Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes

Shcherbina, Liliya; Edlund, Anna; Esguerra, Jonathan L.S.; Abels, Mia; Zhou, Yunan; Ottosson-Laakso, Emilia; Wollheim, Claes B.; Hansson, Ola; Eliasson, Lena; Wierup, Nils

doi:10.1016/j.mce.2017.02.027

Cited by 13 publications

(8 citation statements)

References 55 publications

(70 reference statements)

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“…S6D-G). Because these neuropeptides are known to be expressed both in the periphery(25)(26)(27)(28)(29) and CNS (24), we used a local viral delivery approach to target these neurons and avoid CNS effects. Injection of retrograde adeno-associated virus (AAVrg)-FLEX-tdTomato (30) revealed a prominent population of tdTomato+ neurons in the ileum, and colon myenteric plexus of Cartpt Cre(31) and Npy Cre (32) mice(Fig.…”

mentioning

confidence: 99%

Microbiota–modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Müller

Schneeberger

Matheis

et al. 2020

Preprint

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Microbial density and diversity increase towards the distal intestine, affecting tissue physiology, metabolism, and function of both immune and nervous systems. Intrinsic enteric-associated neurons (iEAN) continuously monitor and modulate intestinal functions, including nutrient absorption and motility.Through molecular, anatomic and functional approaches, we characterized the influence of the microbiota on iEAN. We found that iEAN are functionally adapted to the intestinal segment they occupy, with a stronger microbiota influence on distal intestine neurons. Chemogenetic characterization of microbiotainfluenced iEAN identified a subset of viscerofugal CART+ neurons, enriched in the distal intestine, able to modulate feeding through insulin-glucose levels. Retro-and anterograde tracing revealed that CART+ viscerofugal neurons send axons to the gut sympathetic ganglion and are synaptically connected to the liver and pancreas. Our results demonstrate a region-specific adaptation of enteric neurons and indicate that specific iEAN subsets are capable of regulating host physiology independently from the central nervous system. One Sentence Summary:Microbes impact regionally defined intrinsic enteric neuron translatomes, including a novel CART+ glucoregulatory viscerofugal population. Main Text:EAN comprise a numerous and heterogeneous population of neurons within the gastrointestinal (GI) tract that monitor and respond to various environmental cues such as mechanical stretch and luminal metabolites (1, 2). The vast majority of luminal stimuli are derived from the diet and commensal microbes, which may be sensed directly by EAN fibers positioned along the intestinal epithelium. Luminal perturbations can also be transmitted to EAN indirectly, via signals derived from epithelial, glial, or immune cells inhabiting the same compartment (1, 3). Intrinsic EAN (iEAN), which comprise a component of the enteric nervous system (ENS), are neural crest-derived and organized in two distinct layers, the myenteric or Auerbach's plexus and submucosal or Meissner's plexus (2). iEAN can operate autonomously and are primarily tasked with modulation of intestinal motility and secretory function (2). Recent studies have demonstrated that the gut microbiota influence the basal activity of intestine-associated cells, including the excitability of EAN and the activation state of immune cells (2-5). Additionally, microbial dysbiosis has a potential role in a host of metabolic disorders including obesity and diabetes (6, 7). Yet, whether the metabolic effects of the microbiota are mediated through the nervous system is still not known. These studies highlight the impact of the gut microbiota on EAN and key mammalian physiological processes, however the cellular circuits and molecular components that mediate gut-EAN or gut-brain communication remain poorly understood. We sought to determine how the microbiota impacts iEAN to better characterize their role in host physiology.To profile iEAN, we opted for a translating ribosomal affinity purificat...

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mentioning

confidence: 99%

Microbiota–modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Müller

Schneeberger

Matheis

et al. 2020

Preprint

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“…First, we used the PubMed database [ 75 ] and characterized each of the 39 novel PAG-related DEGs of the tame and aggressive rats ( Table 2 ) by answering the question as to how under- or overexpression of their human orthologs can aggravate or alleviate ARDs [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , ...…”

Section: Resultsmentioning

confidence: 99%

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

Shikhevich

Chadaeva

Khandaev

et al. 2023

IJMS

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Mainstream transcriptome profiling of susceptibility versus resistance to age-related diseases (ARDs) is focused on differentially expressed genes (DEGs) specific to gender, age, and pathogeneses. This approach fits in well with predictive, preventive, personalized, participatory medicine and helps understand how, why, when, and what ARDs one can develop depending on their genetic background. Within this mainstream paradigm, we wanted to find out whether the known ARD-linked DEGs available in PubMed can reveal a molecular marker that will serve the purpose in anyone’s any tissue at any time. We sequenced the periaqueductal gray (PAG) transcriptome of tame versus aggressive rats, identified rat-behavior-related DEGs, and compared them with their known homologous animal ARD-linked DEGs. This analysis yielded statistically significant correlations between behavior-related and ARD-susceptibility-related fold changes (log2 values) in the expression of these DEG homologs. We found principal components, PC1 and PC2, corresponding to the half-sum and the half-difference of these log2 values, respectively. With the DEGs linked to ARD susceptibility and ARD resistance in humans used as controls, we verified these principal components. This yielded only one statistically significant common molecular marker for ARDs: an excess of Fcγ receptor IIb suppressing immune cell hyperactivation.

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“…7c ). In insulin-secreting INS-1 832/13 cells, Cart has been reported to influence the expression and release of insulin 41 . Thus, the impact of PIEZO1 on β-cell function may not be limited to electrical excitability but these changes are likely to operate on a slower timescale than the acute/electrical effects.…”

Section: Resultsmentioning

confidence: 99%

A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells

Barghouth

Dou

et al. 2022

Nat Commun

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Glucose-induced insulin secretion depends on β-cell electrical activity. Inhibition of ATP-regulated potassium (KATP) channels is a key event in this process. However, KATP channel closure alone is not sufficient to induce β-cell electrical activity; activation of a depolarizing membrane current is also required. Here we examine the role of the mechanosensor ion channel PIEZO1 in this process. Yoda1, a specific PIEZO1 agonist, activates a small membrane current and thereby triggers β-cell electrical activity with resultant stimulation of Ca2+-influx and insulin secretion. Conversely, the PIEZO1 antagonist GsMTx4 reduces glucose-induced Ca2+-signaling, electrical activity and insulin secretion. Yet, PIEZO1 expression is elevated in islets from human donors with type-2 diabetes (T2D) and a rodent T2D model (db/db mouse), in which insulin secretion is reduced. This paradox is resolved by our finding that PIEZO1 translocates from the plasmalemma into the nucleus (where it cannot influence the membrane potential of the β-cell) under experimental conditions emulating T2D (high glucose culture). β-cell-specific Piezo1-knockout mice show impaired glucose tolerance in vivo and reduced glucose-induced insulin secretion, β-cell electrical activity and Ca2+ elevation in vitro. These results implicate mechanotransduction and activation of PIEZO1, via intracellular accumulation of glucose metabolites, as an important physiological regulator of insulin secretion.

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Endogenous beta-cell CART regulates insulin secretion and transcription of beta-cell genes

Cited by 13 publications

References 55 publications

Microbiota–modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Microbiota–modulated enteric neuron translational profiling uncovers a CART+ glucoregulatory subset

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic β-cells

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