From PDE3B to the regulation of energy homeostasis

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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.

Highlights

► Acute hormonal regulation of PDE3B involves reversible protein phosphorylation and protein complex formation at different subcellular locations. ► PDE3B plays a key role in the regulation of adipocyte lipolysis. ► PDE3B plays a key role in the regulation of insulin secretion. ► PDE3B plays an important role in overall energy homeostasis. ► PDE3B is downregulated in adipose tissue in human obesity.

Introduction

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 (T2D) (e.g. [1]). It has been reported that over 80% of adults diagnosed with T2D are obese. The connection between obesity and the development of T2D has been the focus of intense research in recent years. It has been demonstrated that low-grade, systemic inflammation originating from adipose tissue is a factor associated with systemic insulin resistance (e.g. [2]). Adipose tissue secretes numerous adipokines which affect whole body insulin sensitivity and dysregulation of production and secretion of these factors could contribute to the development of insulin resistance in obesity (e.g. [2, 3]). Also, excess fatty acids released from the adipocytes of obese persons contribute to ectopic fat storage in non-adipose tissues like liver and muscle, thereby exacerbating their insulin resistance (e.g. [4]).

The composition of cAMP-signalling networks, which play key roles in target tissues of relevance for energy homeostasis, are growing in complexity [5, 6]. Cyclic nucleotide PDEs (phosphodiesterases) are important actors in this context. The PDE superfamily contains eleven structurally related, but functionally distinct, gene families (PDE1–11), which differ in primary structures, affinities for cAMP and cGMP, responses to specific effectors, sensitivities to specific inhibitors, and mechanisms of regulation (e.g. [7]). By virtue of their distinct intrinsic characteristics and their intracellular targeting to different subcellular locations, different PDEs integrate multiple cellular inputs and modulate the amplitude, duration, termination and specificity of cyclic nucleotide signals and actions [6]. The PDE3 family contains two subfamilies, PDE3A and PDE3B [8, 9], which are encoded by distinct but related genes and exhibit distinct, but overlapping, patterns of expression. For example, PDE3A is more highly expressed in the cardiovascular system and PDE3B is more highly expressed in cells of importance for the regulation of glucose and lipid metabolism. This article highlights some key aspects of the role of PDE3B in normal and dysfunctional regulation of energy homeostasis.

Section snippets

Mechanisms for the regulation of PDE3B and related signalling networks

When it comes to the overall regulation of PDE3B functions and the intracellular signalling networks involved in PDE3B regulation and action, the intracellular localization of the enzyme, phosphorylation events, as well as the formation of unique protein complexes containing PDE3B have critical roles.

PDE3B plays a key role in the regulation of insulin secretion

In agreement with results from studies using insulin-secreting cell lines and isolated pancreatic islets as models to modulate PDE3B expression and activity [17•, 18] (Figure 2), mice that specifically overexpress PDE3B in β cells show a PDE3B protein dose-dependent decrease in glucose-induced insulin secretion as well as a decrease in the ability of GLP-1 to potentiate glucose-mediated insulin secretion [19, 20]. Furthermore, the seemingly moderate dysregulation of cAMP in pancreatic β cells

Conclusion

PDE3B is an important actor in the regulation of energy metabolism. However, with regard to PDE3B as a possible target for drugs in the context of treatment for obesity and T2D, one has to keep in mind the dynamic interplay among multiple tissues expressing PDE3B. Indeed, the final outcome of PDE3 inhibitors in the context of dysregulated energy homeostasis is difficult to predict (Figure 4). Tissue-specific delivery systems appear to be necessary since the effects of PDE3B inhibition on

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported, in part, by the NHLBI Intramural program and by the following grants to ED: Medical Research Council, Swedish Diabetes Association and Novo Nordisk Foundation.

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