Abstract
3′–5′-Cyclic adenosine monophosphate (cyclic AMP or cAMP) was first described in 1957 as an intracellular second messenger mediating the effects of glucagon and epinephrine on hepatic glycogenolysis (Berthet et al., J Biol Chem 224(1):463–475, 1957). Since this initial characterization, cAMP has been firmly established as a versatile molecular signal involved in both central and peripheral regulation of energy homeostasis and nutrient partitioning. Many of these effects appear to be mediated at the transcriptional level, in part through the activation of the transcription factor CREB and its coactivators. Here we review current understanding of the mechanisms by which the cAMP signaling pathway triggers metabolic programs in insulin-responsive tissues.
Access provided by Autonomous University of Puebla. Download chapter PDF
Similar content being viewed by others
Keywords
- CBP (CREB Binding Protein)
- CREB (cAMP Response Element Binding protein)
- CRTC (cAMP Regulated Transcriptional Coactivator)
1 Introduction
In mammals, cAMP is produced from ATP by a family of enzymes called adenylate cyclases (ACs). There are nine transmembrane members of this family (tmACs Type I–IX) and one soluble isoform (AC10 or sAC) (Kamenetsky et al. 2006). The soluble AC is conserved across species, from prokaryotes and fungi, to humans (Buck et al. 1999). This enzyme is localized to the cytosol, the nucleus, and the mitochondria where it is activated by increases in bicarbonate from cellular respiration (Zippin et al. 2004; Acin-Perez et al. 2009). The nine transmembrane ACs are expressed at different levels in various cell types (Defer et al. 2000) where they are confined to discrete functional domains together with upstream regulators and downstream targets of cAMP signaling. The most extensively characterized regulators of tmAC activity are heterotrimeric G proteins composed of β and γ subunits (Chen et al. 1995) and either stimulatory (G αs) or inhibitory (G αi) subunits that convert extracellular stimuli engaging G-protein-coupled receptors (GPCRs) into intracellular signals through modulation of tmAC activity. Other signal transducers that regulate tmAC activity include calmodulin (Valverde et al. 1979), protein kinase A (PKA) (Iwami et al. 1995), protein kinase C (PKC) (Yoshimasa et al. 1987), as well as regulator of G-protein signaling 2 (RGS2) (Sinnarajah et al. 2001). These regulators affect specific tmAC types, allowing versatile feedback loops that are cell-type specific and that integrate cAMP signaling with calcium, G αq, and growth factor signals.
Precise regulation of cAMP turnover, clustering of ACs with downstream targets in microdomains, and inhibitory feedback mechanisms all serve the purpose of compartmentalizing the cAMP signal both spatially and temporally. Separation of discrete cAMP signals is the functional basis for the coexistence and fidelity of multiple signaling pathways using cAMP as a second messenger in the same cell (Hayes et al. 1980; Di Benedetto et al. 2008; Zaccolo 2011; Houslay 2010). It is important to note that under physiological conditions, diffusion of cAMP beyond these defined microdomains is insignificant (Zaccolo and Pozzan 2002). Indeed, protein microdomains are instrumental in maintaining distinct cAMP signaling compartments, and the scaffolding proteins known as A-kinase anchor proteins (AKAPs) play a key role in the formation of these microdomains (Dessauer 2009; Smith et al. 2013). Through direct physical interactions, AKAPs station cAMP-effector proteins optimally relative to ACs and phosphodiesterases (PDEs) allowing exposure to cAMP concentrations within their dynamic range.
The physiological outcome of signals eliciting a cellular cAMP response depends on the subcellular localization of the effectors relative to the source of cAMP and to potential downstream targets. Three classes of cAMP-effector proteins have been established to date: PKA (Walsh et al. 1968), exchange proteins directly activated by cAMP (EPACs) (de Rooij et al. 1998), and hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels (DiFrancesco and Tortora 1991). These effectors bind cAMP allosterically, leading to direct effects on downstream targets or permitting them to serve as integrators of the cAMP signal with other secondary messenger systems and signaling pathways. In addition to the three established cAMP-effector mechanisms, PDE10A isozymes (Handa et al. 2008) and Popeye domain-containing (Popdc) proteins (Froese et al. 2012) have been identified as cAMP-binding proteins. The importance of PDE10A and Popdc proteins as cAMP effectors is yet to be determined.
While cAMP synthesis is determined by the activities of ACs, the superfamily of PDEs is the predominant cAMP-lowering mechanism in mammalian cells. These cyclic nucleotide-hydrolyzing enzymes are classified into multiple families (PDE1–11) with distinct expression patterns and specificities. Eight of these families can hydrolyze cAMP to AMP (PDEs 4, 7, and 8 are specific to cAMP), while the others are selective for 3′–5′-cyclic guanosine monophosphate (cGMP). Each family consists of several isozymes with distinct subcellular distributions and means of regulation (for a comprehensive review, see Francis et al. 2011). Dynamic changes in PDE expression, localization, oligomerization, and relative cGMP levels in the case of dual-specificity PDEs are all crucial determinants of total cAMP hydrolytic activity. The magnitude of the cAMP signal and fine-tuning of its kinetics by the PDEs is also coordinated by interactions with regulatory proteins and posttranslational modifications of the PDEs, such as phosphorylation by PKA itself (Francis et al. 2011; Keravis and Lugnier 2010). The amplitude, propagation, and duration of the cAMP signal are not only restricted by localization of PDE activities but are also regulated by a negative feedback mechanism in which cAMP itself activates PDE3 and PDE4 isozymes (Sette et al. 1994; Gettys et al. 1987). As will be discussed later in this chapter, PDEs are widely targeted by pharmacological agents to correct cAMP signaling in human disease.
2 cAMP in Metabolic Control
Cyclic AMP signaling has enormous impact on metabolic pathways both at the cellular and systemic levels. In the following sections, we will focus on inducers, regulators, and effectors of cAMP signals in important metabolic tissues. Mechanisms will be discussed in the context of nutrient homeostasis and the metabolic syndrome, a state of severe metabolic imbalance signified by perturbations in cAMP signaling in multiple tissues.
Most tissues are under the control of the sympathetic nervous system (SNS). Through the coordinated release of epinephrine from the adrenal glands into the circulation and the release of synaptic norepinephrine, the SNS activates membrane-bound adrenergic receptors on target cells. Of these, α2-adrenergic receptors inhibit and β-adrenergic receptors (β1, β2, and β3) stimulate cAMP production through G i and G αs activation, respectively (Insel 1996). The SNS has classically been associated with stress responses (Seematter et al. 2004), but synaptic tone is also involved in regulating basal metabolic rate, glucose disposal, and lipid partitioning (Monroe et al. 2001; Boyda et al. 2013; Arner et al. 1990). In this light, it is interesting to note that a growing body of literature links metabolic disorders like obesity and diabetes to dysregulation of adrenergic receptor signaling (Boyda et al. 2013; Yasuda et al. 2006; Ziegler et al. 2012).
2.1 Liver
Cyclic AMP signaling was first discovered in the liver as a critical mediator of glucose metabolism. Mammals use highly interconnected hormonal signaling mechanisms that include the opposing actions of glucagon and insulin to maintain glucose homeostasis. Decreases in circulating glucose concentrations during fasting trigger the release of pancreatic glucagon, which stimulates gluconeogenesis and provides substrate supply to glucose-dependent tissues like the brain and red blood cell compartments. During feeding, increases in circulating insulin downregulate hepatic gluconeogenesis in part through activation of the Ser/Thr kinase Akt. Increases in insulin resistance promote hyperglycemia, in part due to a failure of insulin to suppress hepatic glucose production. Indeed, lowering hepatic glucose production represents a major objective for treatment of type II diabetic individuals. A potential regulatory target in this process is the transcription factor CREB (Altarejos and Montminy 2011a) and its associated coactivators the CREB-binding protein (CBP) and cAMP-regulated transcriptional coactivators (CRTCs).
Triggering of the glucagon receptor on hepatocytes activates adenylate cyclase, leading to production of cAMP and increases in PKA activity. Following its PKA-mediated phosphorylation, CREB interacts with CREB-binding protein (CBP) (Chrivia et al. 1993a; Eckner et al. 1994) and initiates transcription of key gluconeogenic enzymes such as pyruvate carboxylase (PC), phosphoenolpyruvate carboxykinase (PEPCK-C) (Herzig et al. 2001; Quinn and Granner 1990; Wynshaw-Boris et al. 1986), and glucose-6-phosphatase (Lin et al. 1997). The induction of gluconeogenic genes by CREB is further augmented by the CREB-regulated transcription coactivator 2 (CRTC2), which is dephosphorylated in response to glucagon, where it migrates to the nucleus and associates with CREB over relevant promoters (Koo et al. 2005; Chrivia et al. 1993b). Under feeding conditions, CRTC2 is phosphorylated by salt-inducible kinases (SIKs) and sequestered in the cytoplasm via an association with 14-3-3 proteins. Exposure to glucagon promotes the PKA-mediated phosphorylation and inhibition of SIKs, leading to the dephosphorylation of CRTC2.
The CREB/CRTC2 pathway appears to be active primarily during short-term fasting; with prolonged fasting, forkhead box protein O1 (FOXO1) activity appears critical in maintaining expression of gluconeogenic genes (Liu et al. 2008). The physiological relevance of CREB and CRTC2 in hepatic glucose production is demonstrated in vivo with a mouse model expressing dominant-negative CREB inhibitor A-CREB (Ahn et al. 1998) and in cultured hepatocytes with a knockout of CRTC2 (Wang et al. 2010).
In addition to these transcriptional effects, PKA modulates gluconeogenesis by altering substrate flux. PKA phosphorylates the bifunctional enzyme fructose-2,6-bisphosphatase/phosphofructokinase-2, favoring the phosphatase activity and therefore decreasing production of the metabolic intermediate fructose 2,6-bisphosphate. This metabolite is a powerful allosteric activator of phosphofructokinase-1 (PFK-1), the first rate-limiting enzyme in glycolysis. By depleting the activator, PKA inhibits glycolytic flux through PFK-1, enhancing glucose production and liver glucose output (El-Maghrabi et al. 1982; Richards et al. 1982).
Liver glycogenolysis is another means by which glucose homeostasis is maintained during fasting and exercise or in response to stress as manifested by increased catecholamine signaling. Following its activation by glucagon and epinephrine, PKA phosphorylates and activates phosphorylase kinase, which in turn stimulates glycogen phosphorylase, allowing for glucose release from liver glycogen stores (Studer and Borle 1982; Studer et al. 1984).
In addition to its regulation by fasting and feeding signals, hepatic glucose production is also modulated by the circadian clock. Like other tissues, the liver clock is governed by E-box transcription factors called brain and muscle ARNT-like (BMAL) and circadian locomotor output cycles kaput (CLOCK), which trigger expression of cryptochrome (CRY) and period (PER) proteins. In turn, CRY and PER repress transcription of CLOCK and BMAL, providing feedback regulation. Although they are regarded primarily as transcriptional repressors, CRY1 and CRY2 appear to inhibit expression of the gluconeogenic program during the night-to-day transition by binding to the cytoplasmic G sα subunit of the heterotrimeric G protein. Conversely, decreases in CRY1 and CRY2 levels during the day-to-night transition enhance hepatic glucose production due to increases in cAMP signaling (Zhang et al. 2010). CREB and CRTC2 have been reported to promote the expression of BMAL1, suggesting that this pathway may modulate the core clock (Sun et al. 2015).
2.2 White Adipose Tissue
White adipose tissue (WAT) in mammals serves as an insulation, a storage depot of energy in the form of triglycerides, and an endocrine organ. The characteristics of fat depots throughout the body are largely dictated by their location; they are under complex endocrine, nutritional, neuronal, and immunological control (Rosen and Spiegelman 2014). Many of these regulatory signals are mediated by cAMP, which is known to have a significant role in both adipogenesis and lipid partitioning in white adipose tissue. Mature adipocytes arise from fibroblastic precursors through a dynamic differentiation process that requires extensive chromatin remodeling (Park et al. 2012; Siersbaek et al. 2014; Tang and Lane 2012). The cAMP signaling pathways are among the most well-characterized mechanisms controlling adipocyte differentiation. PDE inhibitors and synthetic cAMP analogs are commonly employed to switch on the adipogenic program in vitro (Russell and Ho 1976). An early increase in preadipocyte cAMP levels stimulates PKA, which in turn phosphorylates and activates the nuclear basic leucine zipper transcription factor cAMP-response element-binding (CREB) protein and members of the ATF family (Zhang et al. 2004; Fox et al. 2006a). These transcriptional activators have been linked to the induction of critical regulators of adipogenesis, including peroxisome proliferator-activated receptor-γ (PPAR-γ) and CCAAT/enhancer-binding protein (C/EBP) α and β (Fox et al. 2006a; Niehof et al. 1997; Birsoy et al. 2008). Expression of constitutively active CREB is sufficient to promote adipogenesis in 3T3-L1 cells (Fox et al. 2006b), highlighting the importance of the cAMP pathway in adipocyte differentiation. Activation of EPAC1 also appears important for a subset of cAMP effects (Petersen et al. 2008) possibly in synergy with the effects of PKA. Adipogenesis is impaired in mice lacking G αs expression in adipose tissue (Chen et al. 2010), providing strong evidence that cAMP is crucial to adipogenesis in vivo. Embryonic fibroblasts isolated from these mice have significantly reduced adipogenic potential in vitro even when PDE activity is inhibited. The nature of the signals stimulating cAMP production during adipogenesis in vivo remains to be elucidated, however.
In addition to its effects on differentiation, cAMP signaling also regulates lipid metabolism in WAT. During instances of high energy demand, such as fasting, triglycerides stored in adipocyte lipid droplets are hydrolyzed to fatty acids and glycerol in a process known as lipolysis (Frayn 2002). For decades, it has been suggested that adipokinetic factors released from the pituitary (e.g., growth hormone), adrenal (e.g., glucocorticoids), and pancreas (e.g., glucagon) can stimulate lipolysis from WAT (Hollenberg et al. 1961; White and Engel 1958). Although some of these factors have been shown to induce lipid breakdown from adipocytes in vitro, the significance of their lipolytic actions in vivo is likely to be of limited importance (Coppack et al. 1994). Rather, lipolytic signals come primarily from sympathetic innervation of the adipose depots (Adler et al. 2012; Dodt et al. 1999; Nishizawa and Bray 1978). In humans, catecholamines are the primary hormones involved in triggering lipolysis in WAT. β-Adrenergic stimuli increase cAMP levels and promote lipid breakdown. However, stimulation of receptors coupled to inhibitory Gi proteins, such as EP3 receptor by prostaglandin E2 (PGE2), will lead to inhibition of adenylate cyclase activity, hindering cAMP synthesis and decreasing lipolysis (Kolditz and Langin 2010; Richelsen and Pedersen 1985; Cummings et al. 1996). By releasing PGE2, adipose tissue macrophages may contribute to catecholamine resistance in certain depots.
Studies of several genetically modified animal models point to an important role for cAMP in lipolysis in vivo. A direct lipolytic function for PKA and cAMP signaling in WAT is further supported by numerous studies documenting PKA phosphorylation and activation of several key regulators of lipolysis in response to elevated cAMP levels. These include the hormone-sensitive lipase (HSL) (Anthonsen et al. 1998), adipocyte-specific triglyceride lipase (ATGL) (Pagnon et al. 2012), and lipid droplet-associated protein perilipin (Brasaemle et al. 2009).
Another genetic mouse model showing increased cAMP-induced lipolysis is the PDE3B knockout mouse. In addition to an increased lipolytic response to adrenergic stimuli in vivo, the well-known anti-lipolytic effect of insulin (Olefsky 1977) is not observed in isolated PDE3B null adipocytes (Choi et al. 2006). This dual phenotype can be explained by the distinct localization of PDE3B in separate microdomains. In wild-type adipocytes, specific pools of PDE3B are phosphorylated and activated by PKA in response to β-adrenergic stimulation, whereas insulin receptor signaling will promote AKT-mediated phosphorylation and activation of other PDE3B pools (Ahmad et al. 2009). PKA maintains temporal autoregulation of the cAMP signal while promoting lipolysis by allowing PDE3B fine-tuning of the cAMP signal to a concentration range that is ideal to sustain activity, whereas AKT blocks lipolysis by dissociating it from lipolytic signals at least in part by activating discrete pools of PDE3B. Significantly, PDE3B mutant mice show hepatic lipid accumulation and insulin resistance, suggesting that the increase in lipolysis is not accompanied by an increase in fatty acid oxidation and may reflect the redundancy between PDE family members or the diminished importance of PDE3B in the regulation of fatty acid oxidation in non-adipose tissues such as the liver.
2.3 Brown Adipose Tissue
Brown adipose tissue (BAT) is an oxidative tissue specialized in dissipating energy as heat, crucial for maintaining optimal body temperature when exposed to changes in the environment (Rosen and Spiegelman 2014). BAT was initially characterized as an interscapular fat pad in newborn rodents but has since been identified in both infants (Lidell et al. 2013) and adult humans (Virtanen et al. 2009; Cypess et al. 2009; van Marken Lichtenbelt et al. 2009; Huttunen et al. 1981). Unlike WAT, BAT expresses uncoupling protein 1 (UCP1, also known as thermogenin) allowing uncoupling of mitochondrial oxidative phosphorylation and thermogenesis (Cannon et al. 1982; Heaton et al. 1978; Enerback et al. 1997). Cold exposure induces the oxidative and thermogenic capacity of BAT (Cameron and Smith 1964) through SNS activation and adrenergic stimulation of cAMP production (Thomas and Palmiter 1997). Cyclic AMP immediately activates PKA (Skala and Knight 1977) leading to increased lipolysis and activation of UCP1 (Fedorenko et al. 2012). In an adaptive response to prolonged cold exposure, cAMP also contributes to increased UCP1 levels (Mattsson et al. 2011), mitochondrial biogenesis (Bogacka et al. 2005), and expanded BAT mass. These adaptive effects are believed to require transcriptional changes although the exact mechanisms, and the relative importance of these pathways, are still debated. Transcriptional activators that have been found to play prominent roles in BAT adaptation to cold exposure include CREB (Rim and Kozak 2002), PPAR gamma-coactivator 1-alpha (PGC1a), IRF4 (Kong et al. 2014), and PRDM16 (Kajimura et al. 2009; Seale et al. 2007). In particular, PGC1a, which is itself induced by cAMP, is required for commitment of preadipocytes to differentiate into brown adipocytes (Puigserver et al. 1998) and appears to be decreased in the adipose tissue of obese patients (Semple et al. 2004).
In order to sustain thermogenesis, the BAT must fuel ATP synthesis by oxidizing substrate. Cyclic AMP signaling, via adrenergic stimuli from sympathetic innervation, will lead to the increased synthesis of both lipoprotein lipase and GLUT1 (Shimizu et al. 1998). This allows increased release of fatty acids and uptake of glucose for oxidation. Importantly, the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which plays a significant role in glycolysis and lipid metabolism, is also upregulated by norepinephrine and cAMP analogs (Barroso et al. 1999). Bone morphogenic protein 8 (BMP8) was found to enhance thermogenesis in a manner dependent upon on the CREB pathway, and loss of BMP8 was associated with decreased metabolic rate and thermogenesis (Whittle et al. 2012).
Importantly, the thyroid hormone triiodothyronine (T3) (Silva and Larsen 1983; de Jesus et al. 2001) also has a significant effect on obligatory thermogenesis and BAT function. T3 is required for maintaining BAT lipolysis and for sustaining the basic metabolic rate by promoting uncoupling of oxidative phosphorylation (Mullur et al. 2014). T3 levels in the BAT are carefully regulated by conversion of T4 to T3 by deiodinases. In the BAT, adrenergic signaling as well as activation of the bile acid receptor TGR5 leads to cAMP increases, which promote 5′-deiodinase type 2 activity, increasing local T3 levels (Silva 2006; Arrojo et al. 2013).
Induction of cAMP signaling can also trigger “browning” of white adipose tissue to a more oxidative tissue phenotype (Dempersmier et al. 2015). The possibility of inducing BAT characteristics in WAT by modulating cAMP signaling points to cAMP agonists as potential targets for drug development for the treatment of obesity. Indeed, administration of β3-adrenergic agonist to mice with a knockout of phosphodiesterase 3B (PDE3B) increases cAMP accumulation in epididymal WAT, leading to browning of these WAT depots (Guirguis et al. 2013). Furthermore, bone morphogenic protein 7 (BMP7), which is upregulated by cAMP (Ishibashi et al. 1993), also promotes brown adipose characteristics in human adipogenic stem cells (Okla et al. 2015).
2.4 Pancreas
The cAMP pathway contributes importantly to pancreatic β-cell growth and insulin secretion (Furman et al. 2010; Altarejos and Montminy 2011b; Dalle et al. 2011). The incretin hormone glucagon-like peptide-1 (GLP-1) increases cAMP levels by acting through its GPCR, leading to CREB activation, increased glucose-stimulated insulin secretion and β-cell expansion (Wang et al. 1997; Tourrel et al. 2001). Another incretin, glucose-dependent insulinotropic peptide (GIP), also increases cAMP signaling via interaction with its GPCR (Yabe and Seino 2011). However, receptors for this hormone are downregulated in response to high glucose, making it a less attractive target for the treatment of diabetes compared to GLP-1 signaling (Puddu et al. 2015). Insulin-like growth factor 1 (IGF-1), which is produced in the liver, has been shown to be important for proper development, growth, and proliferation of β-cells. Its actions are mediated through insulin response substrate 2 (IRS2), which is known to play a role in the protection of β-cells against apoptosis and in promoting their growth by activating the pro-growth kinase Akt (George et al. 2002; Withers et al. 1999). Cyclic AMP signaling via CREB also activates IRS2 and in this manner will enhance IGF-1 signaling (Jhala et al. 2003). Notably, activation of the IGF-1 pathway also increases the activity of PDE3B, which degrades cAMP (Zhao et al. 1997); cAMP itself activates PDE3B via PKA (Heimann et al. 2010), creating a negative feedback loop and also modulating cAMP levels to ensure proper cAMP signaling and to prevent uncontrolled insulin secretion (Härndahl et al. 2002).
Other signals in addition to GLP-1 appear capable of stimulating islet function. Cyclic AMP levels are also elevated in response to γ-aminobutyric acid (GABA), for example, which prevents apoptosis and increases β-cell mass (Purwana et al. 2014). Indeed, acetylcholine, like glucose, induces membrane depolarization and calcium influx, this stimulating insulin secretion. This effect is dependent on protein kinase C (PKC) and phospholipase C coupled to muscarinic receptors (Love et al. 1998; Niwa et al. 1998). Acetylcholine was also found to activate adenylate cyclase activity and to increase cAMP production in diabetic rat islets, leading to CREB activation and enhanced cell viability (Screaton et al. 2004; Eckert et al. 1996). Whether this effect occurs via increases in Ca2+ or PKC activity or is due to signaling variations in the diabetic islets remains to be fully elucidated.
In addition to PDE3B, several additional mechanisms limit accumulation of cAMP in β-cells. Increases in intracellular Ca2+ in response to glucose elevations activate PDE1, increasing degradation of cAMP. Neuropeptide Y (NPY) (Morgan et al. 1998), PGE2 (Kimple et al. 2013), and adrenaline (Metz 1988) all signal through GPCRs coupled to Gi, inhibiting adenylate cyclase activity and negatively regulating cAMP accumulation.
Insulin secretion from β-cells is tightly regulated by increases in extracellular glucose concentrations. Glucose transport and phosphorylation allow for its subsequent oxidation; the production of ATP stimulates insulin granule release. The primary transporter involved in facilitated diffusion of glucose in human β-cells is GLUT1. This transporter is not hormonally regulated, suggesting that cellular amounts of this protein have a predominant effect on the efficiency of glucose transport (Thorens et al. 2000). The GLUT1 promoter region has been reported to contain a CREB-binding site that mediates induction of this gene by cAMP (Murakami et al. 1992). However, increased GLUT1 expression may not necessarily affect insulin response (Ishihara et al. 1994); increases in hexokinase I enhance insulin secretion in response to glucose. Cyclic AMP has been shown to increase hexokinase I expression and may in this manner contribute to heightened insulin detection (Yokomori et al. 1992; Borboni et al. 1999).
CREB has been demonstrated to protect β-cells from cytokine-mediated apoptosis and glucotoxicity (Jhala et al. 2003; Jambal et al. 2003; Costes et al. 2009). Overexpression of A-CREB led to diminished replication and increased apoptosis of β-cells, causing hyperglycemia in mice (Jhala et al. 2003). Additionally, it has been shown that the CREB coactivator CRTC2 is necessary for glucose-mediated insulin release (Eberhard et al. 2013; Blanchet et al. 2015). These data collectively underscore the centrality of cAMP signaling through CREB in β-cell survival and endurance. Cyclic AMP is also thought to augment insulin secretion by promoting the PKA-mediated phosphorylation of the SUR1 subunit of the ATP-sensitive potassium channel, thereby inhibiting channel activity and enhancing depolarization (Light et al. 2002); by PKA-dependent phosphorylation of voltage-sensitive calcium channels, increasing Ca2+ influx (Leiser and Fleischer 1996; Gerhardstein et al. 1999); and by directly regulating exocytosis of insulin-containing vesicles (Ammälä et al. 1993; Ding and Gromada 1997).
Though most effects of cAMP in β-cells appear to proceed via a PKA-dependent mechanism, a subset of these effects may be mediated by EPACs (Kang et al. 2006; Henquin and Nenquin 2014; Yoshida et al. 2014). The pancreatic β-cell expresses both EPAC1 and EPAC2, which are directly activated by cAMP. Knockdown of EPAC expression in vivo led to abrogation of cAMP-mediated stimulation of glucose-induced insulin secretion from the pancreas and development of metabolic syndrome in vivo (Kashima et al. 2001; Kai et al. 2013), highlighting the importance of alternative cAMP-dependant pathways to β-cell function.
Incretin hormones have been found to promote β-cell replication at least in rodent cells by increasing the expression of the cell cycle regulators cyclins D1 (Kim et al. 2006) and A2 (Song et al. 2008). cAMP also stimulates the expression of Bcl-2 and Bcl-xL (Hui et al. 2003; Kim et al. 2008), which protect β-cells from apoptosis. cAMP may also terminate cell death cascades by inhibiting caspases (Ehses et al. 2003; Welters et al. 2006).
In addition to its effects on insulin secretion, β-cell growth and proliferation, cAMP may also enhance differentiation. GLP-1 appears to increase the expression of pancreatic duodenal homeobox – 1 (PDX-1) (Perfetti et al. 2000), a transcription factor central to the differentiation of pancreatic endocrine, exocrine, and ductal cell populations from endoderm during fetal development (Zhou et al. 2002; Offield et al. 1996). PDX-1 is also necessary for maturation of β-cells and allows selective differentiation of pancreatic endocrine progenitors to form insulin-producing β-cells while suppressing formation of glucagon-producing α-cells (McKinnon and Docherty 2001; Ber et al. 2003; Gao et al. 2014). It has been shown that cAMP, via PKA, is required to maintain GLP-1-mediated PDX-1 increases and PDX-1 translocation to the nucleus. PDX-1 also promotes expression of the GLP-1 receptor, enhancing cAMP production (Wang et al. 2005).
In contrast to PDX-1 expression, the transcription factor MafA is upregulated during the later development of the endocrine pancreas, where it promotes full maturation of β-cells and stimulates insulin biosynthesis (Kaneto et al. 2008; Artner et al. 2010; Hang and Stein 2011). GLP-1 and cAMP agonists were found to increase MafA expression via induction of the CREB pathway, further implicating cAMP in pancreatic development and differentiation (Blanchet et al. 2015).
The role of cAMP in other pancreatic cell types within the islet is not as well understood. GLP-1 has been demonstrated to increase glucagon release from α-cells via the cAMP/PKA pathway (Ding et al. 1997). Inhibiting EPAC-2 activity in α-cells was also found to decrease glucagon gene transcription, suggesting that both pathways (PKA and EPAC) modulate glucagon production (Islam et al. 2009). Though GLP-1 appears to increase glucagon secretion from α-cells in vitro, this effect may be largely inhibited in vivo due to effects of GLP-1 on somatostatin release from pancreatic δ-cells. Indeed, cAMP stimulates somatostatin secretion from δ-cells, thereby inhibiting adenylate cyclase and cAMP synthesis in α-cells via Gi-coupled GPCR (Elliott et al. 2015; Hauge-Evans et al. 2009). Finally, adrenergic stimulation (e.g., adrenaline action) can increase both glucagon (Dai et al. 2014) and somatostatin (Gromada et al. 1997) release via cAMP elevation.
2.5 Muscle
Skeletal muscle has a specialized architecture that directly relates to its function in movement and to its regulation by neuronal inputs. Muscle contraction is dependent upon proper calcium signaling, and cAMP plays a significant role in regulating this process. Beta-adrenergic signaling elevates muscle cAMP and thereby modulates Ca2+-induced Ca2+ release from the sarcoplasmic reticulum, acutely increasing contractile force (Saida and Van Breemen 1984; Cairns and Dulhunty 1993). This effect has been postulated to reflect cAMP-regulated phosphorylation of L-type voltage-dependent Ca2+ channels (Sculptoreanu et al. 1993). Cyclic AMP is also necessary for PKA-mediated activation of the Na+–K+ pump, which is important in membrane hyperpolarization and in the restoration of muscle excitability (Clausen 2003).
Glycogenolysis, which is critical for meeting energy demands of the muscle, is also promoted by cAMP. Acute cAMP effects are especially important during exercise, when energy consumption by the muscle is at its peak and when epinephrine levels are high, leading to increases in muscular cAMP (Ezrailson et al. 1983; Soderling et al. 1970). Significantly, chronic activation of cAMP pathways in the muscle promotes adaptive responses that include increased myofiber size as well as metabolic transition to a more glycolytic fiber type (Chen et al. 2009; Maltin et al. 1989). Activation of β-adrenergic receptors, which stimulate the cAMP pathway, may prove to be an effective mechanism to enhance muscle function and slow atrophy in disease states such as Duchenne’s muscular dystrophy (Harcourt et al. 2007; Hinkle et al. 2007; Ryall et al. 2008).
3 Conclusion
Cyclic AMP mediates the effects of glucagon and beta-adrenergic signals in regulating glucose and lipid metabolism. A key feature of type II diabetes (T2D) is the failure of insulin to trigger glucose uptake into the muscle and to suppress glucose production from the liver (Centers for Disease Control and Prevention 2015; Brown and Goldstein 2008; Basit et al. 2004). Suppressing liver gluconeogenesis and glycogenolysis via inhibition of cAMP signaling or CREB-dependent transcription may have salutary effects on blood glucose concentrations.
While lowering cAMP signaling in the liver may prove beneficial, upregulating cAMP in other tissues may also improve glucose and lipid homeostasis. The chronic hyperglycemia associated with insulin resistance is accompanied initially by compensatory increases in pancreatic islet mass and in insulin secretion. However, unremitting insulin resistance eventually causes β-cell failure and apoptosis, ultimately leading to T2D (Poitout and Robertson 2008; Kahn 2003). In some cases, an innate susceptibility of the β-cell may magnify the risk of developing T2D; a number of studies have concluded that prediabetes and youth-onset T2D in certain ethnic groups are more strongly associated with β-cell dysfunction (Gujral et al. 2014; Staimez et al. 2013; Dowse et al. 1990). Developing therapeutic strategies to protect β-cells from glucolipotoxicity may provide effective treatment for T2D in this setting. The cAMP signaling pathway is important for β-cell viability, proliferation, and glucose responsiveness. Increasing cAMP signaling or CREB activity may further potentiate β-cell function and provide therapeutic benefit to insulin-resistant individuals.
Upregulating the cAMP pathway in brown and white adipose tissues may also have positive effects on fat burning and thereby decrease inflammatory infiltrates that contribute to insulin resistance in obesity. In view of the pleiotropic effects of the cAMP pathway on glucose and lipid metabolism, a major challenge will be to target relevant modulators in specific tissues. Based on the considerable number of phosphodiesterases with distinct pharmacological properties and tissue localization, these regulators may prove particularly useful in this regard. Future studies on region-specific cAMP signaling in different organelles may also provide further insight into the regulatory properties of this second messenger.
References
Acin-Perez R et al (2009) Cyclic AMP produced inside mitochondria regulates oxidative phosphorylation. Cell Metab 9(3):265–276
Adler ES et al (2012) Neurochemical characterization and sexual dimorphism of projections from the brain to abdominal and subcutaneous white adipose tissue in the rat. J Neurosci 32(45):15913–15921
Ahmad F et al (2009) Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta3-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes. Biochem J 424(3):399–410
Ahn S et al (1998) A dominant-negative inhibitor of CREB reveals that it is a general mediator stimulus-dependent transcription of c-fos. Mol Cell Biol 18:967–977
Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12(3):141–151
Ammälä C, Ashcroft F, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363(6427):356–358
Anthonsen MW et al (1998) Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro. J Biol Chem 273(1):215–221
Arner P et al (1990) Adrenergic regulation of lipolysis in situ at rest and during exercise. J Clin Invest 85(3):893–898
Arrojo E, Drigo R, Fonseca TL, Werneck-de-Castro JP, Bianco AC (2013) Role of the type 2 iodothyronine deiodinase (D2) in the control of thyroid hormone signaling. Biochim Biophys Acta 1830(7):3956–3964
Artner I, Hang Y, Mazur M, Yamamoto T, Guo M, Lindner J, Magnuson MA, Stein R (2010) MafA and MafB regulate genes critical to beta-cells in a unique temporal manner. Diabetes 59(10):2530–2539
Barroso I, Benito B, Garcí-Jiménez C, Hernández A, Obregón MJ, Santisteban P (1999) Norepinephrine, tri-iodothyronine and insulin upregulate glyceraldehyde-3-phosphate dehydrogenase mRNA during Brown adipocyte differentiation. Eur J Endocrinol 141(2):169–179
Basit A, Hydrie M, Hakeem R, Ahmedani MY, Masood Q (2004) Frequency of chronic complications of type II diabetes. J Coll Physicians Surg Pak 14:79–83
Ber I, Shternhall K, Perl S, Ohanuna Z, Goldberg I, Barshack I, Benvenisti-Zarum L, Meivar-Levy I, Ferber S (2003) Functional, persistent, and extended liver to pancreas transdifferentiation. J Biol Chem 278(34):31950–31957
Berthet J, Rall TW, Sutherland EW (1957) The relationship of epinephrine and glucagon to liver phosphorylase. IV. Effect of epinephrine and glucagon on the reactivation of phosphorylase in liver homogenates. J Biol Chem 224(1):463–475
Birsoy K, Chen Z, Friedman J (2008) Transcriptional regulation of adipogenesis by KLF4. Cell Metab 7(4):339–347
Blanchet E, Van de Velde S, Matsumura S, Hao E, LeLay J, Kaestner K, Montminy M (2015) Feedback inhibition of CREB signaling promotes beta cell dysfunction in insulin resistance. Cell Rep 10:1149–1157
Bogacka I, Ukropcova B, McNeil M, Gimble JM, Smith SR (2005) Structural and functional consequences of mitochondrial biogenesis in human adipocytes in vitro. J Clin Endocrinol Metab 90(12):6650–6656
Borboni P, Porzio O, Pierucci D, Cicconi S, Magnaterra R, Federici M, Sesti G, Lauro D, D’Agata V, Cavallaro S, Marlier LN (1999) Molecular and functional characterization of pituitary adenylate cyclase-activating polypeptide (PACAP-38)/vasoactive intestinal polypeptide receptors in pancreatic beta-cells and effects of PACAP-38 on components of the insulin secretory system. Endocrinology 140(12):5530–5537
Boyda HN et al (2013) Peripheral adrenoceptors: the impetus behind glucose dysregulation and insulin resistance. J Neuroendocrinol 25(3):217–228
Brasaemle DL et al (2009) Perilipin A and the control of triacylglycerol metabolism. Mol Cell Biochem 326(1–2):15–21
Brown MS, Goldstein J (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7:95–96
Buck J et al (1999) Cytosolic adenylyl cyclase defines a unique signaling molecule in mammals. Proc Natl Acad Sci U S A 96(1):79–84
Cairns SP, Dulhunty A (1993) Beta-adrenergic potentiation of E-C coupling increases force in rat skeletal muscle. Muscle Nerve 16:1317–1325
Cameron IL, Smith RE (1964) Cytological responses of brown fat tissue in cold-exposed rats. J Cell Biol 23:89–100
Cannon B, Hedin A, Nedergaard J (1982) Exclusive occurrence of thermogenin antigen in brown adipose tissue. FEBS Lett 150(1):129–132
Centers for Disease Control and Prevention (2015) Diabetes public health resource. http://www.cdc.gov/diabetes/. Accessed June 2015
Chen J et al (1995) A region of adenylyl cyclase 2 critical for regulation by G protein beta gamma subunits. Science 268(5214):1166–1169
Chen M, Feng H, Gupta D, Kelleher J, Dickerson KE, Wang J, Hunt D, Jou W, Gavrilova O, Jin JP, Weinstein LS (2009) G(s)alpha deficiency in skeletal muscle leads to reduced muscle mass, fiber-type switching, and glucose intolerance without insulin resistance or deficiency. Am J Physiol Cell Physiol 296(4):C930–C940
Chen M et al (2010) G(s)alpha deficiency in adipose tissue leads to a lean phenotype with divergent effects on cold tolerance and diet-induced thermogenesis. Cell Metab 11(4):320–330
Choi YH et al (2006) Alterations in regulation of energy homeostasis in cyclic nucleotide phosphodiesterase 3B-null mice. J Clin Invest 116(12):3240–3251
Chrivia JC et al (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365(6449):855–859
Clausen T (2003) Na + −K+ pump regulation and skeletal muscle contractility. Physiol Rev 83(4):1269–1324
Coppack SW, Jensen M, Miles JM (1994) In vivo regulation of lipolysis in humans. J Lipid Res 35(2):177–193
Costes S, Vandewalle B, Tourrel-Cuzin C, Broca C, Linck N, Bertrand G, Kerr-Conte J, Portha B, Pattou F, Bockaert J, Dalle S (2009) Degradation of cAMP-responsive element-binding protein by the ubiquitin-proteasome pathway contributes to glucotoxicity in beta-cells and human pancreatic islets. Diabetes 58:1105–1115
Cummings DE et al (1996) Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 382(6592):622–626
Cypess AM et al (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517
Dai XQ, Spigelman A, Khan S, Braun M, Manning Fox JE, MacDonald PE (2014) SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells. J Physiol 592(Pt 17):3715–3726
Dalle S, Quoyer J, Varin E, Costes S (2011) Roles and regulation of the transcription factor CREB in pancreatic β-cells. Curr Mol Pharmacol 4:187–195
de Jesus LA et al (2001) The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue. J Clin Invest 108(9):1379–1385
de Rooij J et al (1998) Epac is a Rap1 guanine-nucleotide-exchange factor directly activated by cyclic AMP. Nature 396(6710):474–477
Defer N, Best-Belpomme M, Hanoune J (2000) Tissue specificity and physiological relevance of various isoforms of adenylyl cyclase. Am J Physiol Renal Physiol 279(3):F400–F416
Dempersmier J, Sambeat A, Gulyaeva O, Paul SM, Hudak CS, Raposo HF, Kwan HY, Kang C, Wong RH, Sul HS (2015) Cold-inducible Zfp516 activates UCP1 transcription to promote browning of white fat and development of brown fat. Mol Cell 57(2):235–246
Dessauer CW (2009) Adenylyl cyclase--A-kinase anchoring protein complexes: the next dimension in cAMP signaling. Mol Pharmacol 76(5):935–941
Di Benedetto G et al (2008) Protein kinase A type I and type II define distinct intracellular signaling compartments. Circ Res 103(8):836–844
DiFrancesco D, Tortora P (1991) Direct activation of cardiac pacemaker channels by intracellular cyclic AMP. Nature 351(6322):145–147
Ding WG, Gromada J (1997) Protein kinase A-dependent stimulation of exocytosis in mouse pancreatic beta-cells by glucose-dependent insulinotropic polypeptide. Diabetes 46(4):615–621
Ding WG, Renström E, Rorsman P, Buschard K, Gromada J (1997) Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2 + −induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism. Diabetes 46(5):792–800
Dodt C et al (1999) Intraneural stimulation elicits an increase in subcutaneous interstitial glycerol levels in humans. J Physiol 521(Pt 2):545–552
Dowse GK, Qin H, Collins VR, Zimmet PZ, Alberti KG, Gareeboo H (1990) Determinants of estimated insulin resistance and beta-cell function in Indian, Creole and Chinese Mauritians. The Mauritius NCD Study Group. Diabetes Res Clin Pract 10:265–279
Eberhard CE, Fu A, Reeks C, Screaton RA (2013) CRTC2 is required for β-cell function and proliferation. Endocrinology 154:2308–2317
Eckert B, Schwaninger M, Knepel W (1996) Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3′,5′-monophosphate/calcium response element in a pancreatic islet beta-cell line. Endocrinology 137:225–233
Eckner R et al (1994) Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev 8(8):869–884
Ehses JA, Casilla V, Doty T, Pospisilik JA, Winter KD, Demuth HU, Pederson RA, McIntosh CH (2003) Glucose-dependent insulinotropic polypeptide promotes beta-(INS-1) cell survival via cyclic adenosine monophosphate-mediated caspase-3 inhibition and regulation of p38 mitogen-activated protein kinase. Endocrinology 144(10):4433–4445
Elliott AD, Ustione A, Piston DW (2015) Somatostatin and insulin mediate glucose-inhibited glucagon secretion in the pancreatic α-cell by lowering cAMP. Am J Physiol Endocrinol Metab 308(2):E130–E143
El-Maghrabi MR, Claus T, Pilkis J, Pilkis SJ (1982) Regulation of 6-phosphfructo-2-kinase activity by cyclic AMP-dependent phosphorylation. Proc Natl Acad Sci U S A 79:315–319
Enerback S et al (1997) Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese. Nature 387(6628):90–94
Ezrailson EG, Entman M, Garber AJ (1983) Adrenergic and serotonergic regulation of skeletal muscle metabolism in rat. I. The effects of adrenergic and serotonergic antagonists on the regulation of muscle amino acid release, glycogenolysis, and cyclic nucleotide levels. J Biol Chem 258(20):12494–12498
Fedorenko A, Lishko PV, Kirichok Y (2012) Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell 151(2):400–413
Fox KE et al (2006) Depletion of cAMP-response element-binding protein/ATF1 inhibits adipogenic conversion of 3T3-L1 cells ectopically expressing CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBP beta, or PPAR gamma 2. J Biol Chem 281(52):40341–40353
Francis SH, Blount MA, Corbin JD (2011) Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 91(2):651–690
Frayn KN (2002) Adipose tissue as a buffer for daily lipid flux. Diabetologia 45(9):1201–1210
Froese A et al (2012) Popeye domain containing proteins are essential for stress-mediated modulation of cardiac pacemaking in mice. J Clin Invest 122(3):1119–1130
Furman B, Ong W, Pyne NJ (2010) Cyclic AMP signaling in pancreatic islets. Adv Exp Med Biol 654:281–304
Gao T, McKenna B, Li C, Reichert M, Nguyen J, Singh T, Yang C, Pannikar A, Doliba N, Zhang T, Stoffers DA, Edlund H, Matschinsky F, Stein R, Stanger BZ (2014) Pdx1 maintains β cell identity and function by repressing an α cell program. Cell Metab 19(2):259–271
George M, Ayuso E, Casellas A, Costa C, Devedjian JC, Bosch F (2002) Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest 109:1153–1163
Gerhardstein BL, Puri T, Chien AJ, Hosey MM (1999) Identification of the sites phosphorylated by cyclic AMP-dependent protein kinase on the beta 2 subunit of L-type voltage-dependent calcium channels. Biochemistry 38(32):10361–10370
Gettys TW et al (1987) Short-term feedback regulation of cAMP by accelerated degradation in rat tissues. J Biol Chem 262(1):333–339
Gromada J, Bokvist K, Ding WG, Barg S, Buschard K, Renström E, Rorsman P (1997) Adrenaline stimulates glucagon secretion in pancreatic A-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J Gen Physiol 110(3):217–228
Guirguis E, Hockman S, Chung YW, Ahmad F, Gavrilova O, Raghavachari N, Yang Y, Niu G, Chen X, Yu ZX, Liu S, Degerman E, Manganiello V (2013) A role for phosphodiesterase 3B in acquisition of brown fat characteristics by white adipose tissue in male mice. Endocrinology 154(9):3152–3167
Gujral UP, Narayan K, Kahn SE, Kanaya AM (2014) The relative associations of β-cell function and insulin sensitivity with glycemic status and incident glycemic progression in migrant Asian Indians in the United States: the MASALA study. J Diabetes Complications 28:45–50
Handa N et al (2008) Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP. J Biol Chem 283(28):19657–19664
Hang Y, Stein R (2011) MafA and MafB activity in pancreatic β cells. Trends Endocrinol Metab 22(9):364–373
Harcourt LJ, Schertzer J, Ryall JG, Lynch GS (2007) Low dose formoterol administration improves muscle function in dystrophic mdx mice without increasing fatigue. Neuromuscul Disord 17:47–55
Härndahl L, Jing X, Ivarsson R, Degerman E, Ahrén B, Manganiello VC, Renström E, Holst LS (2002) Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta-cell exocytosis and release of insulin. J Biol Chem 277(40):37446–37455
Hauge-Evans AC, King A, Carmignac D, Richardson CC, Robinson IC, Low MJ, Christie MR, Persaud SJ, Jones PM (2009) Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58(2):403–411
Hayes JS, Brunton LL, Mayer SE (1980) Selective activation of particulate cAMP-dependent protein kinase by isoproterenol and prostaglandin E1. J Biol Chem 255(11):5113–5119
Heaton GM et al (1978) Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation. Eur J Biochem 82(2):515–521
Heimann E, Jones H, Resjö S, Manganiello VC, Stenson L, Degerman E (2010) Expression and regulation of cyclic nucleotide phosphodiesterases in human and rat pancreatic islets. PLoS One 5(12):e14191
Henquin JC, Nenquin M (2014) Activators of PKA and Epac distinctly influence insulin secretion and cytosolic Ca2+ in female mouse islets stimulated by glucose and tolbutamide. Endocrinology 155(9):3274–3287
Herzig S et al (2001) CREB regulates hepatic gluconeogenesis via the co-activator PGC-1. Nature 413:179–183
Hinkle RT, Lefever F, Dolan ET, Reichart DL, Dietrich JA, Gropp KE, Thacker RI, Demuth JP, Stevens PJ, Qu XA, Varbanov AR, Wang F, Isfort RJ (2007) Corticortophin releasing factor 2 receptor agonist treatment significantly slows disease progression in mdx mice. BMC Med 5:18
Hollenberg CH, Raben MS, Astwood EB (1961) The lipolytic response to corticotropin. Endocrinology 68:589–598
Houslay MD (2010) Underpinning compartmentalised cAMP signalling through targeted cAMP breakdown. Trends Biochem Sci 35(2):91–100
Hui H, Nourparvar A, Zhao X, Perfetti R (2003) Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology 144(4):1444–1455
Huttunen P, Hirvonen J, Kinnula V (1981) The occurrence of brown adipose tissue in outdoor workers. Eur J Appl Physiol Occup Physiol 46(4):339–345
Insel PA (1996) Seminars in medicine of the Beth Israel Hospital, Boston. Adrenergic receptors – evolving concepts and clinical implications. N Engl J Med 334(9):580–585
Ishibashi K, Sasaki S, Akiba T, Marumo F (1993) Expression of bone morphogenic protein 7 mRNA in MDCK cells. Biochem Biophys Res Commun 193(1):235–239
Ishihara H, Asano T, Tsukuda K, Katagiri H, Inukai K, Anai M, Kikuchi M, Yazaki Y, Miyazaki J, Oka Y (1994) Overexpression of hexokinase I but not GLUT1 glucose transporter alters concentration dependence of glucose-stimulated insulin secretion in pancreatic beta-cell line MIN6. J Biol Chem 269(4):3081–3087
Islam D, Zhang N, Wang P, Li H, Brubaker PL, Gaisano HY, Wang Q, Jin T (2009) Epac is involved in cAMP-stimulated proglucagon expression and hormone production but not hormone secretion in pancreatic alpha- and intestinal L-cell lines. Am J Physiol Endocrinol Metab 296(1):E174–E181
Iwami G et al (1995) Regulation of adenylyl cyclase by protein kinase A. J Biol Chem 270(21):12481–12484
Jambal P, Masterson S, Nesterova A, Bouchard R, Bergman B, Hutton JC, Boxer LM, Reusch JE, Pugazhenthi S (2003) Cytokine-mediated down-regulation of the transcription factor cAMP-response element-binding protein in pancreatic beta-cells. J Biol Chem 278:23055–23065
Jhala US, Canettieri G, Screaton RA, Kulkarni RN, Krajewski S, Reed J, Walker J, Lin X, White M, Montminy M (2003) cAMP promotes pancreatic beta-cell survival via CREB-mediated induction of IRS2. Genes Dev 17:1575–1580
Kahn SE (2003) The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia 46:3–19
Kai AK, Lam A, Chen Y, Tai AC, Zhang X, Lai AK, Yeung PK, Tam S, Wang J, Lam KS, Vanhoutte PM, Bos JL, Chung SS, Xu A, Chung SK (2013) Exchange protein activated by cAMP 1 (Epac1)-deficient mice develop β-cell dysfunction and metabolic syndrome. FASEB J 27(10):4122–4135
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM (2009) Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature 460(7259):1154–1158
Kamenetsky M et al (2006) Molecular details of cAMP generation in mammalian cells: a tale of two systems. J Mol Biol 362(4):623–639
Kaneto H, Miyatsuka T, Kawamori D, Yamamoto K, Kato K, Shiraiwa T, Katakami N, Yamasaki Y, Matsuhisa M, Matsuoka TA (2008) PDX-1 and MafA play a crucial role in pancreatic beta-cell differentiation and maintenance of mature beta-cell function. Endocr J 55(2):235–252
Kang G, Chepurny O, Malester B, Rindler MJ, Rehmann H, Bos JL, Schwede F, Coetzee WA, Holz GG (2006) cAMP sensor Epac as a determinant of ATP-sensitive potassium channel activity in human pancreatic beta cells and rat INS-1 cells. J Physiol 573(Pt 3):595–609
Kashima Y, Miki T, Shibasaki T, Ozaki N, Miyazaki M, Yano H, Seino S (2001) Critical role of cAMP-GEFII––Rim2 complex in incretin-potentiated insulin secretion. J Biol Chem 276:46046–46053
Keravis T, Lugnier C (2010) Cyclic nucleotide phosphodiesterases (PDE) and peptide motifs. Curr Pharm Des 16(9):1114–1125
Kim MJ, Kang J, Park YG, Ryu GR, Ko SH, Jeong IK, Koh KH, Rhie DJ, Yoon SH, Hahn SJ, Kim MS, Jo YH (2006) Exendin-4 induction of cyclin D1 expression in INS-1 beta-cells: involvement of cAMP-responsive element. J Endocrinol 188(3):623–633
Kim SJ, Nian C, Widenmaier S, McIntosh CH (2008) Glucose-dependent insulinotropic polypeptide-mediated up-regulation of beta-cell antiapoptotic Bcl-2 gene expression is coordinated by cyclic AMP (cAMP) response element binding protein (CREB) and cAMP-responsive CREB coactivator 2. Mol Cell Biol 28(5):1644–1656
Kimple ME, Keller M, Rabaglia MR, Pasker RL, Neuman JC, Truchan NA, Brar HK, Attie AD (2013) Prostaglandin E2 receptor, EP3, is induced in diabetic islets and negatively regulates glucose- and hormone-stimulated insulin secretion. Diabetes 62(6):1904–1912
Kolditz CI, Langin D (2010) Adipose tissue lipolysis. Curr Opin Clin Nutr Metab Care 13(4):377–381
Kong X, Banks A, Liu T, Kazak L, Rao RR, Cohen P, Wang X, Yu S, Lo JC, Tseng YH, Cypess AM, Xue R, Kleiner S, Kang S, Spiegelman BM, Rosen ED (2014) IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 158(1):69–83
Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437(7062):1109–1111
Leiser M, Fleischer N (1996) cAMP-dependent phosphorylation of the cardiac-type alpha 1 subunit of the voltage-dependent Ca2+ channel in a murine pancreatic beta-cell line. Diabetes 45(10):1412–1418
Lidell ME et al (2013) Evidence for two types of brown adipose tissue in humans. Nat Med 19(5):631–634
Light PE, Manning Fox J, Riedel MJ, Wheeler MB (2002) Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A- and ADP-dependent mechanism. Mol Endocrinol 16(9):2135–2144
Lin B, Morris D, Chou JY (1997) The role of HNF1alpha, HNF3gamma, and cyclic AMP in glucose-6-phosphatase gene activation. Biochemistry 36(46):14096–14106
Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J 3rd, Olefsky J, Guarente L, Montminy M (2008) A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456(7219):269–273
Love JA, Richards N, Owyang C, Dawson DC (1998) Muscarinic modulation of voltage-dependent Ca2+ channels in insulin-secreting HIT-T15 cells. Am J Physiol 274(2 Pt 1):G397–G405
Maltin CA, Hay S, Delday MI, Lobley GE, Reeds PJ (1989) The action of the beta-agonist clenbuterol on protein metabolism in innervated and denervated phasic muscles. Biochem J 261:965–971
Mattsson CL, Csikasz R, Chernogubova E, Yamamoto DL, Hogberg HT, Amri EZ, Hutchinson DS, Bengtsson T (2011) β1-Adrenergic receptors increase UCP1 in human MADS brown adipocytes and rescue cold-acclimated β3-adrenergic receptor-knockout mice via nonshivering thermogenesis. Am J Physiol Endocrinol Metab 301(6):E1108–E1118
McKinnon CM, Docherty K (2001) Pancreatic duodenal homeobox-1, PDX-1, a major regulator of beta cell identity and function. Diabetologia 44(10):1203–1214
Metz SA (1988) Epinephrine impairs insulin release by a mechanism distal to calcium mobilization. Similarity to lipoxygenase inhibitors. Diabetes 37(1):65–73
Monroe MB et al (2001) Direct evidence for tonic sympathetic support of resting metabolic rate in healthy adult humans. Am J Physiol Endocrinol Metab 280(5):E740–E744
Morgan DG, Kulkarni R, Hurley JD, Wang ZL, Wang RM, Ghatei MA, Karlsen AE, Bloom SR, Smith DM (1998) Inhibition of glucose stimulated insulin secretion by neuropeptide Y is mediated via the Y1 receptor and inhibition of adenylyl cyclase in RIN 5AH rat insulinoma cells. Diabetologia 41(12):1482–1491
Mullur R, Liu Y, Brent GA (2014) Thyroid hormone regulation of metabolism. Physiol Rev 94(2):355–382
Murakami T, Nishiyama T, Shirotani T, Shinohara Y, Kan M, Ishii K, Kanai F, Nakazuru S, Ebina Y (1992) Identification of two enhancer elements in the gene encoding the type 1 glucose transporter from the mouse which are responsive to serum, growth factor, and oncogenes. J Biol Chem 267:9300–9306
Niehof M, Manns MP, Trautwein C (1997) CREB controls LAP/C/EBP beta transcription. Mol Cell Biol 17(7):3600–3613
Nishizawa Y, Bray GA (1978) Ventromedial hypothalamic lesions and the mobilization of fatty acids. J Clin Invest 61(3):714–721
Niwa T, Matsukawa Y, Senda T, Nimura Y, Hidaka H, Niki I (1998) Acetylcholine activates intracellular movement of insulin granules in pancreatic beta-cells via inositol trisphosphate-dependent [correction of triphosphate-dependent] mobilization of intracellular Ca2+. Diabetes 47(11):1699–1706
Offield MF, Jetton T, Labosky PA, Ray M, Stein RW, Magnuson MA, Hogan BL, Wright CV (1996) PDX-1 is required for pancreatic outgrowth and differentiation of the rostral duodenum. Development 122(3):983–995
Okla M, Ha J, Temel RE, Chung S (2015) BMP7 drives human adipogenic stem cells into metabolically active beige adipocytes. Lipids 50(2):111–120
Olefsky JM (1977) Insensitivity of large rat adipocytes to the antilipolytic effects of insulin. J Lipid Res 18(4):459–464
Pagnon J et al (2012) Identification and functional characterization of protein kinase A phosphorylation sites in the major lipolytic protein, adipose triglyceride lipase. Endocrinology 153(9):4278–4289
Park BO, Ahrends R, Teruel MN (2012) Consecutive positive feedback loops create a bistable switch that controls preadipocyte-to-adipocyte conversion. Cell Rep 2(4):976–990
Perfetti R, Zhou J, Doyle ME, Egan JM (2000) Glucagon-like peptide-1 induces cell proliferation and pancreatic-duodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats. Endocrinology 141(12):4600–4605
Petersen RK et al (2008) Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes. Mol Cell Biol 28(11):3804–3816
Poitout V, Robertson R (2008) Glucolipotoxicity: fuel excess and beta-cell dysfunction. Endocr Rev 29:351–366
Puddu A, Sanguineti R, Montecucco F, Viviani GL (2015) Effects of high glucose levels and glycated serum on GIP responsiveness in the pancreatic beta cell line HIT-T15. J Diabetes Res 2015:326359
Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM (1998) A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell 92(6):829–839
Purwana I, Zheng J, Li X, Deurloo M, Son DO, Zhang Z, Liang C, Shen E, Tadkase A, Feng ZP, Li Y, Hasilo C, Paraskevas S, Bortell R, Greiner DL, Atkinson M, Prud’homme GJ, Wang Q (2014) GABA promotes human β-cell proliferation and modulates glucose homeostasis. Diabetes 63:4197–4205
Quinn PG, Granner DK (1990) Cyclic AMP-dependent protein kinase regulates transcription of the phosphoenolpyruvate carboxykinase gene but not binding of nuclear factors to the cyclic AMP regulatory element. Mol Cell Biol 10:3357–3364
Richards CS, Yokoyama M, Furuya E, Uyeda K (1982) Reciprocal changes in fructose-2,6-bisphosphate, 2-kinase and fructose-2,6-bisphosphatase activity in response to glucagon and epinephrine. Biochem Biophys Res Commun 104:1073–1079
Richelsen B, Pedersen O (1985) Beta-adrenergic regulation of prostaglandin E2 receptors in human and rat adipocytes. Endocrinology 116(3):1182–1188
Rim JS, Kozak L (2002) Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene. J Biol Chem 277(37):34589–34600
Rosen ED, Spiegelman BM (2014) What we talk about when we talk about fat. Cell 156(1–2):20–44
Russell TR, Ho R (1976) Conversion of 3T3 fibroblasts into adipose cells: triggering of differentiation by prostaglandin F2alpha and 1-methyl-3-isobutyl xanthine. Proc Natl Acad Sci U S A 73(12):4516–4520
Ryall JG, Schertzer J, Alabakis TM, Gehrig SM, Plant DR, Lynch GS (2008) Intramuscular beta2-agonist administration enhances early regeneration and functional repair in rat skeletal muscle after myotoxic injury. J Appl Physiol 105:165–172
Saida K, Van Breemen C (1984) Cyclic AMP modulation of adrenoreceptor-mediated arterial smooth muscle contraction. J Gen Physiol 84(2):307–318
Screaton RA, Conkright M, Katoh Y, Best JL, Canettieri G, Jeffries S, Guzman E, Niessen S, Yates JR 3rd, Takemori H, Okamoto M, Montminy M (2004) The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector. Cell 119:61–74
Sculptoreanu A, Scheuer T, Catterall WA (1993) Voltage-dependent potentiation of L-type Ca2+ channels due to phosphorylation by cAMP-dependent protein kinase. Nature 364(6434):240–243
Seale P, Kajimura S, Yang W, Chin S, Rohas LM, Uldry M, Tavernier G, Langin D, Spiegelman BM (2007) Transcriptional control of brown fat determination by PRDM16. Cell Metab 6(1):38–54
Seematter G et al (2004) Relationship between stress, inflammation and metabolism. Curr Opin Clin Nutr Metab Care 7(2):169–173
Semple RK, Crowley V, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O’Rahilly S (2004) Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int J Obes Relat Metab Disord 28(1):176–179
Sette C, Iona S, Conti M (1994) The short-term activation of a rolipram-sensitive, cAMP-specific phosphodiesterase by thyroid-stimulating hormone in thyroid FRTL-5 cells is mediated by a cAMP-dependent phosphorylation. J Biol Chem 269(12):9245–9252
Shimizu Y, Satoh S, Yano H, Minokoshi Y, Cushman SW, Shimazu T (1998) Effects of noradrenaline on the cell-surface glucose transporters in cultured brown adipocytes: novel mechanism for selective activation of GLUT1 glucose transporters. Biochem J 330(Pt 1):397–403
Siersbaek R et al (2014) Molecular architecture of transcription factor hotspots in early adipogenesis. Cell Rep 7(5):1434–1442
Silva JE (2006) Thermogenic mechanisms and their hormonal regulation. Physiol Rev 86(2):435–464
Silva JE, Larsen PR (1983) Adrenergic activation of triiodothyronine production in brown adipose tissue. Nature 305(5936):712–713
Sinnarajah S et al (2001) RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature 409(6823):1051–1055
Skala JP, Knight BL (1977) Protein kinases in brown adipose tissue of developing rats. State of activation of protein kinase during development and cold exposure and its relationship to adenosine 3′:5′-monophosphate, lipolysis, and heat production. J Biol Chem 252(3):1064–1070
Smith FD et al (2013) Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. Elife 2:e01319
Soderling TR, Hickenbottom J, Reimann EM, Hunkeler FL, Walsh DA, Krebs EG (1970) Inactivation of glycogen synthetase and activation of phosphorylase kinase by muscle adenosine 3′,5′-monophosphate-dependent protein kinases. J Biol Chem 245:6317–6328
Song WJ, Schreiber W, Zhong E, Liu FF, Kornfeld BD, Wondisford FE, Hussain MA (2008) Exendin-4 stimulation of cyclin A2 in beta-cell proliferation. Diabetes 57(9):2371–2381
Staimez LR, Weber M, Ranjani H, Ali MK, Echouffo-Tcheugui JB, Phillips LS, Mohan V, Narayan KM (2013) Evidence of reduced β-cell function in Asian Indians with mild dysglycemia. Diabetes Care 36:2772–2778
Studer RK, Borle AB (1982) Differences between male and female rats in the regulation of hepatic glycogenolysis. The relative role of calcium and cAMP in phosphorylase activation by catecholamines. J Biol Chem 257(14):7987–7993
Studer RK, Snowdowne KW, Borle AB (1984) Regulation of hepatic glycogenolysis by glucagon in male and female rats. Role of cAMP and Ca2+ and interactions between epinephrine and glucagon. J Biol Chem 259(6):3596–3604
Sun X, Dang F, Zhang D, Yuan Y, Zhang C, Wu Y, Wang Y, Liu Y (2015) Glucagon-CREB/CRTC2 signaling cascade regulates hepatic BMAL1 protein. J Biol Chem 290(4):2189–2197
Tang QQ, Lane MD (2012) Adipogenesis: from stem cell to adipocyte. Annu Rev Biochem 81:715–736
Thomas SA, Palmiter RD (1997) Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline. Nature 387(6628):94–97
Thorens B, Guillam M, Beermann F, Burcelin R, Jaquet M (2000) Transgenic reexpression of GLUT1 or GLUT2 in pancreatic beta cells rescues GLUT2-null mice from early death and restores normal glucose-stimulated insulin secretion. J Biol Chem 275(31):23751–23758
Tourrel C, Bailbé D, Meile MJ, Kergoat M, Portha B (2001) Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 50:1562–1570
Valverde I et al (1979) Calmodulin activation of adenylate cyclase in pancreatic islets. Science 206(4415):225–227
van Marken Lichtenbelt WD et al (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508
Virtanen KA et al (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525
Walsh DA, Perkins JP, Krebs EG (1968) An adenosine 3′,5′-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem 243(13):3763–3765
Wang Y, Perfetti R, Greig NH, Holloway HW, DeOre KA, Montrose-Rafizadeh C, Elahi D, Egan JM (1997) Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 99:2883–2889
Wang H, Iezzi M, Theander S, Antinozzi PA, Gauthier BR, Halban PA, Wollheim CB (2005) Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells. Diabetologia 48(4):720–731
Wang Y, Inoue H, Ravnskjaer K, Viste K, Miller N, Liu Y, Hedrick S, Vera L, Montminy M (2010) Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc Natl Acad Sci U S A 107(7):3087–3092
Welters HJ, Diakogiannaki E, Mordue JM, Tadayyon M, Smith SA, Morgan NG (2006) Differential protective effects of palmitoleic acid and cAMP on caspase activation and cell viability in pancreatic beta-cells exposed to palmitate. Apoptosis 11(7):1231–1238
White JE, Engel FL (1958) Lipolytic action of corticotropin on rat adipose tissue in vitro. J Clin Invest 37(11):1556–1563
Whittle AJ, Carobbio S, Martins L, Slawik M, Hondares E, Vázquez MJ, Morgan D, Csikasz RI, Gallego R, Rodriguez-Cuenca S, Dale M, Virtue S, Villarroya F, Cannon B, Rahmouni K, López M, Vidal-Puig A (2012) BMP8B increases brown adipose tissue thermogenesis through both central and peripheral actions. Cell 149(4):871–885
Withers DJ, Burks D, Towery HH, Altamuro SL, Flint CL, White MF (1999) Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling. Nat Genet 23:32–40
Wynshaw-Boris A, Short J, Loose DS, Hanson RW (1986) Characterization of the phosphoenolpyruvate carboxykinase (GTP) promoter-regulatory region. I. Multiple hormone regulatory elements and the effects of enhancers. J Biol Chem 261:9714–9720
Yabe D, Seino Y (2011) Two incretin hormones GLP-1 and GIP: comparison of their actions in insulin secretion and β cell preservation. Prog Biophys Mol Biol 107(2):248–256
Yasuda K et al (2006) Adrenergic receptor polymorphisms and autonomic nervous system function in human obesity. Trends Endocrinol Metab 17(7):269–275
Yokomori N, Tawata M, Hosaka Y, Onaya T (1992) Transcriptional regulation of hexokinase I mRNA levels by TSH in cultured rat thyroid FRTL5 cells. Life Sci 51(20):1613–1619
Yoshimasa T et al (1987) Cross-talk between cellular signalling pathways suggested by phorbol-ester-induced adenylate cyclase phosphorylation. Nature 327(6117):67–70
Yosida M, Dezaki K, Uchida K, Kodera S, Lam NV, Ito K, Rita RS, Yamada H, Shimomura K, Ishikawa SE, Sugawara H, Kawakami M, Tominaga M, Yada T, Kakei M (2014) Involvement of cAMP/EPAC/TRPM2 activation in glucose- and incretin-induced insulin secretion. Diabetes 63(10):3394–3403
Zaccolo M (2011) Spatial control of cAMP signalling in health and disease. Curr Opin Pharmacol 11(6):649–655
Zaccolo M, Pozzan T (2002) Discrete microdomains with high concentration of cAMP in stimulated rat neonatal cardiac myocytes. Science 295(5560):1711–1715
Zhang JW et al (2004) Role of CREB in transcriptional regulation of CCAAT/enhancer-binding protein beta gene during adipogenesis. J Biol Chem 279(6):4471–4478
Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA (2010) Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16(10):1152–1156
Zhao AZ, Zhao H, Teague J, Fujimoto W, Beavo JA (1997) Attenuation of insulin secretion by insulin-like growth factor 1 is mediated through activation of phosphodiesterase 3B. Proc Natl Acad Sci U S A 94(7):3223–3228
Zhou J, Pineyro M, Wang X, Doyle ME, Egan JM (2002) Exendin-4 differentiation of a human pancreatic duct cell line into endocrine cells: involvement of PDX-1 and HNF3beta transcription factors. J Cell Physiol 192(3):304–314
Ziegler MG et al (2012) Epinephrine and the metabolic syndrome. Curr Hypertens Rep 14(1):1–7
Zippin JH et al (2004) Bicarbonate-responsive “soluble” adenylyl cyclase defines a nuclear cAMP microdomain. J Cell Biol 164(4):527–534
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Ravnskjaer, K., Madiraju, A., Montminy, M. (2015). Role of the cAMP Pathway in Glucose and Lipid Metabolism. In: Herzig, S. (eds) Metabolic Control. Handbook of Experimental Pharmacology, vol 233. Springer, Cham. https://doi.org/10.1007/164_2015_32
Download citation
DOI: https://doi.org/10.1007/164_2015_32
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-29804-7
Online ISBN: 978-3-319-29806-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)