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Functional expression of melanocortin 4 receptor in monocytes to suppress aortic aneurysm and atherosclerosis in mice

ABSTRACT: Melanocortin-4 receptor (MC4R) mediates most anorectic leptin response effects to an agonist, α-melanocyte-stimulating hormone (α-MSH). MC4R mutations are considered to be the main cause of monogenetic obesity in humans. It has been reported that the activity loss of MC4R gene increases body mass index and cardiovascular event risk in humans. This study aimed to investigate our hypothesis that MC4R signaling directly modulates vascular functions and that MC4R signaling loss leads to vascular diseases, such as vascular vulnerability and abdominal aortic aneurysm (AAA). To understand the molecular mechanism by which myeloid MC4R inhibits atherosclerosis and Ang II-induced AAA in mice, we first conducted a microarray analysis of LysM (+);MC4RTB/TB and MC4RTB/TB mouse primary BM-derived macrophages.

ORGANISM(S): Mus musculus

PROVIDER: GSE198975 | GEO | 2022/03/21

REPOSITORIES: GEO

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Project description:Neurons in the arcuate nucleus (ARC) sense the fed/fasted state and regulate hunger. ARCAgRP neurons release GABA, NPY and the melanocortin-4 receptor (MC4R) antagonist, AgRP, and are activated by fasting1-4. When stimulated, they rapidly and potently drive hunger5,6. ARCPOMC neurons, in contrast, release the MC4R agonist, α-MSH, and are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to decreased hunger2,4,7. Together, ARCAgRP and ARCPOMC neurons constitute the ARC feeding center. Against this, however, is the finding that ARCPOMC neurons, unlike ARCAgRP neurons, fail to affect food intake over the timescale of minutes to hours following opto- or chemogenetic stimulation5,8. This suggests a rapidly acting component of the ARC satiety pathway is missing. Here, we show that excitatory ARC neurons identified by expression of vesicular glutamate transporter 2 (VGLUT2) and the oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on MC4R-expressing neurons in the paraventricular hypothalamus (PVHMC4R neurons), which are known to mediate satiety9. ARCPOMC neurons also send dense projections to the PVH. Importantly, the α-MSH they release post-synaptically potentiates glutamatergic synaptic activity onto PVHMC4R neurons – including that emanating from ARCVglut2 neurons. This suggests a means by which α-MSH can bring about satiety – via postsynaptic potentiation of this novel ARCVglut2 to PVHMC4R satiety circuit. Thus, while fast (GABA and NPY) and slow (AgRP) ARC hunger signals are delivered together by ARCAgRP neurons10,11, the temporally analogous satiety signals from the ARC, glutamate and α-MSH, are delivered separately by two parallel, interacting projections (from ARCVGLUT2 and ARCPOMC neurons). Discovery of this rapidly acting excitatory ARC → PVH satiety circuit, and its regulation by α-MSH, provides new insight into regulation of hunger/satiety.

Project description:In a thermal proteome profiling experiment we have identified 300 unique proteins that become thermally stabilized or destabilized downstream of signal activation of the melanocortin 3 receptor (MC3R) when expressed in HEK293 cells. Upon stimulation with either one of the endogenous MC3R-agonists ACTH, alpha-, or gamma-MSH, derived from the pro-opiomelanocortin (POMC) prohormone, we found that the majority of these thermally affected proteins is related to immunoregulatory processes including signaling cascades up- and downstream of the key transcription factors IRF, STAT and NFkappaB. Here, we have developed a computational pipeline that allows assessment of thermal melting curves from data obtained with label-free quantitation from ion-mobility enhanced LC-MS data. It enables differential expression analysis within the data obtained from a thermal proteome profiling experiment, since all relative abundance information is retained. We found with principal component analysis that the three POMC-peptides act in very distinguished ways on the expression pattern in the MC3R-expressing HEK293 cells. This is consistent with our findings from thermal proteome profiling analysis where we identified 142, 107 and 95 proteins to be thermally affected by ACTH, alpha- and gamma-MSH, respectively, with only 4 proteins identified across all three agonists, and an additional 36 proteins shared pairwise between the agonists. Interestingly, we found proteins involved in immune responses to be enriched according to gene set enrichment analysis with Reactome pathways. As a result of these findings, we inferred transcription factor activities of the involved thermally affected transcription factors using Bayesian analysis based on differential expression data. Our findings on transcription factor activity were validated with patterns of peptide phosphorylation abundance analysis. These combined efforts revealed that all three agonists act via the cAMP-PKA-CREB pathway but that there are differences in the further downstream affected pathways and the identities of the thermally affected pathways proteins in particular kinases.

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Functional expression of melanocortin 4 receptor in monocytes to suppress aortic aneurysm and atherosclerosis in mice

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