited a previously well-established model of AgRP neurons' feeding regulatory effects. Our current understanding of AgRP neurons has increased in complexity and revealed a fine-tuned regulation of their activity dynamics across the whole sequence of feeding-related behaviours. This review focuses on recent studies that refined and re-evaluated our understanding of the regulatory principles and behavioural effects of AgRP circuits. We aim to cover major discoveries on the dynamic regulation of AgRP neuronal activity by exteroceptive and interoceptive food-related cues, their pleiotropic effects in feeding and whole-body homeostasis, and the associated AgRP circuits. The function and regulation of AgRP neuron will be sequentially discussed across the temporal series of behavioural and physiological changes occurring during the appetitive (food craving and foraging), the anticipatory (discovery of food-predicting cues), and the consummatory/postingestive phase of feeding (calorie ingestion).

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“…Interestingly, this circuit appears to extend to include forebrain hypothalamic neurons as well. Gastrointestinal infusions of nutrients, but not non-nutrients, rapidly reduce the neurophysiological activity of a subpopulation of hypothalamic neurons expressing orexigenic agouti related peptide (AGRP) (Beutler et al, 2017), and work of Blouet and colleagues has, in turn, implicated AGRP neuronal activity as an important determinant of BAT thermogenesis (Burke et al, 2017). Activating AGRP neurons reduces sympathetic outflow to BAT and reduces thermogenesis, while inhibiting these neurons leads to increased sympathetic outflow and increased BAT thermogenesis.…”

Section: Non-canonical Roles For Gut Vagal Afferent Signalingmentioning

confidence: 99%

Roles for gut vagal sensory signals in determining energy availability and energy expenditure

Schwartz

2018

Brain Research

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The gut sensory vagus transmits a wide range of meal-related mechanical, chemical and gut peptide signals from gastrointestinal and hepatic tissues to the central nervous system at the level of the caudal brainstem. Results from studies using neurophysiological, behavioral physiological and metabolic approaches that challenge the integrity of this gut-brain axis support an important role for these gut signals in the negative feedback control of energy availability by limiting food intake during a meal. These experimental approaches have now been applied to identify important and unanticipated contributions of the vagal sensory gut-brain axis to the control of two additional effectors of overall energy balance: the feedback control of endogenous energy availability through hepatic glucose production and metabolism, and the control of energy expenditure through brown adipose tissue thermogenesis. Taken together, these studies reveal the pleiotropic influences of gut vagal meal-related signals on energy balance, and encourage experimental efforts aimed at understanding how the brainstem represents, organizes and coordinates gut vagal sensory signals with these three determinants of energy homeostasis.

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mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice

Cited by 7 publications

References 66 publications

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

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

AgRP neuronal activity across feeding‐related behaviours

Roles for gut vagal sensory signals in determining energy availability and energy expenditure

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