‘Dysfunctional’ adipose tissue in cardiovascular disease: a reprogrammable target or an innocent bystander?

The obesity pandemic1 is recognized as a global health problem linked with metabolic abnormalities (like diabetes mellitus), triggers the development of cardiovascular risk factors (like hypertension) and has clear detrimental effects on the cardiovascular system, leading to heart failure2,3 and vascular disease pathogenesis. However, there are numerous reports highlighting that the association of body mass index with mortality (cardiovascular or not) has a J shape,4 with this changing into a U-shape association in patients with chronic diseases like heart failure, advanced atherosclerosis or chronic kidney disease; this is called the ‘obesity paradox’.5 So what is the real role of adipose tissue in cardiovascular homeostasis, in health and in disease? Why is adipose tissue surrounding our vessels (perivascular fat) and our heart (epicardial fat)? Why having more adipose tissue mass does not always lead to metabolic abnormalities or cardiovascular disease, and why is low body weight in chronic diseases associated with worse outcomes? Can adipose tissue communicate with the cardiovascular system, and if it does, how? And why? These simple questions don’t have simple answers, and have been the topic of an ongoing debate over the last decade. It is clear that we first need to understand how adipose tissue regulates its own function, and then we need to decipher the communication code by which it ‘senses’ signals coming from the cardiovascular system and how it ‘talks’ to the vessels and the heart. This spotlight issue published in Cardiovascular Research, addresses some of these fundamental questions, aiming to simplify and condense a huge volume of inter-disciplinary information coming from cardiovascular medicine, endocrinology, molecular biology and other field of science. To understand how adipose tissue interacts with the cardiovascular system, we first need to accept that this is a heterogeneous tissue.6 It includes mature adipocytes, but also a large variety of cell types within the stromal fraction6; inflammatory cells (predominantly macrophages and lymphocytes) of various phenotypic characteristics, fibroblasts, stem cells as well as vascular cells coming from microvascular structures embedded into the tissue. In this spotlight issue, Badimon et al.6 highlights the key mechanisms by which these cell types communicate to each other and how inflammatory signals drive the properties of adipose tissue-derived stem cells, modifying the expansion of various adipose tissue depots in obesity. All cell types contribute to the so called adipose tissue secretome, which may include predominantly anti-inflammatory and anti-atherogenic adipocytokines (e.g. adiponectin,7 interleukin 108 and possibly omentin-19) in metabolically healthy individuals, or it may shift towards the secretion of pro-inflammatory and pro-atherogenic adipocytokines (e.g. resistin, leptin, visfatin, monocyte chemoattractant protein one, etc) in metabolically unhealthy obesity.10 Each adipose tissue type has its’ own transcriptomic and secretomic profile, largely driven by the variability of its cellular composition as well as the inherent biology of the local adipocytes and their interactions with the local infiltrating inflammatory cells.11,12 The adipocytokines secreted by the adipose tissue, can exert paracrine effects on the neighbouring vascular wall (i.e. perivascular adipose tissue)13 or myocardium (i.e. epicardial adipose tissue),14 as well as endocrine effects (i.e. ‘remote’ depots like subcutaneous) on the cardiovascular system through the circulation.15 Importantly, adipose tissue plays a critical role in controlling the systemic pro-thrombotic state related with obesity, triggering indirectly vascular disease pathogenesis. The links between metabolically unhealthy obesity and pro-thrombotic mechanisms, are extensively discussed by Vilahur et al.16 in the current spotlight issue. Adipose tissue and the cardiovascular system share common receptor-mediated signalling pathways, like the mineralocorticoid receptor-mediated signalling17 that regulates insulin resistance and modifies adipose tissue secretome, while at the same time it also controls cardiovascular biology (e.g. cardiovascular redox signalling, inflammatory mechanisms, and others). In addition, adipose-tissue microRNAs are key players in adipose-tissue homeostasis, playing also the role of ‘messengers’, modifying gene expression in cardiovascular tissues.18 These effects involve rapid changes in cardiovascular redox signalling and inflammation,19 with a critical role in cardiovascular disease pathogenesis. Further to the effects on large vessels, the adipose tissue secretome also plays a role in the regulation of microvascular tone by modifying microvascular endothelial function and contractility, resulting into multi-organ pathologies such as chronic kidney disease, pulmonary hypertension, microvascular dementia and others, as discussed in this spotlight issue by Sorop et al.20 The mechanisms controlling the shift between the different types of adipose tissue secretome in metabolically healthy vs. metabolically unhealthy obesity, are described in this spotlight issue by Guzik et al.,10 while the exact responses of the vascular cells or the cardiomyocytes to adipose tissue-derived signals are discussed by Akoumianakis et al.19 The role of micro-RNAs in the regulation of cardiovascular disease pathogenesis are presented by Icli et al.18 Further to the endocrine and paracrine effects of adipose tissue on the cardiovascular system, recent evidence suggests that the vascular wall as well as the myocardium2,21 also send signals to the adipose tissue (paracrine or endocrine inside-to-outside signalling), modifying its phenotypic characteristics. This reverse, inside-to-outside signals were first described by Margaritis et al.13 and it is considered now as part of the human defences against cardiovascular inflammation and oxidation.19 Moreover, the secretory profile of perivascular adipose tissue is also modified by its sensory innervation, that largely drives the secretion of leptin and other adipokines with paracrine effects on the vascular wall.22 In conclusion, adipose tissue and the cardiovascular system are in continuous, bi-directional communication to each other, and they act as components of a unified system, complementing each other in maintaining homeostasis. In conditions like diabetes or metabolically abnormal obesity, this harmony between adipose tissue and the cardiovascular system is disturbed, and the former is turned from an ally into an enemy, exerting detrimental endocrine and paracrine effects on the vessels and the heart. The efforts should now focus on developing strategies to ‘reprogramme’ the dysfunctional adipose tissue in these metabolically unhealthy conditions, by targeting not only the function of adipocytes and inflammatory cells consisting the tissue, but also by targeting the cell–cell and tissue–tissue interactions between adipose tissue and the cardiovascular system. This could be the solution to obesity pandemic. Conflict of interest: Unrestricted grant from Sanofi, consultancy to Mitsubishi-Tanabe, and unrestricted grant by NovoNordisk. CA is funded by the British Heart Foundation (FS/16/15/32047 and TG/16/3/32687).