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Endocrinology Vol. 147, No. 2 672-673
Copyright © 2006 by The Endocrine Society

The Free Fatty Acid Receptor GPR40 Generates Excitement in Pancreatic ß-Cells

Jesper Gromada

Lilly Research Laboratories Essener Bogen 7 D-22419 Hamburg, Germany

Address all correspondence and requests for reprints to: Dr. Jesper Gromada, Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany. E-mail: gromada{at}lilly.com.

Free fatty acids (FFAs) provide an important energy source and also act as signaling molecules. Accumulating evidence suggests that FFAs exert a variety of physiological responses via an emerging family of G protein-coupled transmembrane receptors. GPR40 and GPR120 are activated by medium- and long-chain FFAs, whereas GPR41 and GPR43 can be activated by short-chain FFAs (1, 2, 3, 4, 5). GPR40, which is preferentially expressed in pancreatic ß-cells, mediates the majority of the effects of FFAs on insulin secretion (3, 6, 7, 8).

Blood glucose concentration is the most important regulator of insulin secretion from the pancreatic ß-cell. The ß-cell is electrically excitable and generates action potentials when exposed to insulin-releasing glucose concentrations. The voltage-gated Ca2+ and K+ currents that underlie ß-cell electrical activity have been described in some detail (9). As in other excitable cells, the outward voltage-gated K+ current keeps the action potential short and thus limits the period of Ca2+ influx and insulin secretion (Fig. 1Go). Thus, voltage-gated K+ channels potentially represent important regulators of insulin secretion.



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  		FIG. 1. Regulation of insulin secretion by glucose and GPR40. Glucose metabolism in glycolysis and Krebs cycle leads to generation of ATP at the expense of ADP. The resulting increase in the ATP-to-ADP ratio causes closure of the ATP-sensitive K+-channels (K-ATP), cell membrane depolarization (Depol.), and stimulation of Ca2+ influx through voltage-dependent Ca2+-channels (VDCC). The resulting increase in [Ca2+]i is the trigger signal for exocytosis of the insulin-containing secretory granules. Opening of voltage-gated K+ (Kv) channels in response to membrane depolarization will repolarize the ß-cell, close the VDCC, and limit Ca2+ influx. Binding of FFA to GPR40 leads to IP3 production, activation of intracellular IP3 receptors (IP3R), and mobilization of intracellular Ca2+ from the endoplasmic reticulum (ER). GPR40 activation also stimulates Ca2+ influx through VDCC. The resulting increase in [Ca2+]i stimulates insulin secretion. Binding of FFA to GPR40 also produces an increase in intracellular cAMP levels, which antagonizes the activity of Kv channels further enhancing Ca2+ influx. The dotted line indicates that it is not yet established whether GPR40 activation by FFA directly stimulates cAMP production.

 
FFAs are known to have pleiotropic effects on the pancreatic ß-cell. Although acute administration of FFAs stimulates insulin release, chronic exposure to high levels of FFAs results in the impairment of ß-cell function and secretory capacity, a phenomenon recognized as lipotoxicity (10). It has always been assumed that, to exert a stimulatory effect on insulin release, FFAs must be transported across the plasma membrane into the cell and metabolized into long-chain fatty acyl-coenzyme A (11, 12). However, this assumption has recently been challenged and it is now clear that FFAs amplify glucose-dependent insulin secretion in a GPR40-dependent manner (1, 3, 6, 8). It is against this background that the report by Feng et al. (13) published in this issue of Endocrinology should be considered. The authors show that the unsaturated FFA linoleic acid (C18:2) reduces the voltage-gated K+ current in rat pancreatic ß-cells through a GPR40-mediated increase in cAMP levels and protein kinase A activity, leading to enhanced ß-cell excitability and insulin secretion.

The K+ current generated by voltage-gated K+ channels is composed of mainly two subtypes, a fast transient current and a slow inactivating delayed rectifying current (14). Feng et al. (13) establish that the effects of linoleic acid on voltage-gated K+ current is due to inhibition of delayed rectifying K+ channels, which comprise the majority (>95%) of the total voltage-gated K+ current in ß-cells. Using small interfering RNA expected to selectively silence GPR40 expression, Feng et al. (13) elegantly show that the ability of linoleic acid to antagonize voltage-gated K+ currents is mediated via GPR40. This is further supported by the observation that linoleic acid did not affect voltage-gated K+ currents in GH3 cells, which do not express GPR40. Finally, methyl linoleic acid, which has a similar structure to linoleic acid but does not bind to GPR40, did not affect K+ currents in ß-cells.

Previous research suggests that FFA binding to GPR40 activates phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate into inositol trisphosphate (IP3), which mobilizes intracellular Ca2+ from the endoplasmic reticulum (Fig. 1Go) (15, 16). The FFA-evoked increase in the intracellular Ca2+ concentration ([Ca2+]i) also involves enhanced Ca2+ influx through voltage-gated Ca2+ channels (15, 16, 17, 18) (Fig. 1Go). Regardless of the mechanism, the FFA-induced [Ca2+]i increase is only observed in the presence of elevated glucose levels (and, therefore, already elevated [Ca2+]i levels), and inhibition of Ca2+ influx suppresses FFA stimulation of insulin release (15). These findings shed light on the mechanism(s) by which FFAs increase [Ca2+]i and thus enhance insulin secretion. The data by Feng et al. (13) suggest that the insulinotropic effect of FFAs may be mediated in part by an inhibition of delayed rectifying voltage-gated K+ channels, leading to enhanced action potential amplitude and duration. Indeed, FFAs enhanced glucose-stimulated electrical activity in vitro (18) and stimulated in vivo ß-cell electrical activity in fasted mice (19). Feng et al. (13) further demonstrate that the effect of FFA is mediated by protein kinase A activation and that linoleic acid produced an increase in intracellular cAMP levels. There is precedence for this scenario, and glucagon-like peptide-1, which stimulates insulin secretion by increasing intracellular cAMP levels, has been reported to also inhibit the voltage-gated K+ current (20). At this stage it remains unresolved precisely how linoleic acid-induced activation of GPR40 stimulates cAMP production in ß-cells. It is tempting to speculate that the observed increase in intracellular cAMP levels produced with linoleic acid could be secondary to elevations in [Ca2+]i and subsequent activation of Ca2+-dependent adenylate cyclase isoform(s) in the ß-cell. This could be tested using pharmacological inhibitors of intracellular Ca2+ release channels. Interestingly, the activation of cAMP signaling pathway by Gq{alpha}-coupled receptors may be a more general phenomenon that is observed not only for GPR40 but also for muscarinic receptors in ß-cells (21, 22).

GPR40 and related receptors have also been implicated in the control of cell growth and survival via activation of the ERK and phosphatidylinositol 3-kinase/protein kinase B (Akt) signaling pathways (23, 24, 25). Future studies will have to address to what extent these FFA-induced signaling pathways and changes in intracellular cAMP levels contribute to the antiapoptotic and proliferative effects of GPR40 in ß-cells. It is also essential to examine the potential beneficial role of GPR40-mediated cAMP increases in modulation of ß-cell function under long-term FFA exposure. Paradoxically, under chronic conditions, ß-cells from GPR40-deficient mice are protected from lipotoxicity, whereas overexpression of GPR40 in ß-cells leads to impaired ß-cell function, hypoinsulinemia, and diabetes (8). Clearly, the identification of GPR40 selective non-FFA agonists and antagonists would help resolve this apparent controversy. This begs further research in this exciting but fledgling area and could open the door to exciting ideas in research and treatment.


   Acknowledgments
 
I thank Patrik Rorsman for critical review of the manuscript.


   Footnotes
 
Abbreviations: [Ca2+]i, Free intracellular Ca2+ concentration; FFA, free fatty acid; IP3, inositol trisphosphate.

Received November 1, 2005.

Accepted for publication November 10, 2005.


   References
Top
 References
 

  1. Briscoe CP, Tadayyon M, Andrews JL, Benson WG, Chambers JK, Eilert MM, Eillis C, Elshourbagy NA, Goetz AS, Minnick DT, Murdock PR, Sauls HR, Shabon U, Spinage LD, Strum JC, Szekeres PG, Tan KB, Way JM, Ignar DM, Wilson S, Muir AI 2003 The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J Biol Chem 278:11303–11311[Abstract/Free Full Text]
  2. Brown AJ, Goldsworthy SM, Barnes AA, Eilert MM, TcheangL, Daniels D, Mjuir AI, Wigglesworth MJ, Kinghorn I, Fraser NJ, Pike NB, Strum JC, Steplewski KM, Murdock PR, Holder JC, Marshall FH, Szekeres PG, Wilson S, Ignar DM, Foord SM, Wise A, Dowell SJ 2003 The orphan G protein-coupled receptor GPR41 and GPR43 are activated by propionate and other short chain carboxylic acids. J Biol Chem 278:11312–11319[Abstract/Free Full Text]
  3. Itoh Y, Kawamata Y, Harada M, Kobayashi M, Fujii R, Fukusumi S, Ogi K Hosoya M, Tanaka Y, Uejima H, Tanaka H, Maruyama M, Satoh R, Okubo S, Kizawa H, komatsu H, Matsumura F, Noguchi Y, Shinohara T, Hinuma S, Fujisawa Y, Fujino M 2003 Free fatty acids regulate insulin secretion from pancreatic ß cells through GPR40. Nature 422:173–176[CrossRef][Medline]
  4. Hirasawa A, Tsumaya K, Awaji T, Katsuma S, Adachi T, Yamada M, Sugimoto Y, Miyazaki S, Tsujimoto G 2005 Free fatty acids regulate gut incretin glucagons-like peptide-1 secretion through GPR120. Nat Med 11:90–94[CrossRef][Medline]
  5. Le Poul E, Loison C, Struyf S, Springael J-Y, Lannoy V, Decobecq M-E, Brezillon S, Dupriez V, Vassart G, Van Damme J, Parmentier M, Detheux M 2003 Functional characterization of human receptor for short chain fatty acids and their role in polymorphonuclear cell activation. J Biol Chem 278:25481–25489[Abstract/Free Full Text]
  6. Kotarsky K, Nilsson NE, Flodgren E, Owman C, Olde B 2003 A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs. Biochem Biophys Res Commun 301:406–410[CrossRef][Medline]
  7. Salehi A, Flodgren E, Nilsson NE, Jimenez-Feltstrom J, Miyazaki J, Owman C, Olde B 2005 Free fatty acid receptor 1 (FFA1R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion. Cell Tissue Res 322:207–215[CrossRef][Medline]
  8. Steneberg P, Rubins N, Bartoov-shifman R, Walker MD, Edlund H 2005 The FFA receptor GPR40 links hyperinsulinemia hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab 1:245–257[CrossRef][Medline]
  9. Rorsman P 1997 The pancreatic ß-cell as a fuel sensor: an electrophysiologist’s viewpoint. Diabetologia 40:487–495[CrossRef][Medline]
  10. McGarry JD, Dobbins RL 1999 Fatty acid, lipotoxicity and insulin secretion. Diabetologia 42:128–138[CrossRef][Medline]
  11. Corkey BE, Deeney JT, Yaney GC, Tornheim K, Prentki M 2000 The role of long-chain fatty acyl-CoA esters in ß-cell signal transduction. J Nutr 130(2S Suppl):299S–304S
  12. Prentki M, Joly E, El-Assaad W, Roduit R 2002 Malonyl-CoA signaling, lipid partitioning, and glucolipotocixity. Diabetes 51(Suppl 3):S405–S413
  13. Feng DD, Luo Z, Roh S-G, Hernandez M, Tawadros N 2006 Reduction in voltage-gated K+ currents in primary cultured rat pancreatic ß-cells by linoleic acid. Endocrinology 147:674–682[Abstract/Free Full Text]
  14. Göpel SO, Kanno T, Barg S, Rorsman P 2000 Patch-clamp characterisation of somatostatin-secreting {delta}-cells in intact mouse pancreatic islets. J Physiol 528:497–507[Abstract/Free Full Text]
  15. Fujiwara K, Maekawa F, Yada T 2005 Oleic acid interacts with GPR40 to induce Ca2+ signaling in rat islet ß-cells: mediation by PLC and L-type Ca2+ channel and link to insulin secretion. Am J Physiol Endocrinol Metab 289:E670–E677
  16. Shapiro H, Shachar S, Sekler I, Hershfinkel M, Walker MD 2005 Role of GPR40 in fatty acid action on the ß cell line INS-1E. Biochem Biophys Res Commun 335:97–104[CrossRef][Medline]
  17. Olofsson CS, Salehi A, Holm C, Rorsman P 2004 Palmitate increases L-type Ca2+ currents and the size of the readily releasable granule pool in mouse pancreatic ß-cells. J Physiol 557:935–948[Abstract/Free Full Text]
  18. Warnotte C, Gilon P, Nenquin M, Henquin JC 1994 Mechanisms of the stimulation of insulin release by saturated fatty acids. Diabetes 43:703–711[Abstract]
  19. Fernandez J, Valdeolmillos M 1998 Increased levels of free fatty acids in fasted mice stimulate in vivo ß-cell electrical activity. Diabetes 47:1707–1712[Abstract]
  20. MacDonald PE, Salapatek AM, Wheeler MB 2002 2002 Glucagon-like peptide-1 receptor activation antagonizes voltage-dependent repolarizing K+ currents in ß-cells. Diabetes 51(Suppl 3):S443–S447
  21. Tian Y, Laychock SG 2001 Protein kinase C and calcium regulation of adenylyl cyclase in isolated rat pancreatic islets. Diabetes 50:2505–2513[Abstract/Free Full Text]
  22. Dolz M, Bailbé D, Giroix MH, Calderari S, Gangnerau MN, Serradas P, Rickenbach K, Irminger JC, Portha B 2005 Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of ß-cell muscarinic receptor activation on cAMP production. Diabetes 54:3229–3237[Abstract/Free Full Text]
  23. Hardy S, St-Onge GG, Joly E, Langelier Y, Prentki M 2005 Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem 280:13285–13291[Abstract/Free Full Text]
  24. Katsuma S, Hatae N, Yano T, Ruikes Y, Kumuara M, Hirasawa A, Tsujimoto G 2005 Free fatty acids inhibit serum deprivation-induced apoptosis through GPR120 in a murine enteroendocrine cell line STC-1. J Biol Chem 280:19507–19515[Abstract/Free Full Text]
  25. Yonezawa T, Katoh K, Obara Y 2004 Existence of GPR40 functioning in a human breast cancer cell line, MCF-7. Biochem Biophys Res Commun 314:805–809[CrossRef][Medline]



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