MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R

Bernard, Adélaïde; Naharros, Irene Ojeda; Yue, Xinyu; Mifsud, François; Blake, Abbey; Bourgain-Guglielmetti, Florence; Ciprin, Jordi; McDaid, Erin; Kim, Kellan; Nachury, Maxence V.; Reiter, Jeremy F.; Vaisse, Christian

doi:10.1172/jci.insight.155900

Cited by 8 publications

(9 citation statements)

References 47 publications

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“…Within each group, the trials were sorted by their agonist response. Consistent with previous biochemical characterizations 29,30,41,142 , POMC stimulation drove mostly cAMP increments (>12% of the trials) while AgRP stimulation drove mostly cAMP decrements (>20%). The opposite-direction hits (i.e., cAMP decrements during POMC stimulation and increments during AgRP stimulation) occur in less than 1% of the trials, lending credibility to the classification scheme.…”

Section: Classifier Of Camp Increments and Decrementssupporting

confidence: 90%

“…The 100-µm spatial impact of neuropeptide signaling While it is proposed that most MC4Rs are found in the primary cilium near the PVH MC4R soma [142][143][144] , POMC synapses are most commonly found on the distal dendrites of PVH neurons 73 . The ~100 μm impact diameter during stochastic release of feeding-related neuropeptides (Figure 4N) may resolve this discrepancy due to the spread of peptidergic signals throughout much of the somatodendritic span of a given neuron.…”

Section: Peptide Competition Enables Accurate Representation Of Energ...mentioning

confidence: 99%

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Competition between stochastic neuropeptide signals calibrates the rate of satiation

Andermann

Zhang

Kim

et al. 2023

Preprint

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We investigated how transmission of hunger- and satiety-promoting neuropeptides, NPY and αMSH, is integrated at the level of intracellular signaling to control feeding. Receptors for these peptides use the second messenger cAMP. How cAMP integrates opposing peptide signals to regulate energy balance, and the in vivo spatiotemporal dynamics of endogenous peptidergic signaling, remain largely unknown. We show that AgRP axon stimulation in the paraventricular hypothalamus evokes probabilistic NPY release that triggers stochastic cAMP decrements in downstream MC4R-expressing neurons (PVHMC4R). Meanwhile, POMC axon stimulation triggers stochastic, αMSH-dependent cAMP increments. Release of either peptide impacts a ~100 µm diameter region, and when these peptide signals overlap, they compete to control cAMP. The competition is reflected by hunger-state-dependent differences in the amplitude and persistence of cAMP transients: hunger peptides are more efficacious in the fasted state, satiety peptides in the fed state. Feeding resolves the competition by simultaneously elevating αMSH release and suppressing NPY release, thereby sustaining elevated cAMP in PVHMC4R neurons. In turn, cAMP potentiates feeding-related excitatory inputs and promotes satiation across minutes. Our findings highlight how biochemical integration of opposing, quantal peptide signals during energy intake orchestrates a gradual transition between stable states of hunger and satiety.

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Section: Classifier Of Camp Increments and Decrementssupporting

confidence: 90%

Section: Peptide Competition Enables Accurate Representation Of Energ...mentioning

confidence: 99%

Competition between stochastic neuropeptide signals calibrates the rate of satiation

Andermann

Zhang

Kim

et al. 2023

Preprint

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“…Although we did not observe a significant difference in terms of the varying relative expressions of MRAP2 and MC4R, a reduction in MRAP2 expression relative to a 1:1 stoichiometry could have a profound impact on MC4R pharmacology and thus physiology in vivo . Cell-type specific expression of MRAP2 emerges thus as an additional tool that organisms can use to modulate and bias GPCR signaling in a context-dependent fashion 20 . In addition, more aspects of MRAP2 besides monomerization might exist.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, more aspects of MRAP2 besides monomerization might exist. For example a role of MRAP2 in cilial localization of MC4R was recently reported that is supposed to be critical for MC4R function 20 .…”

Section: Discussionmentioning

confidence: 99%

“…MRAP2 is predominantly expressed in tissues impacting metabolism and glucose homeostasis, including the central nervous system (CNS), the pancreas, the gut and adipose tissues 17 . Within the mouse CNS, especially in the hypothalamus and in the paraventricular nucleus (PVN), MRAP2 is co-expressed in some neurons together with the MC4R, where it is important for some functions of the MC4R 4,[18][19][20] . Furthermore, MRAP2 and MC4R messenger RNAs were both found in human PVN (The Human Protein Atlas) at a ratio around 3:1 (Supplementary table 1).…”

Section: Introductionmentioning

confidence: 99%

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MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

Sohail,

Laurin,

Kleinau

et al. 2024

Preprint

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The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) and a key regulator of appetite and metabolism. It can interact with the melanocortin-receptor accessory protein 2 (MRAP2), a single transmembrane helix protein known to interplay with several different GPCRs. However, the consequences of this interaction are not completely understood. Here we report that co-expression of MRAP2 has multiple effects on the MC4R: it enhances G protein-mediated signaling and simultaneously impairs beta-arrestin2 recruitment and, consequently, internalization. In addition, co-expression of MRAP2 leads to an increased number of monomers of MC4R by disrupting receptor oligomers. A structural model of the active state MC4R-MRAP2 complex supports the experimentally observed monomerization. Taken together, our data indicate that MRAP2 is an accessory protein that interacts with and influences MC4R structure, biasing its signaling towards G protein-mediated effects.

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Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity

Zuccaro,

LeDuc,

Thaker

2024

Curr Obes Rep

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MRAP2 regulates energy homeostasis by promoting primary cilia localization of MC4R

Cited by 8 publications

References 47 publications

Competition between stochastic neuropeptide signals calibrates the rate of satiation

Competition between stochastic neuropeptide signals calibrates the rate of satiation

MRAP2 modifies the signaling and oligomerization state of the melanocortin-4 receptor

Updates on Rare Genetic Variants, Genetic Testing, and Gene Therapy in Individuals With Obesity

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