Dysregulation of glucose metabolism leads to an array of metabolic disorders, including obesity and type-2 diabetes. These two chronic disorders rank amongst the top causes of morbidity and mortality worldwide (1–3). Several biological processes influence glucose metabolism, not least amongst them is lipid metabolism. Glucose homeostasis is intricately linked with lipid metabolism because glucose can serve as substrate for endogenous synthesis of fatty acids by de-novo lipogenesis. Moreover, fatty acids can compensate for glucose deficiency by replacing glucose as the source of oxidative fuel in several metabolic tissues.

This review focusses on mechanisms by which exocrine and endocrine molecules that are secreted in response to lipid ingestion activate cell surface receptors that regulate systemic glucose homeostasis. One such exocrine factor is bile which is released into the intestine to aid emulsification, hydrolysis and uptake of ingested lipids. Bile originates from hepatocytes and is composed of bile acids/salts, bilirubin phospholipid, cholesterol, amino acids, steroids, enzymes, porphyrins, vitamins, and heavy metals (4). The bile acid component of bile, and the fatty acids from intestinal fat hydrolysis possess endocrine properties, and thus serve as ligand activators of specific GPCRs on enteroendocrine cells. This leads to release of gut-specific hormones such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), that are crucial to systemic glucose homeostasis by activating their respective receptors on pancreatic beta cells to promote insulin secretion. Accordingly, several pharmacological agents that mimic the beneficial effects of bile and fatty acids against metabolic diseases via GPCRs are under clinical investigation to treat obesity-associated diseases such as type-2 diabetes (5–7).

It is worth mentioning that, under pathophysiological conditions such as obesity and type-2 diabetes, the circulating levels of fatty acids and bile acids are altered. Whereas fatty acid levels are elevated in obesity and type-2 diabetes (8–10), higher levels of circulating bile acids have been reported in persons who have undergone bariatric surgery to correct obesity (11, 12). However, and as discussed below, the individual fatty and bile acids differ in their physiological functions. Therefore, their physiological benefits or detrimental impact on metabolic diseases depend on the extent of altered levels of specific bile or fatty acids under different pathophysiological conditions. There are different sub-classifications of bile acids based on structural modifications that occur as bile acids travel along the enterohepatic path. Similarly, there is heterogeneity among dietary and endogenously synthesized fatty acids based on length of carbon chain, degree of saturation, or cis-trans bond configuration. These structural differences influence the potency of specific bile and fatty acids to serve as ligands for specific GPCRs that affect glucose homeostasis.

This review highlights the heterogeneity amongst bile and fatty acids, and addresses how GPCR-mediated signaling by these biomolecules regulate systemic glucose homeostasis. Clearly, a deeper understanding of the regulation of systemic glucose metabolism via lipid-derived signaling molecules can unravel novel therapeutic targets, and enhance approaches to treat diseases characterized by aberrant glucose and lipid metabolism.

SCFAs, including acetate, propionate, and butyrate, are small-molecule metabolites generated by gut microbiota through anaerobic fermentation of non-digestible carbohydrates. SCFAs are known to contribute to many metabolic disorders including obesity (45) and diabetes (46), suggesting that SCFAs affect multiple pathways involved in glucose/lipid metabolism and inflammation. As already mentioned above, SCFAs act on two major GPCRs, FFAR2 and FFAR3. Based on the expression profiles of FFAR2 and FFAR3, we focus on the signaling effects of SCFAs on glucose metabolism in different metabolically important tissues, including gut, pancreas, and adipose tissue.

The following section on unsaturated fatty acids will focus on cis-configurated long-chain mono- and poly-unsaturated fatty acids that contain at least 12 carbons and are mostly found in plant-based vegetable oils, nuts, and seeds.

In mouse MIN6 beta cells, an array of unsaturated fatty acids including oleic, linoleic, eicosapentaenoic acid, and docosahexaenoic acid induced insulin secretion in a dose-dependent manner under hyperglycemic conditions (80). This effect was FFAR1-dependent, since siRNA knockdown of FFAR1 expression significantly reduced insulin secretion by linoleic acid, the most potent fatty acid agonist of FFAR1 in mice (80). In agreement with this observation, Schnell and colleagues found that long-chain mono- and polyunsaturated fatty acids increased intracellular Ca²⁺ levels and insulin release in primary mouse beta-cells and INS-1 cells; this effect was abrogated in INS-1 cells upon siRNA-mediated downregulation of FFAR1 (81). In a related study conducted with rat pancreatic beta-cells, oleic acid (1-10 μM) dose-dependently increased intracellular Ca²⁺ levels at increasing concentrations of glucose (82). Moreover, when rat beta-cells where transfected with FFAR1 siRNA, the oleic acid-induced increase in intracellular Ca²⁺ was impeded due to decreased PLC activity, resulting in impaired insulin release (82). Another study also reported that in isolated rat islets, linoleic acid dose-dependently stimulated glucagon release at both low (3 mM) and high (15 mM) glucose levels, although higher glucose concentrations expectedly decreased basal glucagon levels (83). However, inhibition of FFAR1 abrogated the effect of linoleic acid on glucagon release, along with decreased intracellular Ca²⁺ levels stemming from impaired PLC activity (83). Similarly, Flodgren and colleagues showed that linoleic acid dose-dependently increase glucagon secretion in isolated mouse islets, an effect which was annulled by antisense treatment against FFAR1 (84). The tendency of activated FFAR1 signaling to increase the release of both insulin and glucagon under hyperglycemic conditions appears surprising, given the fact that these two hormones are considered functional antagonists. However, recent studies using different experimental models have shown that glucagon release from alpha cells can promote insulin release via paracrine signaling under hyperglycemic conditions (85–88). FFAR1 is also expressed by incretin-releasing enteroendocrine cells (39). Following a HFD challenge, mice with global deletion of FFAR1 showed decreased plasma levels of GLP-1 and GIP, which led to a moderate decrease in plasma insulin and a concomitant increase in plasma glucose levels (39). These data suggest that insulin release following fatty acid activation of FFAR1 can occur directly or indirectly through action of incretins.

As already mentioned, FFAR4 is another GPCR activated by long chain fatty acids that contributes to the regulation of glucose homeostasis (35). Interestingly, morbidly obese subjects have reduced FFAR4 expression levels in visceral adipose tissue and in peripheral blood mononuclear cells (89). Another study reported that the anti-inflammatory effects of oleic acid and docosahexaenoic acid in human visceral adipocytes were mediated by FFAR4 (90), which has an indirect effect on insulin signaling and glucose homeostasis. In humans, a non-synonymous mutation of FFAR4 associated with obesity whereas global knockout of FFAR4 in HFD mice led to weight gain, glucose intolerance, fatty liver, and insulin resistance, suggesting that intact FFAR4 signaling is critical for maintaining systemic glucose homeostasis (91). In murine RAW264.7 and mouse primary intraperitoneal macrophages, docosahexaenoic acid and eicosapentaenoic acid repressed inflammation, and also reduced immune infiltration in adipose tissue of mice, along with improved insulin sensitivity, in a FFAR4-dependent manner (92). In line with this, when FFAR4-KO mice and WT controls were maintained on HFD supplemented with the selective FFAR4 agonist, Compound A, there was significant improvement in glucose tolerance and insulin sensitivity in the WT mice, but not in the FFAR4-KO mice (93). In mice, delivery of α-linoleic acid directly into the stomach increased plasma levels of GLP-1 and insulin in a FFAR4-dependent manner (94). Complementary experiments in STC-1 cells revealed that knockdown of FFAR4 but not FFAR1 reduced α-linoleic acid-mediated GLP-1 secretion (94). In isolated mouse pancreatic islets and clonal pancreatic BRIN-BD11 cells, α-linoleic acid, eicosapentaenoic acid, and docosahexaenoic acid mimicked the actions of a FFAR4-specific agonist, GW-9508, in stimulating insulin release, an effect that was accompanied by significant elevations in intracellular Ca²⁺ and cAMP (95). Accordingly, treatment (i.p.) of mice with α-linoleic acid augmented insulin secretion, leading to improved glucose tolerance (95).

The effect of FFAR4 activation by unsaturated fatty acids on glucagon release has also been explored in a limited number of studies. In islets isolated from whole-body FFAR4-KO mice, docosahexaenoic acid-induced glucagon secretion was significantly reduced, when compared to control mice (96). FFAR4 is also well expressed in somatostatin-producing delta cells in pancreatic islets (69, 97). In agreement with this observation, glucose-stimulated somatostatin secretion was significantly decreased by omega-3 long-chain PUFAs in pancreatic islets from WT mice (98) but not in islets from FFAR4-KO mice (97). However, the physiological relevance of this effect remains to be established.

Taken together, available evidence shows that unsaturated fatty acids, and especially omega-3 PUFAs influence glucose homeostasis by serving as potent ligands for FFAR1 and FFAR4 expressed by pancreatic islets and enteroendocrine cells.

Saturated fatty acids (SFAs) lack double bonds in their hydrocarbon chain. Studies of the effect of SFAs on glucose homeostasis have focused on specific fatty acids such as palmitate. Palmitate is a highly abundant dietary SFA and known as very potent FFAR1 agonist (80). In humans, the intake of dietary fat rich in the palmitic acid leads to adverse effects on postprandial glycemic control, due to reduced β-cell function and decreased insulin sensitivity (99). A related study showed that 7-day exposure of human islets to 0.5 mM of palmitate impaired GSIS, most likely due to GLP-1 receptor-dependent upregulation of inflammatory markers such as SOCS2, IL-1B, and TNFα (100). This effect of palmitate on human islets was recapitulated in mouse MIN6 pseudoislets, but was abrogated following siRNA-mediated knockdown of Socs2 (100). This observation agrees with the well-described pro-inflammatory effects of palmitate and other SFAs in human and murine cell types (101, 102) as well as the anti-inflammatory effects of GLP-1 receptor signaling (103, 104). In isolated mouse islets, palmitate induced glucagon secretion in a FFAR4-dependent manner, although the absence of FFAR4 had no effect on GSIS (96). Similarly, palmitate has been shown to stimulate glucagon secretion in WT mouse islets through enhanced Ca²⁺ entry into alpha cells to promote alpha-cell exocytosis (105). Clearly, additional studies are needed to explore the mechanisms underlying the effects of different SFAs on systemic glucose metabolism.

In humans that have undergone bariatric surgery to correct obesity, there exists a positive correlation between improved glucose metabolism and increased levels of circulating bile acids (106–108). It is now established that modulation of bile acid composition affects systemic glucose metabolism through alterations in intestinal lipid absorption or via activation of receptor-mediated signaling through farnesoid X-receptor (FXR) and GPBAR1 (109, 110). As a GPCR, GPBAR1, following the binding of bile acids, couples to Gαs (111). GPBAR1 shows highest affinity for lithocholic acid (EC₅₀ ~0.53 μM), followed by conjugated and unconjugated forms of deoxycholic acid, chenodeoxycholic acid, and cholic acid (EC₅₀ ~1.0, 4.4 7.7 μM, respectively) (109, 110, 112). Interestingly, mice with elevated levels of lithocholic and chenodeoxycholic acids show improved systemic glucose tolerance (113, 114), possibly through increased secretion of GLP-1 (115). This finding agrees with reports of relatively high expression of GPBAR1 in small intestine, colon, and enteroendocrine L-cells (116–118) ( Figure 1 ), and the observation that treatment of STC-1 cells with GPBAR1 agonists enhances GLP-1 secretion (44). Additionally, GPBAR1 agonists improves whole-body glucose tolerance in mice, via increased secretion of GLP-1 and insulin (119). Hyocholic acid is a major primary bile acid in pigs, a specie noted for great resistance against type-2 diabetes (120). Based on this rationale, Zheng and colleagues investigated the anti-diabetic effect of hyocholic acid by demonstrating that the levels of hyocholic acid and blood glucose levels in humans with type-2 diabetes show an inverse correlation (120, 121). Mechanistically, hyocholic acid enhanced GLP-1 secretion by enteroendocrine cells through simultaneous activation of GPBAR1 and inhibition of FXR, leading to improved glucose tolerance. Moreover, hyocholic acid showed a stronger potency at stimulating cAMP production in comparison to the endogenous GPBAR1 agonist, lithocholic acid (121). In isolated mouse pancreatic islets, taurine-conjugated ursodeoxycholic acid (TUDCA) enhanced GSIS through the cAMP/PKA pathway (122). Similarly, in both human and mouse islets, as well as in MIN6 beta cells, the activation of GPBAR1 by lithocholic acid increased intracellular cAMP and Ca²⁺ levels and increased insulin secretion (123). In agreement with this finding, lithocholic acid and synthetic GPBAR1 agonists improved glucose tolerance in mice through increases in GLP-1 and insulin release (124), as well as increased L-cell differentiation and abundance (125). Moreover, the metabolic outcome of GPBAR1 expression/activation has been investigated in other important metabolically relevant tissues such as the skeletal muscle and brain. In the postprandial state, most circulating glucose is disposed by skeletal muscle, indicative of the key role of skeletal muscle in maintaining euglycemia (126–128). In mice, GPBAR1 activation enhanced insulin-stimulated glucose uptake by skeletal muscle (124), and skeletal muscle-specific overexpression of GPBAR1 improved glucose tolerance (129). Based on reports that bile acids reach the brain (130) and GPBAR1 is expressed in the central nervous system (40, 131), Perion and colleagues investigated the central effects of bile acids. They found that bile acids exert an anorexigenic effect by activating hypothalamic GPBAR1; however, this study did not measure the effects on systemic glucose homeostasis (132). Another study showed that reduced hypothalamic bile acid content in diet-induced obese mice can be counteracted by bile acid supplementation or by central administration of the selective TGR5 agonist, (2-chlorophenyl)-N-(4-chlorophenyl)-N,5-dimethyl-4-isoxazolecarboxamide, leading to decreased body weight and fat mass, via GPBAR1-mediated activation of the sympathetic nervous system (133). Although reduced adiposity is known to correlate with improved glucose tolerance, the authors did not assess effects on glucose metabolism. However, oral treatment of ob/ob mice with taurocholic acid resulted in improved glucose tolerance via activation of a gut-brain pathway, since the improved glucose tolerance depended on gut-derived FGF15 and intact melanocortin signaling (45).

Taken together, in vivo studies in humans and mice, as well as in vitro experiments with isolated islets and cultured cells demonstrate that specific bile acids show strong effects on glucose homeostasis through activation of GPBAR1, resulting in multiple beneficial metabolic effects including increased insulin secretion. These findings strongly suggest that targeting the bile acid-GPBAR1 axis may prove useful for the development of novel antidiabetic drugs.

Maintaining systemic glucose levels within a physiological range during fasting and feeding relies on the coordinated regulation of endogenously secreted insulin and glucagon. GPCRs that are responsive to specific bio-metabolites play a central role in regulating the release of these two important hormones. For example, SCFAs act on FFAR2 and FFAR3, bile acids on GPBAR1, and saturated and unsaturated fatty acids on FFAR1 and FFAR4, respectively ( Figure 1 ). Most studies reported that SCFAs, bile acids, and unsaturated fatty acids have positive effects on glucose homeostasis, due in part by promoting incretin and insulin release, resulting in reduced glucose excursions in the post-prandial state. However, long chain SFAs seem to have adverse effects on systemic glucose homeostasis due to their pro-inflammatory effects and limited efficacy in inducing GPCR-mediated release of incretins and insulin. Among saturated fatty acids, the metabolic effect of palmitic acid has been studied in considerable detail, in contrast to other SFAs such as capric, lauric, myristic, and stearic acids. It would thus be of interest to interrogate the potential metabolic roles and signaling properties of these latter SFAs. The data discussed in this brief review indicate that GPBAR1 and FFARs 1, 2, 3 and 4 all represent potential pharmacological targets for improving impaired glucose homeostasis in type-2 diabetes and related metabolic disorders. More studies are needed to explore whether simultaneous targeting of several of these receptors might provide even greater therapeutic benefits. Additionally, because these GPCRs are expressed in multiple cells and tissues, the tissue- and cell-type specific effects of targeting these receptors need to be explored in more detail by using conditional and inducible mouse knockout models. This is especially true for FFAR2, due to the discordant reports obtained from studies in global KO mice. Such studies will provide important new insights into the mechanisms through which the different receptors affect glucose and lipid metabolism, providing a rational basis for the design of novel drugs aimed at treating various important metabolic diseases.

A-BO and LL conceptualized and wrote the manuscript. A-BO is responsible for the final content of the manuscript. All authors contributed to the article and approved the submitted version.