Mayu Kasubuchi

Dietary Gut Microbial Metabolites, Short-chain Fatty Acids, and Host Metabolic Regulation

During feeding, the gut microbiota contributes to the host energy acquisition and metabolic regulation thereby influencing the development of metabolic disorders such as obesity and diabetes. Short-chain fatty acids (SCFAs) such as acetate, butyrate, and propionate, which are produced by gut microbial fermentation of dietary fiber, are recognized as essential host energy sources and act as signal transduction molecules via G-protein coupled receptors (FFAR2, FFAR3, OLFR78, GPR109A) and as epigenetic regulators of gene expression by the inhibition of histone deacetylase (HDAC). Recent evidence suggests that dietary fiber and the gut microbial-derived SCFAs exert multiple beneficial effects on the host energy metabolism not only by improving the intestinal environment, but also by directly affecting various host peripheral tissues. In this review, we summarize the roles of gut microbial SCFAs in the host energy regulation and present an overview of the current understanding of its physiological functions.

Free fatty acid receptors as therapeutic targets for the treatment of diabetes

Nutrition regulates energy balance; however, dysfunction of energy balance can cause metabolic disorders, such as obesity and diabetes. Fatty acids are an essential energy source and signaling molecules that regulate various cellular processes and physiological functions. Recently, several orphan G protein-coupled receptors were identified as free fatty acid receptors (FFARs). GPR40/FFAR1 and GPR120/FFAR4 are activated by medium- and/or long-chain fatty acids, whereas GPR41/FFAR3 and GPR43/FFAR2 are activated by short-chain fatty acids. FFARs are regarded as targets for novel drugs to treat metabolic disorders, such as obesity and type 2 diabetes, because recent studies have showed that these receptors are involved in the energy metabolism in various tissues, including adipose, intestinal, and immune tissue. In this review, we summarize physiological roles of the FFARs, provide a comprehensive overview of energy regulation by FFARs, and discuss new prospects for treatment of metabolic disorders.

Nutritional Signaling via Free Fatty Acid Receptors

Excess energy is stored primarily as triglycerides, which are mobilized when demand for energy arises. Dysfunction of energy balance by excess food intake leads to metabolic diseases, such as obesity and diabetes. Free fatty acids (FFAs) provided by dietary fat are not only important nutrients, but also contribute key physiological functions via FFA receptor (FFAR)-mediated signaling molecules, which depend on FFAs’ carbon chain length and the ligand specificity of the receptors. Functional analyses have revealed that FFARs are critical for metabolic functions, such as peptide hormone secretion and inflammation, and contribute to energy homeostasis. In particular, recent studies have shown that the administration of selective agonists of G protein-coupled receptor (GPR) 40 and GPR120 improved glucose metabolism and systemic metabolic disorders. Furthermore, the anti-inflammation and energy metabolism effects of short chain FAs have been linked to the activation of GPR41 and GPR43. In this review, we summarize recent progress in research on FFAs and their physiological roles in the regulation of energy metabolism.

The role of short-chain fatty acid on blood pressure regulation.

Purpose of reviewThe gut microbiota and its metabolites have been implicated in the regulation of host physiological functions such as inflammatory and metabolic responses. The short-chain fatty acid (SCFA) receptor is expressed in the kidney and blood vessels as well, and has been reported to function as a regulator of blood pressure (BP). This review highlights the role of SCFAs derived from gut microbial fermentation in the regulation of BP. Recent findingsOlfactory receptor 78 (Olfr78) is a member of the G-protein-coupled receptor family, and it plays a key role as a chemosensor in various tissues. Both Olfr78 and G protein-coupled receptor 41 (GPR41) are expressed in smooth muscle cells of blood vessels and they recognize SCFAs. Oral administration of SCFAs was found to change BP in vivo, an effect that was altered in Olfr78 and GPR41-deficient mice. SummaryThe regulation of BP via SCFA receptors has provided new insights into the interactions between the gut microbiota and BP control systems. We summarize these interactions and describe their contributions to a novel pathway involved in BP regulation. These recent findings could open new avenues for the development of therapeutic strategies for the treatment of cardiovascular diseases.

A Novel Antidiabetic Therapy: Free Fatty Acid Receptors as Potential Drug Target

Excessive dietary intake of fat is strongly involved in the development of type 2 diabetes (T2D). Free fatty acids (FFAs), which are provided from dietary fat, are not only important nutrients, but also act as signaling molecules and stimulate key biological functions. Recent physiological and pharmacological studies have shown that several G-protein coupled receptors, such as FFAR1-4, are receptors for FFAs. FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids, whereas FFAR2 and FFAR3 are activated by short-chain fatty acids (SCFAs). These FFA receptors (FFARs) mediate various physiological functions, depending on the carbon chain length of the FFAs and the ligand specificity of the FFARs. Functional analyses have revealed that FFARs mediate important metabolic functions, such as peptide hormone secretion and inflammation, and thereby contribute to energy homeostasis. Since imbalances in energy homeostasis lead to metabolic disorders, such as obesity and T2D, FFARs are considered to be key therapeutic targets in these diseases. In particular, recent studies have shown that the administration of selective agonists of FFAR1 and FFAR4 improved glucose metabolism and ameliorated systemic metabolic disorders. Furthermore, the biological functions of SCFAs in anti-inflammation and energy metabolism are linked with the activation of FFAR2 and FFAR3. Hence, in this review, we summarize the physiological functions of FFARs and discuss the potential of selective ligands of FFARs for development as drugs to treat metabolic disorders, such as T2D and obesity.

Anti-Inflammatory and Insulin-Sensitizing Effects of Free Fatty Acid Receptors

Chronic low-grade inflammation in macrophages and adipose tissues can promote the development of obesity and type 2 diabetes. Free fatty acids (FFAs) have important roles in various tissues, acting as both essential energy sources and signaling molecules. FFA receptors (FFARs) can modulate inflammation in various types of cells and tissues; however the underlying mechanisms mediating these effects are unclear. FFARs are activated by specific FFAs; for example, GPR40 and GPR120 are activated by medium and long chain FFAs, GPR41 and GPR43 are activated by short chain FFAs, and GPR84 is activated by medium-chain FFAs. To date, a number of studies associated with the physiological functions of G protein-coupled receptors (GPCRs) have reported that these GPCRs are expressed in various tissues and involved in inflammatory and metabolic responses. Thus, the development of selective agonists or antagonists for various GPCRs may facilitate the establishment of novel therapies for the treatment of various diseases. In this review, we summarize current literature describing the potential of GPCRs as therapeutic targets for inflammatory and metabolic disorders.

Perspectives On Membrane-associated Progesterone Receptors As Prospective Therapeutic Targets

Progesterone receptor membrane components 1 and 2, neudesin, and neuferricin belong to the membraneassociated progesterone receptor (MAPR) family. Recently, sex steroid membrane receptors have gained attention because of their potential involvement in sex hormone-mediated rapid non-genomic effects, which cannot currently be explained by the genomic action of nuclear receptors. Progesterone may increase cell proliferation and survival via nongenomic effects including the activation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3- kinase (PI3K) pathways through MAPRs. Moreover, the unique expression of MAPRs suggests that they could be used as biomarkers and drug targets for sex steroid-related cancers and other diseases. In this review, we summarize the physiological roles of the MAPRs, provide a comprehensive overview of their progesterone-mediated non-genomic actions, and discuss new insights into their potential as therapeutic targets.

Barley β-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice

Dietary intake of barley β-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD)-induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber β-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG-fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs.

α-Linolenic acid–derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40

Among dietary fatty acids with immunologic effects, ω‐3 polyunsaturated fatty acids, such as a‐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. FASEB J. 32, 304‐318 (2018). www.fasebj.org

Membrane progesterone receptor beta (mPRβ/Paqr8) promotes progesterone-dependent neurite outgrowth in PC12 neuronal cells via non-G protein-coupled receptor (GPCR) signaling

Recently, sex steroid membrane receptors garnered world-wide attention because they may be related to sex hormone-mediated unknown rapid non-genomic action that cannot be currently explained by their genomic action via nuclear receptors. Progesterone affects cell proliferation and survival via non-genomic effects. In this process, membrane progesterone receptors (mPRα, mPRβ, mPRγ, mPRδ, and mPRε) were identified as putative G protein-coupled receptors (GPCRs) for progesterone. However, the structure, intracellular signaling, and physiological functions of these progesterone receptors are still unclear. Here, we identify a molecular mechanism by which progesterone promotes neurite outgrowth through mPRβ (Paqr8) activation. Mouse mPRβ mRNA was specifically expressed in the central nervous system. It has an incomplete GPCR topology, presenting 6 transmembrane domains and did not exhibit typical GPCR signaling. Progesterone-dependent neurite outgrowth was exhibited by the promotion of ERK phosphorylation via mPRβ, but not via other progesterone receptors such as progesterone membrane receptor 1 (PGRMC-1) and nuclear progesterone receptor in nerve growth factor-induced neuronal PC12 cells. These findings provide new insights of regarding the non-genomic action of progesterone in the central nervous system.