1. GPCR-Mediated Signaling of Metabolites
Anna Sofie Husted, Mette Trauelsen, Olga Rudenko, Siv A. Hjorth, Thue W. Schwartz 
Cell Metabolism 
Volume 25, Issue 4, Pages (April 2017)
DOI: /j.cmet
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2. Cell Metabolism 2017 25, 777-796DOI: (10.1016/j.cmet.2017.03.008)
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3. Figure 1
Selected Signaling Metabolites and Their Interaction with Metabolite GPCRs
(A) Structures of selected signaling metabolites. The main GPCR target for each of the signaling metabolites is indicated to the right. As indicated by the arrows, some metabolites target more than one GPCR and some of the metabolite GPCRs recognize more than one metabolite. In fact, some metabolite receptors have several different ligands as indicated in Table 1.
(B) Dose-response curve for β-hydroxybutyrate (β-OHB) on HCA2 (GPR109A) (Taggart et al., 2005) with the range of plasma concentrations for β-OHB under different metabolic conditions indicated in green (Owen et al., 1969; Bonnefont et al., 1990).
(C) Dose-response curve for acetate on FFA2 (GPR43) (Brown et al., 2003) with the range of plasma concentrations in normal subjects and type 2 diabetic patients indicated in green (Akanji et al., 1989) and concentrations in the gut lumen indicated in brown (Cummings et al., 1987).
(D) Dose-response curve for butyrate on FFA2 (GPR43) (Brown et al., 2003) with the range of plasma concentrations in normal subjects indicated in green (Cummings et al., 1987) and concentrations in the gut lumen indicated in brown (Cummings et al., 1987).
(E) Dose-response curve for L-tryptophan on GPR142 (Wang et al., 2016a) with the range of plasma concentrations in normal subjects indicated in green (Badawy, 2015; Breum et al., 2003).
(F) Dose-response curve for palmitate on FFA1 (GPR40) (Briscoe et al., 2003) with the range of plasma concentrations in normal subjects indicated in green (Itoh et al., 2003; Spector and Hoak, 1975).
(G) Dose-response curve for succinate on GPR91 (He et al., 2004) with the range of plasma concentrations in normal subjects indicated in green (Sadagopan et al., 2007; Kushnir et al., 2001). The individual dose-response curves in panels (B)–(G) are idealized curves with Hill coefficients of 1.0 for human receptors based on dose-response curves and EC50 values reported in the indicated references and results from the authors’ laboratory.
Cell Metabolism  , DOI: ( /j.cmet )
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4. Figure 2
Schematic Overview of Signaling Metabolites Depicting Their Passage through the Intestinal Epithelium of the GI Tract and Interaction with Target GPCRs
At the upper left, nutrient-derived signaling metabolites and their interactions (red arrows) with metabolite receptors expressed on enteroendocrine cells (EEC) to stimulate hormone secretion and on enterocytes are depicted. To the upper right, select signaling metabolites generated by the gut microbiota, their interactions (black arrows) with metabolite receptors on enteroendocrine cells and enterocytes in the epithelium (mainly after being absorbed), as well as immune cells and enteric nerves in the lamina propria, are indicated. The concentrations of metabolites are relatively high in the intestinal lumen (Figures 1B and 1C) as compared to those in the lamina propria and portal vein. Thus, several metabolite receptors cannot function as luminal sensors of changes in the concentrations of metabolites in the gut lumen (see text). Consequently, most of the interaction of metabolites with their metabolite receptors occurs not at the luminal but at the basolateral membrane of both enteroendocrine cells and enterocytes as indicated. For simplicity, only a few selected types of immune cells are shown in the lamina propria, i.e., a generic macrophage and a neutrophil granulocyte. As discussed in the text, the expression of specific metabolite receptors on tissue-resident immune cells is still rather unclear; nevertheless, we propose expression of some metabolite receptors based on their expression profile in basic immune cell types.
Cell Metabolism  , DOI: ( /j.cmet )
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5. Figure 3
Schematic Overview of Selected Signaling Metabolites Derived from Cellular Intermediary Metabolism in Liver
Increased accumulation and excretion of succinate from hepatocytes during ischemia and metabolic stress as a result of reverse action of succinate dehydrogenase (Ariza et al., 2012) and its function as a paracrine activator of neighboring stellate cells via GPR91 are indicated. Acetoacetate and β-hydroxybutyrate (β-OHB) being produced during fasting, diabetes, and ketogenic diet, where β-OHB acts both as a classical metabolite and as a signaling metabolite through HCA2 on, for example, β cells and adipocytes (Figures 4 and 5). Hepatocytes also express HCA2 (GPR109A) (Li et al., 2010), as well as other metabolite GPCRs, such as HCA1 and FFA4, and accordingly, β-OHB may possibly act as an autocrine regulator of liver metabolism. β-hydroxyoctanoate is produced by hepatocytes during β-oxidation to act as a signaling metabolite on HCA3 expressed on for example adipocytes (Figure 5).
Cell Metabolism  , DOI: ( /j.cmet )
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6. Figure 4
Schematic Overview of Selected Metabolites Acting Mainly in an Autocrine and Paracrine Manner on β Cells Postprandially and under Metabolic Stress
In DIO mice, acetate synthesized by the β cell accumulates to act in an autocrine manner as a negative regulator of insulin secretion through the joint action of FFA2 and FFA3 (Tang et al., 2015). SCFAs derived from gut microbiota in increased amounts in DIO mice could also be involved. Circulating plasma levels of LCFAs and 2-MAG are probably too low to affect receptor function (see Figure 1F and text). Consequently, LCFAs and 2-MAG are proposed to be produced locally through lipoprotein lipase degradation of triglycerides from chylomicrons (dietary fat) in the islet capillaries or potentially through lipolysis of lipid droplets within the β cell to act as autocrine ligands. The circulating levels of aromatic amino acids from the diet are too low to be physiological activators of GPR142 (see Figure 1E). Consequently, essential aromatic amino acids proposed to be generated in the β cell from autophagy could activate GPR142 and the CasR. Also indicated is circulating β-OHB that can inhibit insulin secretion through HCA2 (see Figure 1B) (Wang et al., 2016b).
Cell Metabolism  , DOI: ( /j.cmet )
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7. Figure 5
Schematic Overview of Selected Metabolites Acting on and Affecting the Function of Adipocytes
Excreted lactate produced from glucose will activate HCA1 and thereby inhibit lipolysis through Gi, which is an important part of the insulin-induced inhibition of lipolysis, while HCA1 is not involved in the exercise-induced inhibition of lipolysis (Ahmed et al., 2010). Acetate, proposed to be produced by the adipocytes during metabolic stress similar to its production in β cells (see Figure 4), is excreted to activate FFA2, which can both inhibit lipolysis and stimulate adipokine production. Succinate, produced during metabolic stress in the adipocytes similar to its production in hepatocytes (see Figure 3), is excreted to act on GPR91, which in turn inhibits lipolysis through Gi. Circulating β-OHB and β-hydroxyoctanoate produced mainly in the liver act on HCA2 and HCA3, respectively, to inhibit lipolysis through Gi. It is proposed that LCFAs/NEFAs produced by the adipocytes through lipolysis act in an autocrine feedback mechanism on FFA4 to increase glucose uptake through Gq and perhaps also to inhibit lipolysis through Gi. However, postprandially FFA4 will also be exposed to LCFAs generated through local degradation of triglycerides from chylomicrons in the capillaries of the adipose tissue. Here, the generated 2-MAG only acts as a classical metabolite and not as a signaling metabolite as GPR119 is not expressed in adipocytes. It is likely that several of the metabolite receptors may affect other adipocyte functions beyond what is indicated in the figure.
Cell Metabolism  , DOI: ( /j.cmet )
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