Selective novel inverse agonists for human GPR43 augment GLP-1 secretion

Park, Bi-Oh; Kim, Seong Heon; Kong, Gye Yeong; Kim, Da Hui; Kwon, Mi So; Lee, Su Ui; Kim, Mun-Ock; Cho, Sungchan; Lee, Sangku; Lee, Hyun Jun; Han, Sang‐Bae; Kwak, Young Shin; Lee, Sung Bae; Kim, Sunhong

doi:10.1016/j.ejphar.2015.12.010

Cited by 42 publications

(34 citation statements)

References 37 publications

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“…Moreover, as anticipated for a defined G q /G 11 -mediated end point, AZ1729 was unable to recapitulate the incretin effect of C3, further confirming that FFA2 modulates GLP-1 secretion via a G q/11 mechanism in mouse colonic crypts. It is interesting to note in this regard that compound BTI-A-404, recently described as a selective and potent competitive inverse agonist of human FFA2/GPR43 (52), has been reported to promote GLP-1 secretion in a human cell line. Whether there is divergence between mouse and human FFA2 signal transduction at this end point thus requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bolognini

Moss

Nilsson

et al. 2016

Journal of Biological Chemistry

104

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The short chain fatty acid receptor FFA2 is able to stimulate signaling via both Gi- and Gq/G11-promoted pathways. These pathways are believed to control distinct physiological end points but FFA2 receptor ligands appropriate to test this hypothesis have been lacking. Herein, we characterize AZ1729, a novel FFA2 regulator that acts as a direct allosteric agonist and as a positive allosteric modulator, increasing the activity of the endogenously produced short chain fatty acid propionate in Gi-mediated pathways, but not at those transduced by Gq/G11. Using AZ1729 in combination with direct inhibitors of Gi and Gq/G11 family G proteins demonstrated that although both arms contribute to propionate-mediated regulation of phospho-ERK1/2 MAP kinase signaling in FFA2-expressing 293 cells, the Gq/G11-mediated pathway is predominant. We extend these studies by employing AZ1729 to dissect physiological FFA2 signaling pathways. The capacity of AZ1729 to act at FFA2 receptors to inhibit β-adrenoreceptor agonist-promoted lipolysis in primary mouse adipocytes and to promote chemotaxis of isolated human neutrophils confirmed these as FFA2 processes mediated by Gi signaling, whereas, in concert with blockade by the Gq/G11 inhibitor FR900359, the inability of AZ1729 to mimic or regulate propionate-mediated release of GLP-1 from mouse colonic preparations defined this physiological response as an end point transduced via activation of Gq/G11.

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Section: Discussionmentioning

confidence: 99%

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

Bolognini

Moss

Nilsson

et al. 2016

Journal of Biological Chemistry

104

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“…Immune-dysregulation could result from factors that ablate the normal microbiota, such as antibiotics, thereby suppressing microbial interactions with toll-like receptors and Treg cells in the gut 120 , 121 , 122 or the production of immuno-regulatory metabolites, such as short-chain fatty acids (SCFAs). 122 , 123 , 124 Alternatively, factors that trigger dysbiosis, such as high fat consumption, could act by promoting the production of pro-inflammatory bacterial metabolites. 125 In addition, the dysbiotic changes in the gut microbiota could influence inflammation and CNS function through changes in activation of vagal and/or spinal nerve pathways.…”

Section: The Role Of the Microbiome In Brain Developmentmentioning

confidence: 99%

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

et al. 2016

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The human body hosts an enormous abundance and diversity of microbes, which perform a range of essential and beneficial functions. Our appreciation of the importance of these microbial communities to many aspects of human physiology has grown dramatically in recent years. We know, for example, that animals raised in a germ-free environment exhibit substantially altered immune and metabolic function, while the disruption of commensal microbiota in humans is associated with the development of a growing number of diseases. Evidence is now emerging that, through interactions with the gut–brain axis, the bidirectional communication system between the central nervous system and the gastrointestinal tract, the gut microbiome can also influence neural development, cognition and behaviour, with recent evidence that changes in behaviour alter gut microbiota composition, while modifications of the microbiome can induce depressive-like behaviours. Although an association between enteropathy and certain psychiatric conditions has long been recognized, it now appears that gut microbes represent direct mediators of psychopathology. Here, we examine roles of gut microbiome in shaping brain development and neurological function, and the mechanisms by which it can contribute to mental illness. Further, we discuss how the insight provided by this new and exciting field of research can inform care and provide a basis for the design of novel, microbiota-targeted, therapies.

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“…In HEK293 cells that expressed the FFAR2-FFAR3 heteromer (FFAR-FFAR3-HEK293 or FFAR3tTa-FFAR2-HEK293), the antagonism of FFAR2 ( via CATPB (30, 31)) attenuated agonist-induced Ca 2+ signaling (Fig. 3 E ), β-arrestin-2 binding (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Unless otherwise stated, cells were pretreated for 15 min with either 10 μM YM254890 (G αq inhibitor) or 10 µM (S)-3-[2-(3-chlorophenyl)acetamido]-4-[4-(trifluoromethyl) phenyl]butanoic acid (CATPB; a FFAR2 antagonist) (30, 31) or for 2 h with 500 ng/ml pertussis toxin (Thermo Fisher Scientific, Waltham, MA, USA); and before activation with FFAR2/3 agonists: 10 mM acetate, 10 mM propionate, 10 mM butyrate, and 10 µM (2S)-2-(4-chlorophenyl)-3,3-dimethyl- N -(5-phenylthiazol-2- yl )butanamide (CFMB; Calbiochem, San Diego, CA, USA) (ChemSpider ID 24656891) (EC 50 of ∼0.7 µM) (32), or 10 µM N -(2,5-dichlorophenyl)-4-(furan-2- yl )-2-methyl-5-oxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxamide (AR420626; Glixx Laboratories, Southborough, MA, USA) (EC 50 of ∼0.7 µM) (33). …”

Section: Methodsmentioning

confidence: 99%

FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing

Ang

Xiong

et al. 2017

FASEB j.

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Free fatty acid receptors 2 and 3 (FFAR2/FFA2/GPR43 and FFAR3/FFA3/GPR41) are mammalian receptors for gut microbiota–derived short-chain fatty acids (SCFAs). These receptors are promising drug targets for obesity, colitis, colon cancer, asthma, and arthritis. Here, we demonstrate that FFAR2 and FFAR3 interact to form a heteromer in primary human monocytes and macrophages via proximity ligation assay, and during heterologous expression in HEK293 cells via bimolecular fluorescence complementation and fluorescence resonance energy transfer. The FFAR2-FFAR3 heteromer displayed enhanced cytosolic Ca2+ signaling (1.5-fold increase relative to homomeric FFAR2) and β-arrestin-2 recruitment (30-fold increase relative to homomeric FFAR3). The enhanced heteromer signaling was attenuated by FFAR2 antagonism (CATPB), Gαq inhibition (YM254890), or Gαi inhibition (pertussis toxin). Unlike homomeric FFAR2/3, the heteromer lacked the ability to inhibit cAMP production but gained the ability to induce p38 phosphorylation in HEK293 and inflammatory monocytes via a CATPB- and YM254890-sensitive mechanism. Our data, taken together, reveal that FFAR2 and FFAR3 may interact to form a receptor heteromer with signaling that is distinct from the parent homomers—a novel pathway for drug targeting.—Ang, Z., Xiong, D., Wu, M., Ding, J. L. FFAR2-FFAR3 receptor heteromerization modulates short-chain fatty acid sensing.

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Selective novel inverse agonists for human GPR43 augment GLP-1 secretion

Cited by 42 publications

References 37 publications

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

A Novel Allosteric Activator of Free Fatty Acid 2 Receptor Displays Unique Gi-functional Bias

From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways

FFAR2‐FFAR3 receptor heteromerization modulates short‐chain fatty acid sensing

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