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Review
. 2011 Dec;11(6):676-82.
doi: 10.1016/j.coph.2011.09.015. Epub 2011 Oct 14.

From PDE3B to the regulation of energy homeostasis

Eva Degerman  1 , Faiyaz Ahmad, Youn Wook Chung, Emilia Guirguis, Bilal Omar, Lena Stenson, Vincent Manganiello
Affiliations
Review

From PDE3B to the regulation of energy homeostasis

Eva Degerman et al. Curr Opin Pharmacol. 2011 Dec.

Abstract

The incidence of obesity in the developed world is increasing at an alarming rate. Concurrent with the increase in the incidence of obesity is an increase in the incidence of type 2 diabetes. Cyclic AMP (cAMP) and cGMP are key second messengers in all cells; for example, when it comes to processes of relevance for the regulation of energy metabolism, cAMP is a key mediator in the regulation of lipolysis, glycogenolysis, gluconeogenesis and pancreatic β cell insulin secretion. PDE3B, one of several enzymes which hydrolyze cAMP and cGMP, is expressed in cells of importance for the regulation of energy homeostasis, including adipocytes, hepatocytes, hypothalamic cells and β cells. It has been shown, using PDE3 inhibitors and gene targeting approaches in cells and animals, that altered levels of PDE3B result in a number of changes in the regulation of glucose and lipid metabolism and in overall energy homeostasis. This article highlights the complexity involved in the regulation of PDE3B by hormones, and in the regulation of downstream metabolic effects by PDE3B in several interacting tissues.

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Figures

Figure 1
Figure 1. Structural organization of PDE3B
The structural organization of PDE3B involves the catalytic domain conserved among all PDEs in the C-terminal portion of the enzymes followed by a hydrophilic C-terminal region. The catalytic domain hydrolyzes both cAMP and cGMP and is the target for PDE3 inhibitors. The regulatory N-terminal portion contains large hydrophobic regions with predicted transmembrane helical segments. Downstream of the hydrophobic regions lies regulatory serine residues that are phosphorylated in intact cells. Signalling induced by cAMP and cGMP primarily involves their activation of cAMP- and cGMP-activated protein kinases (PKA and PKG), with subsequent phosphorylation of critical effectors. However, direct interactions of cyclic nucleotides with binding proteins are now recognized as alternative mechanisms for transduction of their signals. These binding proteins include cAMP-activated guanine nucleotide exchange factors (GEFs) also called Epacs (exchange proteins activated by cAMP or cAMP GEF) which regulate Rap1, cyclic nucleotide-gated channels and several PDEs, which contain allosteric, non-catalytic cyclic nucleotide-binding sites located in GAF domains (the GAF domain is named after some of the proteins it is found in: cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA).
Figure 2
Figure 2. Role of PDE3B in the regulation of insulin secretion
The main stimulator of insulin secretion is glucose, which is metabolized inside the β cell. The subsequent increase in ATP/ADP ratio causes closure of KATP-dependent ion channels, resulting in depolarization of the plasma membrane. In consequence, L-type Ca2+ channels are opened, leading to influx of Ca2+. The increased intracellular concentration of Ca2+ stimulates exocytosis of insulin. cAMP initiates processes to enhance insulin secretion, including activation of PKA and binding to Epac2. Exocytosis of insulin is then stimulated through multiple pathways, only a few of which have been established so far. Glucagon-like peptide (GLP)-1 is an insulinoptropic gut hormone, which acts through a G-protein-coupled receptor to activate adenylate cyclase (AC) and thereby trigger an increase in cAMP. PDE3B in turn has been shown to negatively regulate insulin secretion through its cAMP-hydrolyzing activity. Other hormones known to activate β cell PDE3B are insulin, IGF-1 and leptin. The red ball indicates phosphorylation-sites.
Figure 3
Figure 3. Role of PDE3B in hormone-mediated regulation of adipocyte functions
Activation of PDE3B leads to increased hydrolysis of cAMP and thereby inhibition of catecholamine-induced lipolysis, a process which involves PKA-dependent phosphorylation of hormone-sensitive lipase (HSL) and perilipin. Insulin-mediated phosphorylation and activation of PDE3B involves tyrosine phosphorylation of insulin receptor substrates (IRS) catalyzed by the activated insulin receptor tyrosine kinase (IRTK), activation of PI3K and increased production of phosphatidyl inositol 3,4/3,4,5 phosphates. This is followed by the activation of PKB which is believed to be one important kinase that phosphorylates and activates PDE3B. Phosphorylation and activation of PDE3B by cAMP-increasing hormones are thought to be important in feedback-regulation of cAMP and cAMP-mediated responses. PDE3B is also important in insulin-induced regulation of glucose uptake and lipogenesis which involves PKA as well as Epac proteins. Finally, PDE3B as well as PDE4 seem to regulate cAMP pools that affect the activation/phosphorylation state of AMPK. ATGL (adipose triglyceride lipase).
Figure 4
Figure 4
Multiple effects of PDE3 inhibitors. It is a challenge to target PDE3Bs to prevent and treat dysregulated metabolic states due to the different responses in different tissues.
See this image and copyright information in PMC

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