ReviewPost screenGPR120 agonism as a countermeasure against metabolic diseases
Introduction
The search for a panacea against metabolic diseases has identified a number of G-protein-coupled receptors (GPCRs) that are responsive to fatty acids (FAs) or their derivatives as candidates for new pharmaceutical treatments against these insidious conditions. Metabolic diseases are commonly the result of undesirable diet and lifestyle choices that lead to excessive systemic adiposity (obesity), insulin resistance, overt type 2 diabetes mellitus (T2DM) and cardiovascular diseases (CVD). Together, obesity, T2DM and CVD represent a major cause of morbidity and premature mortality in Westernized societies, which comes at an immense financial burden to healthcare systems globally. Therefore, significant research efforts are being directed at attenuating the increasing prevalence of these conditions. However, research into the selective manipulation of GPCRs as a treatment option for these conditions remains in its relative infancy.
Of the GPCRs under investigation for their potential as drug targets, GPR120 [also known as free fatty acid receptor (FFA)4] is among those that have been progressed as a potential targeted receptor for the alleviation of metabolic diseases. GPR120 has been identified as a member of a family of free fatty acid receptors including GPR40 (also known as FFA1), GPR41 (FFA3) and GPR43 (FFA2), which have been reviewed extensively elsewhere 1, 2, 3, 4. As the name suggests, this family of receptors are activated by free FAs of varying chain length with GPR41 and GPR43 being activated predominantly by short-chain FAs, whereas GPR40 and GPR120 are activated by long-chain FAs (LCFAs) [4]. As a result of this, efforts to understand the explicit functions of these receptors in isolation have been clouded by nonspecific endogenous and synthetic ligands for GPR40 and GPR120. Ongoing works have been able to develop more selective chemical agonists and antagonists at these receptors, which has enhanced the current understanding of the roles of these receptors. But caution is still needed in many instances in attributing changes in function solely to one of these receptors.
When looking at GPR120 specifically, this receptor has been implicated in a number of processes including release of gastrointestinal peptides, inflammation, adipogenesis, lipogenesis, glucose intolerance, insulin sensitivity and food preference 5, 6, 7, 8, 9, 10. These factors interrelate to influence systemic metabolic function in physiological and pathophysiological conditions. Herein, we discuss the recent advances in research regarding the roles of GPR120 and how pharmaceutical agents at this receptor could be used in the prevention and treatment of metabolic diseases.
Section snippets
GPR120
GPR120 was first identified as an orphan GPCR by Fredriksson et al. [11], who determined the chromosomal location for human GPR120 to be 10q23.33. Human GPR120 was subsequently shown to exist as two splice variants, a short (361 amino acids; accession numbers: RNA – GenBank ID: BC101175 and Protein – GenBank ID: AAI01176.1) and a long (377 amino acid; accession numbers: RNA – NCBI Reference Sequence ID: NM_181745 and Protein – NCBI Reference Sequence ID: NP_859529.2) isoform 6, 10, 12, 13 (Fig.
Tissue distribution of GPR120
GPR120 is widely expressed in a number of tissue types, and is most abundantly expressed in lung and colonic tissues [6]. This diverse localization of GPR120 is likely related to the broad spectrum of effects GPR120 elicits with expression also being reported in tissues involved in homeostatic regulation of metabolic health and inflammatory and/or immune processes, including the brain, thymus, pituitary, small intestine, white adipose tissues, taste buds, skeletal muscle, heart and liver 6, 7,
Ligands for GPR120
GPR120 is a receptor specific for LCFAs [6]. FAs are generated during lipolysis [23]. Free FAs released into the plasma then circulate and not only provide substrate for energy production but importantly also act as endogenous ligands to modulate the expression of genes and proteins that regulate a diverse range of physiological and pathophysiogical functions including those related to energy homeostasis 24, 25. Studies to date have shown that unsaturated FAs with a carbon chain length of
GPR120 signaling
GPR120 has been shown to couple to Gαq and β-arrestin 2 mediated pathways 6, 8 (Fig. 2). Coupling of GPR120 induces increases in intracellular calcium transients 6, 10 and is without effect on intracellular cyclic adenosine monophosphate concentration [6]. Activation of GPR120 has been shown to lead to receptor internalization [8]. Oh et al. [8] show that, in RAW 264.7 cells, DHA stimulation induced translocation of β-arrestin 2 to the plasma membrane where it co-localizes with GPR120. Further
Physiological functions of GPR120 and the implications for metabolic disease
GPR120 is proposed as a drug candidate largely for the treatment of metabolic diseases and, in view of the current literature, agonists at this receptor are expected to be of benefit 5, 6, 7, 8, 33. Metabolic diseases are often the consequence of a chronic energy imbalance where intake exceeds requirements leading to a prolonged positive energy balance [34]. This is complicated by hedonic and hedonistic factors influencing energy intake and expenditure and, over the longer term, is reflected by
Adipogenesis
GPR120 is abundantly expressed in adipocyte and adipose tissue extracts 5, 7, 8, yet is undetectable in pre-adipocytes 7, 21. Moreover, GPR120 expression increases in parallel with lipid accumulation in the cells upon induction of differentiation in 3T3-L1 cells 7, 21. Small interference RNA against GPR120 was shown to reduce the expression of adipogenic genes and reduced lipid droplet accumulation in 3T3-L1 adipocytes [7]. Taken together, these data support the contention that GPR120 is an
Gastrointestinal peptides and intestinal health
Gastrointestinal peptides are intimately involved in the regulation of feeding behaviors, energy metabolism and bodyweight 36, 37, 38, 39, 40, 41. GPR120 has been demonstrated to induce secretion of two such peptides: GLP-1 and cholecystokinin (CCK), from enteroendocrine STC-1 cells in vitro 6, 9, 10. In both instances, transient knockdown of GPR120 ablated the effect of α-LA on secretion of GLP-1 and CCK, to confirm that GPR120 is indeed responsible for this effect 6, 9. GLP-1 is an
Spontaneous taste preference
Hedonia is a major determinant of dietary intake to which taste is intimately linked [50]. Lipid-rich foods are typically highly palatable and energy dense [50]. This palatability predisposes to excessive consumption of lipid-rich foods that, owing to the high energy density, contribute greatly to daily caloric intake. Thus, chronic overconsumption of lipid-rich foods can increase bodyweight and facilitate the development of obesity and associated co-morbidities.
GPR120 is expressed in cells
Inflammation
GPR120 is expressed abundantly in adipose tissues and in macrophages [8]. GPR120 has been shown to exert powerful anti-inflammatory effects [8], which is consistent with activation of GPR120 via omega 3 FAs, α-LA and DHA. These FAs have been widely validated as having anti-inflammatory effects at the tissue-specific and systemic levels [55]. In the study by Oh et al. [8], GPR120 was shown to mediate suppression of the proinflammatory markers IKKβ, JNK, TNF-α, interleukin-6 and toll-like
GPR120 and insulin signaling
The skeletal muscle is a major site of insulin-stimulated glucose uptake 56, 57 and thus is implicit in maintaining systemic euglycaemia. Cornall et al. [15] show increased GPR120 mRNA expression in the EDL skeletal muscle which comprises predominantly glycolytic and/or fast-twitch fibers 58, 59, therefore relying largely on glucose for energy production. Activity at GPR120 has been shown to have insulin-sensitizing effects [8] and protects from glucose intolerance induced by ingestion of a
GPR120 modulation of systemic metabolic health
GPR120 is a ubiquitous receptor with pleiotropic functioning that supports a role for this receptor in mediating systemic metabolic health (Fig. 3). Regulation of adiposity is modulated by the propensity for adipocytes to store excess energy from ingested lipids and glucose in the form of fat. Partitioning of substrate (i.e. glucose and FAs) away from oxidative pathways predisposes to their storage in adipose tissues as an energy reserve. GPR120 is indeed suggested to be adipogenic 5, 7, 8, 21.
Concluding remarks
Overall, GPR120 agonism appears likely to have positive outcomes on health and the current data suggest GPR120 activation to be a valid pharmaceutical target for the treatment of metabolic disease. However the findings of Wu et al. [16] demonstrating that GPR120 activation promoted tumor formation and angiogenesis suggest that GPR120 agonists could be contraindicated in terms of cancer promotion and progression. Thus, despite promising early findings in terms of metabolic health, it is
Acknowledgements
L.M.C. was supported by a scholarship (PB 10 M 5472) from the National Heart Foundation of Australia. A.J.M. was supported by the Australian Government's Collaborative Research Networks (CRN) program.
References (69)
The regulation of adipogenesis through GPR120
Biochem. Biophys. Res. Commun.
(2007)GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects
Cell
(2010)Seven evolutionarily conserved human rhodopsin G-protein-coupled receptors lacking close relatives
FEBS Lett.
(2003)- et al.
Agonism with the omega-3 fatty acids alpha-linolenic acid and docosahexaenoic acid mediates phosphorylation of both the short and long isoforms of the human GPR120 receptor
Biochem. Biophys. Res. Commun.
(2010) Cloning, expression, and pharmacological characterization of the GPR120 free fatty acid receptor from cynomolgus monkey: comparison with human GPR120 splice variants
Comp. Biochem. Physiol. B: Biochem. Mol. Biol.
(2009)Colocalization of GPR120 with phospholipase-Cbeta2 and alpha-gustducin in the taste bud cells in mice
Neurosci. Lett.
(2009)Lipid-mediated release of GLP-1 by mouse taste buds from circumvallate papillae: putative involvement of GPR120 and impact on taste sensitivity
J. Lipid Res.
(2012)- et al.
Is there a single mechanism for fatty acid regulation of gene transcription?
Biochem. Pharmacol.
(2002) Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1
J. Biol. Chem.
(2005)Targeting GPR120 and other fatty acid-sensing GPCRs ameliorates insulin resistance and inflammatory diseases
Trends Pharmacol. Sci.
(2011)
Gut hormones and the control of appetite
Trends Endocrinol. Metab.
Gastrointestinal peptides controlling body weight homeostasis
Gen. Comp. Endocrinol.
De novo lipogenesis, lipid kinetics, and whole-body lipid balances in humans after acute alcohol consumption
Am. J. Clin. Nutr.
Activation of tongue-expressed GPR40 and GPR120 by non caloric agonists is not sufficient to drive preference in mice
Neuroscience
Omega 3 fatty acids and GPR120
Cell Metab.
PPAR signaling in the control of cardiac energy metabolism
Trends Cardiovasc. Med.
Mitochondrial dysfunction in diabetic cardiomyopathy
Biochim. Biophys. Acta
Fat in the intestine as a regulator of appetite – role of CCK
Physiol. Behav.
Obesity and leptin resistance: distinguishing cause from effect
Trends Endocrinol. Metab.
The therapeutic potential of GPR43: a novel role in modulating metabolic health
Cell. Mol. Life Sci.
Free fatty acid receptors and drug discovery
Biol. Pharm. Bull.
The role of G-protein-coupled receptors in mediating the effect of fatty acids on inflammation and insulin sensitivity
Curr. Opin. Clin. Nutr. Metab. Care
Free fatty acids-sensing G-protein-coupled receptors in drug targeting and therapeutics
Curr. Med. Chem.
Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human
Nature
Free fatty acids regulate gut incretin glucagon-like peptide-1 secretion through GPR120
Nat. Med.
Free fatty acids induce cholecystokinin secretion through GPR120
Naunyn. Schmiedebergs. Arch. Pharmacol.
Cloning and characterization of the rat free fatty acid receptor GPR120: in vivo effect of the natural ligand on GLP-1 secretion and proliferation of pancreatic beta cells
Naunyn. Schmiedebergs. Arch. Pharmacol.
Differential signaling by splice variants of the human free fatty acid receptor GPR120
Mol. Pharmacol.
Diet-induced obesity up-regulates the abundance of GPR43 and GPR120 in a tissue specific manner
Cell. Physiol. Biochem.
Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma
Oncogene
Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability
J. Am. Geriatr. Soc.
Gustducin couples fatty acid receptors to GLP-1 release in colon
Am. J. Physiol. Endocrinol. Metab.
Unsaturated fatty acids revert diet-induced hypothalamic inflammation in obesity
PLoS ONE
Distribution and regulation of protein expression of the free fatty acid receptor GPR120
Naunyn. Schmiedebergs. Arch. Pharmacol.
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