Unmasking cAMP signalling in adipocytes

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In recent years, the prevalence of obesity has reached pandemic proportions. In 2016, the World Health Organisation estimated that ca. 3 million people die each year due to complications from being overweight or obese. With more overweight population than ever, finding new targets to counteract obesity has become crucial. Recruitment and activation of brown adipose tissue (BAT) has been postulated as a potential target to increase thermogenic energy expenditure (EE) in order to treat or prevent obesity and its comorbidities.Cyclic adenosine monophosphate (cAMP) is a second messenger important in many biological processes. BAT thermogenesis is primarily mediated by activation of Gs‐coupled receptors such as the beta‐3 adrenergic receptor and the adenosine A2A receptor, which both increase intracellular cAMP. In mature brown adipocytes, cAMP is well known to induce lipolysis and UCP1‐mediated mitochondrial uncoupling through activation of protein kinase A (PKA). However, the precise role of cAMP signaling in adipocyte precursor cells has so far not been well studied. Furthermore, the role of other cAMP effectors (e.g. Exchange proteins activated by cAMP (EPAC)) in adipose tissue metabolism is not clear.Treatment of brown adipocyte precursor cells using analogs specific to different cAMP effectors induce distinct cellular responses. Here, we used genetic and pharmacological approaches to decipher the role of cAMP effectors, focusing on EPAC proteins, in adipocytes. We demonstrate that activation of mature adipocytes and proliferation of brown preadipocytes require the activation of distinct effectors and signaling pathways downstream of cAMP. Furthermore, browning of white adipocytes appears to follow similar patterns. Our data indicate that, depending on the effector, either PKA or EPAC, cAMP regulates browning of white adipocytes by different mechanisms. Moreover, in vivo deletion of EPAC leads to reduced oxygen consumption after high fat diet, demonstrating that the role of cAMP in adipocytes is still not fully understood. In conclusion, we show that the effects of cAMP in BAT and browning of WAT differ vastly depending on both the state of adipocyte differentiation as well as the downstream effector.Support or Funding InformationInstitute of Pharmacology and Toxicology, University of Bonn, 53127 Bonn, GermanySFB1328, Universitätsklinikum Hamburg‐Eppendorf, 20246 Hamburg, Germany