• BMB Reports
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• v.47 no.3
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• pp.173-178
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• 2014

There is rapidly growing interest in the human microbiome because of its implication in metabolic disorders and inflammatory diseases. Consequently, understanding the biology of short chain fatty acids and their receptors has become very important for identifying novel therapeutic avenues. GPR41 and GPR43 have been recognized as the cognate receptors for SCFAs and their roles in metabolism and inflammation have drawn much attention in recent years. GPR43 is highly expressed on immune cells and has been suggested to play a role in inflammatory diseases such as inflammatory bowel disease. Both GPR41 and GPR43 have been implicated in diabetes and obesity via the regulation of adipose tissue and gastrointestinal hormones. So far, many studies have provided contradictory results, and therefore further research is required to validate these receptors as drug targets. We will also discuss the synthetic modulators of GPR41 and GPR43 that are critical to understanding the functions of these receptors.

• The Korean Journal of Physiology and Pharmacology
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• v.28 no.1
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• pp.1-10
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• 2024

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and dyslipidemia. Carvacrol (CAR) has demonstrated the potential to mitigate dyslipidemia. This study aims to investigate whether CAR can modulate blood glucose and lipid levels in a T2DM rat model by regulating short-chain fatty acids (SCFAs) and the GPR41/43 pathway. The T2DM rat model was induced by a high-fat diet combined with low-dose streptozocin injection and treated with oral CAR and/or mixed antibiotics. Fasting blood glucose, oral glucose tolerance, and insulin tolerance tests were assessed. Serum lipid parameters, hepatic and renal function indicators, tissue morphology, and SCFAs were measured. In vitro, high glucose (HG)-induced IEC-6 cells were treated with CAR, and optimal CAR concentration was determined. HG-induced IEC-6 cells were treated with SCFAs or/and GPR41/43 agonists. CAR significantly reduced blood lipid and glucose levels, improved tissue damage, and increased SCFA levels in feces and GPR41/43 expression in colonic tissues of T2DM rats. CAR also attenuated HG-induced apoptosis of IEC-6 cells and enhanced GPR41/43 expression. Overall, these findings suggest that CAR alleviates blood lipid and glucose abnormalities in T2DM rats by modulating SCFAs and the GPR41/43 pathway.

• Biomolecules & Therapeutics
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• v.30 no.1
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• pp.48-54
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• 2022

GPR43 (also known as FFAR2), a metabolite-sensing G-protein-coupled receptor stimulated by short-chain fatty acid (SCFA) ligands is involved in innate immunity and metabolism. GPR43 couples with Gα_i/o and Gα_q/11 heterotrimeric proteins and is capable of decreasing cyclic AMP and inducing Ca²⁺ flux. The GPR43 receptor has additionally been shown to bind β-arrestin 2 and inhibit inflammatory pathways, such as NF-κB. However, GPR43 shares the same ligands as GPR41, including acetate, propionate, and butyrate, and determination of its precise functions in association with endogenous ligands, such as SCFAs alone, therefore remains a considerable challenge. In this study, we generated novel synthetic agonists that display allosteric modulatory effects on GPR43 and downregulate NF-κB activity. In particular, the potency of compound 187 was significantly superior to that of pre-existing compounds in vitro. However, in the colitis model in vivo, compound 110 induced more potent attenuation of inflammation. These novel allosteric agonists of GPR43 clearly display anti-inflammatory potential, supporting their clinical utility as therapeutic drugs.

• Asian-Australasian Journal of Animal Sciences
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• v.33 no.4
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• pp.651-661
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• 2020

Objective: We hypothesized that Cr source can alter adipogenic-related transcriptional regulations and cell signaling. Therefore, the objective of the study was to evaluate the biological effects of chromium acetate (CrAc) on bovine intramuscular (IM) and subcutaneous (SC) adipose cells. Methods: Bovine preadipocytes isolated from two different adipose tissue depots; IM and SC were used to evaluate the effect of CrAc treatment during differentiation on adipogenic gene expression. Adipocytes were incubated with various doses of CrAc: 0 (differentiation media only, control), 0.1, 1, and 10 μM. Cells were harvested and then analyzed by real-time quantitative polymerase chain reaction in order to measure the quantity of adenosine monophosphate-activated protein kinase-α (AMPK-α), CCAAT enhancer binding protein-β (C/EBPβ), G protein-coupled receptor 41 (GPR41), GPR43, peroxisome proliferator-activated receptor-γ (PPARγ), and stearoyl CoA desaturase (SCD) mRNA relative to ribosomal protein subunit 9 (RPS9). The ratio of phosphorylated-AMPK (pAMPK) to AMPK was determined using a western blot technique in order to determine changing concentration. Results: The high dose (10 μM) of CrAc increased C/EBPβ, in both IM (p = 0.02) and SC (p = 0.02). Expression of PPARγ was upregulated by 10 μM of CrAc in IM but not in SC. Expression of SCD was also increased in both IM and SC with 10 μM of CrAc treatment. Addition of CrAc did not alter gene expression of glucose transporter 4, GPR41, or GPR43 in both IM and SC adipocytes. Addition of CrAc, resulted in a decreased pAMPKα to AMPKα ration (p<0.01) in IM. Conclusion: These data may indicate that Cr source may influence lipid filling in IM adipocytes via inhibitory action of AMPK phosphorylation and upregulating expression of adipogenic genes.

• Journal of Life Science
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• v.22 no.11
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• pp.1571-1586
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• 2012

On earth, there are about 5,400 kinds of mammals, of which about 1,000 kinds are herbivores. Among herbivores, about 250 kinds are known to be ruminants. As for cattle and sheep, which are ruminants, fermentation takes places mainly in their rumen; in contrast, for pigs and men, which are non-ruminants, fermentation takes place mainly in their caecum, colon, and rectum. As for the kind and dominance of rumen microorganisms, Bacteroidetes account for 51% and Firmicutes for 43%. As for the dominance of the large intestine microorganisms in men, Firmicutes account for 65% and Bacteroidetes for 25%. Cell wall components are decomposed by microorganisms, and short chain fatty acids (SCFAs) are generated through fermentation; the ratio of acetate, propionate, and butyrate generate is 60:25:15. Butyrate absorbed through the primary butyrate transporter MCT1 (mono carboxylate transports-1) in the intestines activates such SCFA receptors as GPR43 and GPR41. Butyrate has a strong anti-tumorigenic function. Butyrate is characterized by the fact that it has an effect on many cancer cells, contributes to the coordination of functions in the cells, and induces cancer apoptosis. Butyrate activates caspase but inhibits the activity of HDAC (histone deacetylase), so as to induce apoptosis. In addition, it increases p53 expression, so as to induce cell cycle arrest and apoptosis. Anti-inflammation actions of SCFA include the reduction of IL-8 expression in intestinal epithelial cells, the inhibition of NO synthesis, and the restraint of the activity of NF-${\kappa}B$ (nuclear factor ${\kappa}B$), so as to suppress the occurrence of cancers caused by inflammation. Butyrate plays an important role in maintaining physiological functions of intestinal mucous membranes and is used as a cure for inflammatory bowel disease (IBD).