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Endocrinology 147(2):672– 673
Copyright © 2006 by The Endocrine Society
doi: 10.1210/en.2005-1388
The Free Fatty Acid Receptor GPR40 Generates
Excitement in Pancreatic ␤-Cells
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 (1–5). GPR40, which is
preferentially expressed in pancreatic ␤-cells, mediates the
majority of the effects of FFAs on insulin secretion (3, 6 – 8).
Blood glucose concentration is the most important regulator
of insulin secretion from the pancreatic ␤-cell. The ␤-cell is
electrically excitable and generates action potentials when exposed to insulin-releasing glucose concentrations. The voltagegated Ca2⫹ and K⫹ currents that underlie ␤-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. 1). Thus, voltage-gated K⫹ channels
potentially represent important regulators of insulin secretion.
FFAs are known to have pleiotropic effects on the pancreatic ␤-cell. Although acute administration of FFAs stimulates insulin release, chronic exposure to high levels of FFAs
results in the impairment of ␤-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 ␤-cells through a GPR40-mediated increase in cAMP levels and protein kinase A activity,
leading to enhanced ␤-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 voltagegated K⫹ current is due to inhibition of delayed rectifying K⫹
channels, which comprise the majority (⬎95%) of the total
voltage-gated K⫹ current in ␤-cells. Using small interfering
RNA expected to selectively silence GPR40 expression, Feng
et al. (13) elegantly show that the ability of linoleic acid to
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 insulincontaining secretory granules. Opening of voltage-gated K⫹ (Kv)
channels in response to membrane depolarization will repolarize the
␤-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.
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 ␤-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. 1) (15, 16). The FFA-evoked increase in the intracellular Ca2⫹ concentration ([Ca2⫹]i) also involves enhanced
Ca2⫹ influx through voltage-gated Ca2⫹ channels (15–18) (Fig.
1). 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
Abbreviations: [Ca2⫹]i, Free intracellular Ca2⫹ concentration; FFA,
free fatty acid; IP3, inositol trisphosphate.
Endocrinology is published monthly by The Endocrine Society (http://
www.endo-society.org), the foremost professional society serving the
endocrine community.
672
Gromada • News & Views
Endocrinology, February 2006, 147(2):672– 673
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 ␤-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 acidinduced activation of GPR40 stimulates cAMP production in
␤-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 ␤-cell. This
could be tested using pharmacological inhibitors of intracellular
Ca2⫹ release channels. Interestingly, the activation of cAMP
signaling pathway by Gq␣-coupled receptors may be a more
general phenomenon that is observed not only for GPR40 but
also for muscarinic receptors in ␤-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 (23–25). 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 ␤-cells.
It is also essential to examine the potential beneficial role of
GPR40-mediated cAMP increases in modulation of ␤-cell
function under long-term FFA exposure. Paradoxically, under chronic conditions, ␤-cells from GPR40-deficient mice are
protected from lipotoxicity, whereas overexpression of
GPR40 in ␤-cells leads to impaired ␤-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.
Jesper Gromada
Lilly Research Laboratories
Essener Bogen 7
D-22419 Hamburg, Germany
Acknowledgments
I thank Patrik Rorsman for critical review of the manuscript.
Received November 1, 2005. Accepted November 10, 2005.
Address all correspondence and requests for reprints to: Dr. Jesper
Gromada, Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany. E-mail: [email protected].
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Endocrinology is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the
endocrine community.