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Fatty acids are metabolized and synthesized as energy substrates during biological responses. Long- and medium-chain fatty acids derived mainly from dietary triglycerides, and short-chain fatty acids (SCFAs) produced by gut microbial fermentation of the otherwise indigestible dietary fiber, constitute the major sources of free fatty acids (FFAs) in the metabolic network. Recently, increasing evidence indicates that FFAs serve not only as energy sources but also as natural ligands for a group of orphan G protein-coupled receptors (GPCRs) termed free fatty acid receptors (FFARs), essentially intertwining metabolism and immunity in multiple ways, such as via inflammation regulation and secretion of peptide hormones. To date, several FFARs that are activated by the FFAs of various chain lengths have been identified and characterized. In particular, FFAR1 (GPR40) and FFAR4 (GPR120) are activated by long-chain saturated and unsaturated fatty acids, while FFAR3 (GPR41) and FFAR2 (GPR43) are activated by SCFAs, mainly acetate, butyrate, and propionate. In this review, we discuss the recent reports on the key physiological functions of the FFAR-mediated signaling transduction pathways in the regulation of metabolism and immune responses. We also attempt to reveal future research opportunities for developing therapeutics for metabolic and immune disorders.

Indigestible polysaccharides, such as dietary fibers, benefit the host by improving the intestinal environment. Short-chain fatty acids (SCFAs) produced by gut microbial fermentation from dietary fibers exert various physiological effects. The bacterial polysaccharide curdlan benefits the host intestinal environment, although its effect on energy metabolism and SCFA production remains unclear. Hence, this study aimed to elucidate the effect of curdlan intake on gut microbial profiles, SCFA production, and energy metabolism in a high-fat diet (HFD)-induced obese mouse model. Gut microbial composition of fecal samples from curdlan-supplemented HFD-fed mice indicated an elevated abundance of Bacteroidetes, whereas a reduced abundance of Firmicutes was noted at the phylum level compared with that in cellulose-supplemented HFD-fed mice. Moreover, curdlan supplementation resulted in an abundance of the family Bacteroidales S24-7 and Erysipelotrichaceae, and a reduction in Deferribacteres in the feces. Furthermore, curdlan supplementation elevated fecal SCFA levels, particularly butyrate. Although body weight and fat mass were not affected by curdlan supplementation in HFD-induced obese mice, HFD-induced hyperglycemia was significantly suppressed with an increase in plasma insulin and incretin GLP-1 levels. Curdlan supplementation elevated fecal bile acid and SCFA production, improved host metabolic functions by altering the gut microbial composition in mice., Highlights • Curdlan improves gut microbial composition in high-fat diet-fed (HFD) mice. • The effects of HFD-induced hyperglycemia are mitigated by curdlan supplementation. • Curdlan supplementation increases plasma insulin and GLP-1 levels. • Curdlan increases fecal short-chain fatty acids (SCFAs) and secondary bile acids.

The purpose of this study is to compare the impact of four low-viscosity soluble dietary fibers (DFs) on the intestinal microenvironment, in terms of microbiota composition, short-chain fatty acid (SCFA) production, proportion of colonic peripherally induced regulatory T cells (pTregs), and experimental colitis in mice.Mice are administered 5% w/v low-viscosity soluble DFs in drinking water for 2 weeks. The gut microbiota composition is determined using 16S rRNA sequencing. Luminal SCFAs are quantified by gas chromatography, and colonic pTregs are analyzed using flow cytometry. All low-viscosity soluble DFs promote the growth of beneficial bacteria such as Akkermansia muciniphila and Bacteroides acidifaciens, while eliminating pathogenic bacteria such as Clostridium perfringens. Moreover, two low-viscosity soluble DFs significantly increase the abundance of commensal bacteria and promote the accumulation of propionate and butyrate, leading to marked induction of colonic pTregs. Consistently, these two fibers, in particular α-cyclodextrin, show remarkable anti-inflammatory properties in a colitis mouse model.Mice administered any low-viscosity soluble DF show comparable gut microbiota compositions, but differ in terms of bacterial abundance, SCFA concentration, pTreg population, and colitis development. This exploratory study suggests that administration of α-cyclodextrin may be a possible strategy for the prevention of colitis.

Significance Ketone bodies, mainly β-hydroxybutyrate and acetoacetate, are important alternative energy sources in a state of energy deficit or metabolic crisis. The consumption of ketogenic diets, such as low-carbohydrate and medium-chain triglyceride diets, and time-restricted feeding lead to ketogenesis, which influences longevity and health. β-Hydroxybutyrate also acts as a signaling molecule via GPR109A and GPR41; however, to date, the specific G protein-coupled receptors responsible for acetoacetate and its physiological functions remain unknown. In this study, we demonstrate that acetoacetate acts as an endogenous agonist of GPR43 by ligand screening in a heterologous expression system, and that it, rather than short-chain fatty acids, maintains energy homeostasis via GPR43-mediated lipid metabolism under ketogenic conditions., 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.

Diabetes & Metabolism - In Press.Proof corrected by the author Available online since mardi 1 aout 2017

IntroductionTreatment using sodium-glucose cotransporter (SGLT) 2 inhibitor and low-carbohydrate diet (LCD) for obesity and type 2 diabetes are similar in terms of carbohydrate limitation. However, their mechanisms of action differ, and the effects on the body remain unclear. We investigated the effects of SGLT2 inhibitor and LCD on body composition and metabolic profile using the db/db mouse model for obesity and type 2 diabetes.Research design and methodsEight-week-old male db/db mice were divided into four groups: mice receiving normal diet and vehicle or canagliflozin (Cana) administration and mice receiving LCD and vehicle or Cana administration for 8 weeks. Consumed calories were adjusted to be equal among the groups.ResultsBoth Cana administration and LCD feeding resulted in significant weight gain. Cana administration significantly decreased plasma glucose levels and increased plasma insulin levels with preservation of pancreatic β cells. However, LCD feeding did not improve plasma glucose levels but deteriorated insulin sensitivity. LCD feeding significantly reduced liver weight and hepatic triglyceride content; these effects were not observed with Cana administration. Combined treatment with LCD did not lead to an additive increase in blood β-ketone levels.ConclusionsSGLT2 inhibitors and LCD exert differential effects on the body. Their combined use may achieve better metabolic improvements in obesity and type 2 diabetes.

Aims The protein myostatin is a member of the transforming growth factor β superfamily. This is mainly expressed in skeletal muscle and negatively regulates skeletal muscle growth. The present study aimed to elucidate the associations among circulating myostatin level, skeletal muscle mass, and metabolic profiles in Japanese obese patients. Methods Japanese obese outpatients (n = 74) were enrolled. We measured clinical parameters, quantified serum myostatin levels, and examined their associations in a cross-sectional manner. Results Both total skeletal muscle mass and serum myostatin level were higher in males than in females. Among 74 patients, serum myostatin level was positively correlated with skeletal muscle mass and serum immunoreactive insulin (IRI) level [correlation coefficient (r) = 0.294, P = 0.011; r = 0.262, P = 0.024, respectively]. Furthermore, multivariate linear regression analysis revealed that serum myostatin level was positively correlated with IRI after adjusting for gender and skeletal muscle mass (β-coefficient = 0.230, P = 0.029, R2 = 0.236). Conclusions In obese patients, serum myostatin level was elevated in conjunction with an increase in IRI level independent of skeletal muscle mass. This may imply possible novel pathological implications of serum myostatin in muscle mass and metabolism in obese patients with hyperinsulinemia.

Among dietary fatty acids with immunologic effects, ω-3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-β and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Gut microbiota can regulate the host energy metabolism; however, the underlying mechanisms that could involve gut microbiota-derived compounds remain to be understood. Therefore, in this study, we investigated the effects of KetoA [10-oxo-12(Z)-octadecenoic acid]-a linoleic acid metabolite produced by gut lactic acid bacteria-on whole-body energy metabolism and found that dietary intake of KetoA could enhance energy expenditure in mice, thereby protecting mice from diet-induced obesity. By using Ca2+ imaging and whole-cell patch-clamp methods, KetoA was noted to potently activate transient receptor potential vanilloid 1 (TRPV1) and enhance noradrenalin turnover in adipose tissues. In addition, KetoA up-regulated genes that are related to brown adipocyte functions, including uncoupling protein 1 (UCP1) in white adipose tissue (WAT), which was later diminished in the presence of a β-adrenoreceptor blocker. By using obese and diabetic model KK-Ay mice, we further show that KetoA intake ameliorated obesity-associated metabolic disorders. In the absence of any observed KetoA-induced antiobesity effect or UCP1 up-regulation in TRPV1-deficient mice, we prove that the antiobesity effect of KetoA was caused by TRPV1 activation-mediated browning in WAT. KetoA produced in the gut could therefore be involved in the regulation of host energy metabolism.-Kim, M., Furuzono, T., Yamakuni, K., Li, Y., Kim, Y.-I., Takahashi, H., Ohue-Kitano, R., Jheng, H.-F., Takahashi, N., Kano, Y., Yu, R., Kishino, S., Ogawa, J., Uchida, K., Yamazaki, J., Tominaga, M., Kawada, T., Goto, T. 10-oxo-12(Z)-octadecenoic acid, a linoleic acid metabolite produced by gut lactic acid bacteria, enhances energy metabolism by activation of TRPV1.

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

Fermented foods represent a significant portion of human diets with several beneficial effects. Foods produced by bacterial fermentation are enriched in short-chain fatty acids (SCFAs), which are functional products of dietary fibers via gut microbial fermentation. In addition to energy sources, SCFAs also act as signaling molecules via G-protein coupled receptors such as FFAR2 and FFAR3. Hence, dietary SCFAs in fermented foods may have a direct influence on metabolic functions. However, the detailed mechanism by dietary SCFAs remains unclear. Here, we show that dietary SCFAs protected against high-fat diet-induced obesity in mice in parallel with increased plasma SCFAs without changing cecal SCFA or gut microbial composition. Dietary SCFAs suppressed hepatic weight and lipid synthesis. These effects were abolished in FFAR3-deficient mice but not FFAR2-deficient. Thus, SCFAs supplementation improved hepatic metabolic functions via FFAR3 without influencing intestinal environment. These findings could help to promote the development of functional foods using SCFAs.

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders.

Mouse mothers transfer metabolic mode Obesity and metabolic diseases tend to go together, and humans who become obese are also prone to type 2 diabetes and cardiovascular problems. Starting with the observation that offspring of germ-free mice tended to become obese on high-fat diets, Kimura et al. investigated how the presence of the microbiota might be protective in mice (see the Perspective by Ferguson). Short-chain fatty acids (SCFAs) from the microbiota are known to suppress insulin signaling and reduce fat deposition in adipocytes. Further experiments showed that SCFAs in the bloodstream were able to pass from a non–germ-free mother's gut microbiota across the placenta and into the developing embryos. The authors found that in the embryos, the SCFA propionate mediates not only insulin levels through GPR43 signaling but also sympathetic nervous system development through GPR41 signaling. A high-fiber diet promoted propionate production from the maternal microbiota, and maternal antibiotic treatment resulted in obese-prone offspring. Science , this issue p. eaaw8429 ; see also p. 978

Gut microbiota can regulate the host energy metabolism; however, the underlying mechanisms that could involve gut microbiota-derived compounds remain to be understood. Therefore, in this study, we investigated the effects of KetoA [10-oxo-12(

The protein triggering receptor expressed on myeloid cell 2 (TREM2) is a cell surface receptor exclusively expressed on microglia in the brain. Recent extensive studies reveal that the functions of TREM2 as well as the phenotypes of TREM2-expressing microglia are closely implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease (AD), one of the most common causes of dementia. Furthermore, several recent studies reported a possible novel pathological implication for TREM2 in cognitive impairment associated with diabetes, one of the several metabolic diseases that are reported risk factors of dementia. In this review, we summarize recent advances and future research directions on the pathophysiological significance of TREM2 in AD and other neurodegenerative diseases as well as in metabolic diseases with increased risk for dementia.

Aim The functional significance of the myokines, cytokines and peptides produced and released by muscle cells, has not been fully elucidated. The purpose of the present study was to identify a myokine with increased secretion levels in muscle cells due to saturated fatty acids and to examine the role of the identified myokine in the regulation of myogenesis. Methods Human primary myotubes and mouse C2C12 myotubes were used to identify the myokine; its secretion was stimulated by palmitate loading. The role of the identified myokine in the regulation of the activation, proliferation, differentiation and self-renewal was examined in mouse satellite cells (skeletal muscle stem cells). Results Palmitate loading promoted the secretion of chemokine (C-X-C motif) ligand 1 (CXCL1) in human primary myotubes, and it also increased CXCL1 gene expression level in C2C12 myotubes in a dose- and time-dependent manner. Palmitate loading increased the production of reactive oxygen species along with the activation of nuclear factor-kappa B (NF-κB) signalling. Pharmacological inhibition of NF-κB signalling attenuated the increase in CXCL1 gene expression induced by palmitate and hydrogen peroxide. Palmitate loading significantly increased CXC receptor 2 gene expression in undifferentiated cells. CXCL1 knockdown attenuated proliferation and myotube formation by satellite cells, with reduced self-renewal. CXCL1 knockdown also significantly decreased the Notch intracellular domain protein level. Conclusion These results suggest that secretion of the myokine CXCL1 is stimulated by saturated fatty acids and that CXCL1 promotes myogenesis from satellite cells to maintain skeletal muscle homeostasis. This article is protected by copyright. All rights reserved.