GPR41 modulates insulin secretion and gene expression in pancreatic β‐cells and modifies metabolic homeostasis in fed and fasting states

Veprik, Anna; Laufer, Dana; Weiss, Sara; Rubins, Nir; Walker, Michael D.

doi:10.1096/fj.201500030r

Cited by 73 publications

(87 citation statements)

References 30 publications

(54 reference statements)

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“…Total RNA from single-cell suspensions or snap-frozen skin, liver, colon or ileum was isolated using the miRNeasy Kit (Qiagen) and reverse transcribed into cDNA using the High Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA). The following primers and PowerUP SYBR green polymerase (Applied Biosystems) were used to detect the following transcripts: 5′-CACGGCCTACATCCTCATCT-3′ and 5′-TTGGTAGGTACCAGCGGAAG-3′ ( Gpr43 ); 5′-CTGGCGGAGCTACGTGCT-3′ and 5′-GGGGTCGATACAAGAGT-3′ ( Gpr41 ) 43 ; 5′-ATGGCGAGGCATATCTGTGTAGCA-3′ and 5′-TCCTGCCTGAGCAGAACAAGATGA-3′ ( Gpr109a ) 44 ; 5′-GTCAACCGCACCTTTATGCT-3′ and 5′-GAACAGTTTCTCCCCGATGA-3′ ( IL-22 ); and 5′-TGACCTCAACTACATGGTCTACA-3′ and 5′-CTTCCCATTCTCGGCCTTG-3′ ( Gapdh ) 45 . All reactions were performed according to manufacturer’s instructions.…”

Section: Methodsmentioning

confidence: 99%

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

et al. 2018

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Microbiome-derived metabolites influence intestinal homeostasis and regulate graft-versus-host disease (GVHD), but the molecular mechanisms remain unknown. Here we show the metabolite sensor G-protein-coupled receptor 43 (GPR43) is important for attenuation of gastrointestinal GVHD in multiple clinically relevant murine models. GPR43 is critical for the protective effects of short-chain fatty acids (SCFAs), butyrate and propionate. Increased severity of GVHD in the absence of GPR43 is not due to baseline differences in the endogenous microbiota of the hosts. We confirm the ability of microbiome-derived metabolites to reduce GVHD by several methods, including co-housing, antibiotic treatment, and administration of exogenous SCFAs. The GVHD protective effect of SCFAs requires GPR43-mediated ERK phosphorylation and activation of the NLRP3 inflammasome in non-hematopoietic target tissues of the host. These data provide insight into mechanisms of microbial metabolite-mediated protection of target tissues from the damage caused allogeneic T cells.

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Section: Methodsmentioning

confidence: 99%

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

et al. 2018

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“…Herein, it is noted that butyrate, as a potent inhibitor of histone acetyltransferase and deacetylases (HDACs), epigenetically induces the proliferation and differentiation of immune cells [37] and upregulates the adiponectin-mediated AMPK pathway that stimulates mitochondria biogenesis and fatty acid oxidation [38]. In addition, the SCFA-induced GPR41/GPR43 signaling was reported to be capable of directly acting on pancreatic β cells to regulate insulin secretion [39,40,41,42]. For example, McNeils et al [40] demonstrated in vitro the enhancement of glucose-stimulated insulin secretion and β cell proliferation and gene expression by treating the isolated β cells with a GPR43-specific agonist.…”

Section: Dietary Fiber-derived Short Chain Fatty Acids and Obesitymentioning

confidence: 99%

Gut microbial metabolite short-chain fatty acids and obesity

Shimizu

Kimura

2017

Bioscience of Microbiota, Food and Health

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Over the past decade, the gut microbiota has emerged as an essential mediator in the pathophysiology of obesity and related metabolic disorders. In this context, the reciprocal interactions of the gut microbiota structure and their metabolite profiles with host metabolism predisposing to a range of pathological conditions (e.g., insulin resistance) related to energy homeostasis have been increasingly discussed in various animal models and human cohorts. Remarkably, as the role of gut microbial metabolites as critical signaling molecules that function through the complementary host receptors has come to be appreciated, tremendous attention has been focused on the proposed diet-gut microbiota-host homeostasis axis, entailing extensive cross-disciplinary efforts in medical, pharmaceutical, and agricultural sciences. This review will discuss the recent advances in understanding the mechanisms whereby the gut microbiota modulates the effects of diet and shapes the host metabolism either towards or away from obesity and related metabolic conditions. In particular, the interactions of short chain fatty acids (SCFAs), a subset of key gut microbial metabolites, with their specific receptors will be reviewed in relation to host energy homeostatic regulation and evaluated for potential as novel therapeutic targets for diet-induced obesity.

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“…Stimulates leptin production in adipocytes [154]. Modulates insulin secretion in pancreas [155] Gpr43 (FFAR2) SCFA (acetate, propionate,…”

Section: Butyrate)mentioning

confidence: 99%

The weight of nutrients: kynurenine metabolites in obesity and exercise

et al. 2018

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Obesity ultimately results from an imbalance between energy intake and expenditure. However, in addition to their bioenergetic value, nutrients and their metabolites can function as important signalling molecules in energy homeostasis. Indeed, macronutrients and their metabolites can be direct regulators of metabolism through their actions on different organs. In turn, target organs can decide to use, store or transform the incoming nutrients depending on their physiological context and in coordination with other cell types. Tryptophan-kynurenine metabolites are an example of a family of compounds that can serve as systemic integrators of energy metabolism by signalling to different cell types. These include adipocytes, immune cells and muscle fibres, in addition to the well-known effects of kynurenine metabolites on the central nervous system. In the context of energy metabolism, several of the effects elicited by kynurenic acid are mediated by the G-protein-coupled receptor, GPR35. As GPR35 is expressed in tissues such as the adipose tissue, immune cells and the gastrointestinal tract, this receptor could be a potential therapeutic target for the treatment of obesity, diabetes and other metabolic diseases. In addition, metabolic disorders often coincide with states of chronic inflammation, which further highlights GPR35 as an integration node in conditions where inflammation skews metabolism. Defining the molecular interplay between different tissues in the regulation of energy homeostasis can help us understand interindividual variability in the response to nutrient intake and develop safe and efficient therapies to fight obesity and metabolic disease.

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GPR41 modulates insulin secretion and gene expression in pancreatic β‐cells and modifies metabolic homeostasis in fed and fasting states

Cited by 73 publications

References 30 publications

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

Microbial metabolite sensor GPR43 controls severity of experimental GVHD

Gut microbial metabolite short-chain fatty acids and obesity

The weight of nutrients: kynurenine metabolites in obesity and exercise

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