Abstract
Expanding Duplication of Free Fatty Acid Receptor-2 (GPR43) Genes in the Chicken Genome. Camille Meslin;Colette Desert;Isabelle Callebaut;Anis Djari;Christophe Klopp;Frédérique Pitel;Sophie Leroux;Pascal Martin;Pascal Froment;Edith Guilbert;Florence Gondret;Sandrine Lagarrigue;Philippe Monget. 2015. Genome Biol Evol. 7. PMID: 25912043

Free fatty acid receptors (FFAR) belong to a family of five G-protein coupled receptors that are involved in the regulation of lipid metabolism, so that their loss of function increases the risk of obesity. The aim of this study was to determine the expansion of genes encoding paralogs of FFAR2 in the chicken, considered as a model organism for developmental biology and biomedical research. By estimating the gene copy number using quantitative polymerase chain reaction, genomic DNA resequencing, and RNA sequencing data, we showed the existence of 23 ± 1.5 genes encoding FFAR2 paralogs in the chicken genome. The FFAR2 paralogs shared an identity from 87.2% up to 99%. Extensive gene conversion was responsible for this high degree of sequence similarities between these genes, and this concerned especially the four amino acids known to be critical for ligand binding. Moreover, elevated nonsynonymous/synonymous substitution ratios on some amino acids within or in close-vicinity of the ligand-binding groove suggest that positive selection may have reduced the effective rate of gene conversion in this region, thus contributing to diversify the function of some FFAR2 paralogs. All the FFAR2 paralogs were located on a microchromosome in a same linkage group. FFAR2 genes were expressed in different tissues and cells such as spleen, peripheral blood mononuclear cells, abdominal adipose tissue, intestine, and lung, with the highest rate of expression in testis. Further investigations are needed to determine whether these chicken-specific events along evolution are the consequence of domestication and may play a role in regulating lipid metabolism in this species.
Inter-organ communication in the regulation of lipid metabolism: focusing on the network between the liver, intestine, and heart. Masanori Ito;Satomi Adachi-Akahane. 2013. J Pharmacol Sci. 123. PMID: 24304723

Recent studies have shown that lipid metabolism is regulated through the orchestration of multiple organs. Gut microbiota influences the metabolism of the liver through the production of fatty acids and phosphatidylcholine as well as the modulation of bile acid profile. Microbiota also affects the cardiovascular system through the production of metabolites from nutrients. MicroRNAs (miRNAs) are non-coding RNAs comprised of around 22 nucleotides in length. MiRNAs are released into blood flow from organs and interfere with the gene expression of target organs. MiRNAs are involved in the regulation of metabolic homeostasis including lipoprotein production and cardiovascular functions. Fatty acids are also circulating and distributed to each organ by fatty acid transporting proteins. Fatty acids can act as a ligand of G protein-coupled receptors, such as GPR41 and GPR43, and nuclear receptor PPARα, which bear crucial roles in the regulation of energy expenditure. Therefore the inter-organ communication plays important roles in the systematic regulation of lipid metabolism. Studies on the inter-organ network system will contribute to the development of diagnostic and therapeutic strategies for metabolic diseases. This review discusses how lipid metabolism is regulated by the inter-organ communication, focusing on the network axis between the liver, intestine, and heart.
Ketone body receptor GPR43 regulates lipid metabolism under ketogenic conditions. Junki Miyamoto;Ryuji Ohue-Kitano;Hiromi Mukouyama;Akari Nishida;Keita Watanabe;Miki Igarashi;Junichiro Irie;Gozoh Tsujimoto;Noriko Satoh-Asahara;Hiroshi Itoh;Ikuo Kimura. 2019. Proc Natl Acad Sci U S A. 116. PMID: 31685604

Ketone bodies, including β-hydroxybutyrate and acetoacetate, are important alternative energy sources during energy shortage. β-Hydroxybutyrate also acts as a signaling molecule via specific G protein-coupled receptors (GPCRs); however, the specific associated GPCRs and physiological functions of acetoacetate remain unknown. Here we identified acetoacetate as an endogenous agonist for short-chain fatty acid (SCFA) receptor GPR43 by ligand screening in a heterologous expression system. Under ketogenic conditions, such as starvation and low-carbohydrate diets, plasma acetoacetate levels increased markedly, whereas plasma and cecal SCFA levels decreased dramatically, along with an altered gut microbiota composition. In addition, Gpr43-deficient mice showed reduced weight loss and suppressed plasma lipoprotein lipase activity during fasting and eucaloric ketogenic diet feeding. Moreover, Gpr43-deficient mice exhibited minimal weight decrease after intermittent fasting. These observations provide insight into the role of ketone bodies in energy metabolism under shifts in nutrition and may contribute to the development of preventive medicine via diet and foods.
Differential modulation by Akkermansia muciniphila and Faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids. Sabina Lukovac;Clara Belzer;Linette Pellis;Bart J Keijser;Willem M de Vos;Roy C Montijn;Guus Roeselers. 2014. mBio. 5. PMID: 25118238

UNLABELLED: The gut microbiota is essential for numerous aspects of human health. However, the underlying mechanisms of many host-microbiota interactions remain unclear. The aim of this study was to characterize effects of the microbiota on host epithelium using a novel ex vivo model based on mouse ileal organoids. We have explored the transcriptional response of organoids upon exposure to short-chain fatty acids (SCFAs) and products generated by two abundant microbiota constituents, Akkermansia muciniphila and Faecalibacterium prausnitzii. We observed that A. muciniphila metabolites affect various transcription factors and genes involved in cellular lipid metabolism and growth, supporting previous in vivo findings. Contrastingly, F. prausnitzii products exerted only weak effects on host transcription. Additionally, A. muciniphila and its metabolite propionate modulated expression of Fiaf, Gpr43, histone deacetylases (HDACs), and peroxisome proliferator-activated receptor gamma (Pparγ), important regulators of transcription factor regulation, cell cycle control, lipolysis, and satiety. This work illustrates that specific bacteria and their metabolites differentially modulate epithelial transcription in mouse organoids. We demonstrate that intestinal organoids provide a novel and powerful ex vivo model for host-microbiome interaction studies. IMPORTANCE: We investigated the influence of the gut microbiota and microbially produced short-chain fatty acids (SCFAs) on gut functioning. Many commensal bacteria in the gut produce SCFAs, particularly butyrate, acetate, and propionate, which have been demonstrated to reduce the risk of gastrointestinal disorders. Organoids-small crypt-villus structures grown from ileal intestinal stem cells-were exposed to SCFAs and two specific gut bacteria. Akkermansia muciniphila, found in the intestinal mucus, was recently shown to have a favorable effect on the disrupted metabolism associated with obesity. Faecalibacterium prausnitzii is a commensal gut bacterium, the absence of which may be associated with Crohn's disease. We showed that in our model, A. muciniphila induces stronger effects on the host than F. prausnitzii. We observed that A. muciniphila and propionate affect the expression of genes involved in host lipid metabolism and epigenetic activation or silencing of gene expression. We demonstrated that organoids provide a powerful tool for host-microbe interaction studies.
Maternal sodium butyrate supplement elevates the lipolysis in adipose tissue and leads to lipid accumulation in offspring liver of weaning-age rats. Jiabin Zhou;Shixing Gao;Jinglong Chen;Ruqian Zhao;Xiaojing Yang. 2016. Lipids Health Dis. 15. PMID: 27449927

BACKGROUND: Sodium butyrate (SB) is reported to regulate lipid metabolism in mammals, and the relationship between maternal nutrition and offspring growth has drawn much attention in the last several years. METHODS: To elucidate the effects of maternal dietary SB supplementation on hepatic lipid metabolism in weaning rats, we fed 16 primiparous purebred female SD rats either a chow-diet or a 1 % sodium butyrate diet throughout pregnancy and lactation. At weaning age, samples of the maternal subcutaneous adipose tissue and offspring liver were taken. The serum indexes and expressions of proteins related to lipid metabolism were detected in the mother and offspring, respectively. RESULTS: The results showed that the maternal SB supplement increased the concentration of non-esterified fatty acid (NEFA) in the maternal and offspring serum (P < 0.05). Total cholesterol (Tch) increased significantly in the weaning-rat serum (P < 0.05). Maternal adipose tissue from the SB-supplemented rats showed higher content of protein G-coupled protein (GPR43) and protein kinase A (PKA) (P < 0.05). The expression of protein adipose triglyceride lipase (ATGL), and of total and phosphorylated hormone sensitive lipase (HSL), in the maternal adipose tissue increased significantly (P < 0.05) compared to the control group. However the proteins related to lipogenesis showed no significant changes. Moreover, the concentration of triglyceride in the offspring liver increased significantly, and this likely resulted from an increase in the levels of fatty acids binding protein (FABP) and fatty acid translocase (CD36) protein (P < 0.05). SB exposure during pregnancy and lactation increased the hepatic total cholesterol (Tch) content (P < 0.01), which was related to a significantly up-regulated offspring hepatic expression of low density lipoprotein receptor (LDLR) protein (P < 0.05). CONCLUSION: These results indicate that a maternal SB supplement during pregnancy and the lactation period promotes maternal fat mobilization, which may result in fatty acid uptake and lipid accumulation in the liver of the offspring.
Propionate suppresses hepatic gluconeogenesis via GPR43/AMPK signaling pathway. Hiroki Yoshida;Megumi Ishii;Mitsugu Akagawa. 2019. Arch Biochem Biophys. 672. PMID: 31356781

Short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are generated by gut microbial fermentation of dietary fiber. SCFAs may exert multiple beneficial effects on human lipid and glucose metabolism. However, their actions and underlying mechanisms are not fully elucidated. In this study, we examined the direct effects of propionate on hepatic glucose and lipid metabolism using human HepG2 hepatocytes. Here, we demonstrate that propionate at a physiologically-relevant concentration effectively suppresses palmitate-enhanced glucose production in HepG2 cells but does not affect intracellular neutral lipid levels. Our results indicated that propionate can decline in gluconeogenesis by down-regulation of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) through activation of AMP-activated protein kinase (AMPK), which is a major regulator of the hepatic glucose metabolism. Mechanistic studies also revealed that propionate-stimulated AMPK phosphorylation can be ascribed to Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) activation in response to an increase in intracellular Ca2+ concentration. Moreover, siRNA-mediated knockdown of the propionate receptor GPR43 prevented propionate-inducible activation of AMPK and abrogates the gluconeogenesis-inhibitory action. Thus, our data indicate that the binding of propionate to hepatic GPR43 elicits CaMKKβ-dependent activation of AMPK through intracellular Ca2+ increase, leading to suppression of gluconeogenesis. The present study suggests the potential efficacy of propionate in preventive and therapeutic management of diabetes.
Perturbation of the lipid metabolism and intestinal inflammation in growing pigs with low birth weight is associated with the alterations of gut microbiota. Shi-Meng Huang;Zhen-Hua Wu;Tian-Tian Li;Cong Liu;Dan-Dan Han;Shi-Yu Tao;Yu Pi;Na Li;Jun-Jun Wang. 2020. Sci Total Environ. 719. PMID: 32114228

Low birth weight (LBW) is accompanied by metabolic dysfunction, chronic inflammation and gut microbiota perturbation in piglets during early life. Regulating gut microbiota structure can indirectly or directly affect gut health and the host's metabolism. However, whether gut microbiota dysbiosis impact lipid metabolism and inflammation progression in the LBW pigs later in life is unclear. In the present study, we investigated the role of gut microbiota on homeostasis in organisms using young pigs as a model. The plasma concentrations of High-density lipoproteins (HDLC) and pro-inflammatory cytokines such as Interleukin 6 (IL-6), Tumor necrosis factor alpha (TNF-α) and Interleukin 18 (IL-18) were increased in LBW pigs. The bacterial composition was modified dramatically in LBW group in association with an increase in propionate, butyrate and Short-chain fatty acids (SCFAs) in the ileal digesta. LBW impaired intestine results in damaged Fatty acid-binding protein 1 (FABP2) and Fatty acid-binding protein 4 (FABP4) expressions, and the inhibition of Free fatty acid receptor 1 (FFAR1), Free fatty acid receptor 2 (FFAR2) and G protein-coupled receptor 119 (GPR119) expressions, causing inefficient SCFAs absorption. Meanwhile, the physical barrier and chemical barrier related to functional gene expressions of Occludin, Claudin-1, Mucin 1 (MUC1) and Mucin 2 (MUC2) in both ileum and colon were decreased in the LBW pigs. The genera of Blautia, Bifidobacterium, Subdoligranulum and Coprococcus 3 in the ileum were correlated positively with lipid metabolic dysfunction and pro-inflammatory response in LBW pigs. Collectively, the gut microbiota is critical for perturbation of lipid metabolism and inflammatory progression in LBW pigs, which suggests the interventions for modulating bacterial communities may be therapeutically beneficial for metabolic diseases and chronic inflammation.
Acetate alters the process of lipid metabolism in rabbits. C Fu;L Liu;F Li. 2017. Animal. 12. PMID: 29198236

An experiment was conducted to investigate the effect of acetate treatment on lipid metabolism in rabbits. New Zealand Rabbits (30 days, n=80) randomly received a subcutaneous injection (2 ml/injection) of 0, 0.5, 1.0 or 2.0 g/kg per day body mass acetate (dissolved in saline) for 4 days. Our results showed that acetate induced a dose-dependent decrease in shoulder adipose (P0.05), acetate treatment significantly decreased the plasma adiponectin, insulin and triglyceride concentrations (P<0.05). In adipose, acetate injection significantly up-regulated the gene expression of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), differentiation-dependent factor 1 (ADD1), adipocyte protein 2 (aP2), carnitine palmitoyltransferase 1 (CPT1), CPT2, hormone-sensitive lipase (HSL), G protein-coupled receptor (GPR41), GPR43, adenosine monophosphate-activated protein kinase α1 (AMPKα1), adiponectin receptor (AdipoR1), AdipoR2 and leptin receptor. In addition, acetate treatment significantly increased the protein levels of phosphorylated AMPKα, extracellular signaling-regulated kinases 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (P38 MAPK) and c-jun amino-terminal kinase (JNK). In conclusion, acetate up-regulated the adipocyte-specific transcription factors (PPARγ, C/EBPα, aP2 and ADD1), which were associated with the activated GPR41/43 and MAPKs signaling. Meanwhile, acetate decreased fat content via the upregulation of the steatolysis-related factors (HSL, CPT1 and CPT2), and AMPK signaling may be involved in the process.
Prebiotic attenuation of olanzapine-induced weight gain in rats: analysis of central and peripheral biomarkers and gut microbiota. Amy Chia-Ching Kao;Sonia Spitzer;Daniel C Anthony;Belinda Lennox;Philip W J Burnet. 2018. Transl Psychiatry. 8. PMID: 29540664

Olanzapine is an effective antipsychotic drug but since it causes significant weight gain, it is not well tolerated by psychosis patients. The prebiotic, B-GOS®, attenuates metabolic dysfunction in obese subjects, and in rodents, alters central NMDA receptors and may affect serotonin receptors that are relevant in psychosis. We have determined whether B-GOS® influenced olanzapine-associated weight gain and central NMDA and serotonin receptors. Circulating acetate, IL-1β, IL-8 and TNFα, liver acetyl-CoA carboxylase (ACC), white adipose tissue (WAT) acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Adult female Sprague-Dawley rats were administered a B-GOS® (0.5 g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. The intake of B-GOS® significantly attenuated olanzapine-induced weight gain without altering frontal cortex 5-HT2AR blockade. Cortical GluN1 levels were elevated by olanzapine in the presence of B-GOS®. Plasma acetate concentrations increased following B-GOS® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS®. Co-administration of B-GOS® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS® elevated faecal Bifidobacterium spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS®, was without effect. These data suggest that inclusion of B-GOS® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis. The role of acetate in these effects requires further investigation.
Platycodon grandiflorus Root Ethanol Extract Induces Lipid Excretion, Lipolysis, and Thermogenesis in Diet-Induced Obese Mice. Ye Jin Kim;Ri Ryu;Ji-Young Choi;Myung-Sook Choi. 2019. J Med Food. 22. PMID: 31566484

Adipocytes regulate lipid metabolism according to physiological energy requirements. A dysfunctional lipid metabolism can lead to obesity and its complications such as hepatic steatosis, diabetes, and hyperlipidemia. In our study, the impact of Platycodon grandiflorus root ethanol extract (PGH) on lipid excretion and thermogenesis-related markers in diet-induced obesity mice was analyzed. Our data show that PGH elevated fatty acid uptake in epididymal adipose tissue by increasing Cd36, Slc27a1, Ffar2, and Ffar4 expression, which led to decreased blood free fatty acid concentrations. Moreover, PGH normalized body weight and fat mass in diet-induced obese mice by increasing lipolysis (Plin1, Atgl, and Hsl) and fatty acid oxidation. Changes in the levels of browning-related genes, enzyme activity of carnitine palmitoyltransferase, and the overall transcriptome (Bmp4, Cidec, Ucp3, Sirt3, and Cox4i1) led to promote brown adipose tissue-like features (browning) in epididymal white adipose tissue and enhanced energy expenditure. Our results suggest that PGH promotes lipid excretion and thermogenic function in high-fat diet-induced obese mice, which are mediated by regulation of fat metabolism.
Conjugated linoleic acid (t-10, c-12) reduces fatty acid synthesis de novo, but not expression of genes for lipid metabolism in bovine adipose tissue ex vivo. Seong Ho Choi;David T Silvey;Bradley J Johnson;Matthew E Doumit;Ki Yong Chung;Jason E Sawyer;Gwang Woong Go;Stephen B Smith. 2013. Lipids. 49. PMID: 24293227

We hypothesized that exogenous fatty acids, and especially or 18:2 trans-10, cis-12 conjugated linoleic acid (CLA), would decrease adipogenic and lipogenic gene expression and de novo fatty acid biosynthesis in intramuscular (i.m.) and subcutaneous (s.c.) adipose tissues. Fresh i.m. and s.c. adipose tissues were collected from the longissimus thoracis muscle of Angus steers at 12, 14, and 16 months of age (n = 4 per time point). Adipose tissue explants were incubated in duplicate for 48 h with 40 μM α-linolenic (ALA), oleic, stearic, trans-vaccenic, or CLA. Adipocyte size, acetate and glucose incorporation into fatty acids in vitro and mRNA levels for C/EBPβ, CPT1β, GPR43, PPARγ, PRKAA1 (AMPKα) and SCD1 were measured following the incubations. PRKAA1 and SCD1gene expression were greater (P < 0.001) in s.c. adipose tissue than in i.m. adipose tissue and acetate incorporation into lipids and C/EBPβ, PPARγ, and SCD1gene expression were greater at 16 months of age than at 12 months of age in i.m. adipose (P < 0.01). C/EBPβ gene expression increased by 16 months of age and PRKAA1 gene expression decreased by 16 months of age in s.c. adipose tissue. All fatty acids increased s.c. adipocyte volumes whereas CLA decreased acetate incorporation into lipids in s.c. adipose tissue (P < 0.05), but none of the fatty acids affected gene expression in i.m. or s.c. adipose tissue (P > 0.10). Thus, CLA depressed de novo fatty acid biosynthesis from acetate but neither CLA nor other fatty acids significantly affected adipogenic or lipogenic gene expression.