Cardio-protective Messengers from “Good Fat”

Obesity is a long-established major risk factor for cardiovascular diseases, including heart failure ^{1, 2}, yet there is also a well-recognized phenomena of “obesity paradox” among heart failure patients where overweight conditions appear to provide a significant protection against adverse outcome ³. This contradiction continues to fuel the current debate about the pathogenic vs. protective role of “bad vs. good” fat in cardiac health. While recent studies have made significant inroad to better understand the pathogenic impact as well as the underlying mechanisms implicated in the adverse effect of obesity in cardiovascular health, relatively less is known about the role of adipose tissue in cardio-protection against pathological stress and injuries. In this issue, Zhao et al from Fuyang Zhang and Ling Tao laboratories uncovered a significant contribution of brown adipose tissue (BAT) derived small extracellular vesicles (sEVs, a.k.a. exosomes) in exercise induced cardioprotection against ischemic/reperfusion injury ⁴, marking another important step to unlock the potential beneficial effect from fat against cardiac injury and pathological progression.

Fat is an important energy depot and plays a pivotal role in bioenergetic and nutrient homeostasis. Obese condition often leads to global metabolic dysfunction, as reflected in dysregulated fatty acid and glucose metabolism at systemic level. As one of the most energy demanding organs, the heart is particularly vulnerable to metabolic disturbances in obesity and diabetes, leading to impaired fuel flexibility and diminished reparative capacities in response to mechanical overload or ischemic injury^{5, 6}. This paradigm, however, is challenged by discoveries that fat tissue also functions as an important endocrine organ, regulating systemic health through secretion of hormones, collectively termed adipokines⁷. Indeed, adiponectin, one of the most important adipokines derived from fat, has a potent protective effect in cardiovascular system, and loss of adiponectin production and secretion may underscore the elevated cardiovascular risk and worse adverse outcome associated with obesity. Owing to the advancement in molecular and genomic tools, recent studies have uncovered yet another category of secreted molecules from fat. They are encapsulated in small extracellular vesicles and can be delivered systemically to remote organs, such as heart. Small non-coding RNAs, including miRNAs, are identified as key components of sEVs delivered molecules which can exert significant biological impact on the targeted organ^{8 9}. In the current study by Zhao et al, long-term exercise is found to be associated with expanded brown adipose tissue (BAT) in mice ⁴. While the canonical function of BAT is for thermogenesis, authors found removing BAT surgically diminished the protective effects of exercise, implying a BAT mediated cardio-protective role. This notion was confirmed by the loss of exercise-associated cardioprotection in mice after genetic inhibition of sEV production from BAT. The direct effect of sEVs is further demonstrated by intramyocardial injection of sEVs prepared from BAT. Using unbiased screening as well as targeted validation, three miroRNA species, i.e. miR-125–5p, miR-128–3p and miR30d-5p were identified among the miRNA species detected in BAT derived sEVs based on their enriched expression in BAT, detected in circulation associated with exercise induced BAT expansion and delivered to heart tissue via sEVs. The functional importance of the three BAT derived miRs was further tested in vitro and in vivo by targeted inhibition using antagomir. Finally, the molecular targets of the three BAT derived miRs in heart muscle cells were identified to be the genes involved in MAPK pathways. Therefore, a new regulatory scheme is emerging that long-term exercise induces BAT expansion with elevates the sEV expression of specific miRs, and sEV mediated delivery of these miRs through circulation to heart muscle confers cardio-protection against ischemia/reperfusion injury by targeted suppression of MAPK activation (Figure 1).

Figure 1:

Illustration of miR containing extracellular vesicles (sEVs) are secreted from from white adipose tissue (WAT) and brown adipose tissue (BAT), delivered through circulation and taken up by cardiomyocytes to promote heart failure or to exert cardio-protection.

sEVs mediated inter-organ crosstalk as revealed in this study appears to be a common and pervasive mechanism for remote cell-cell interactions in mammals ^{10, 11}. It is interesting that adipose tissue is the largest contributor to the circulating sEVs miRs ⁹. Indeed, results from this report also showed the cardioprotective miRs in circulating sEVs were mainly generated from BAT rather than other tissues following long-term exercise. In sharp contrast, a recent study by Gan et al uncovered a white adipose tissue (WAT) derived miR (miR-130b-3p) with a detrimental role in cardiac injury and dysfunction in diabetic mice ¹². Combining together, these two cases highlight the fact that different fat tissues (WAT vs. BAT) appear to generate unique sets of miRs in their sEV products, leading to drastically different pathological outcome. Despite of these compelling evidence, questions remain whether each tissue has signature miRs contributing to the entire pool of plasma sEVs. It is intriguing that browning of WAT following long-term exercise failed to reprogram its sEVs miR expression profile, suggesting that the miR expression in fat derived sEVs are perhaps less plastic than other genes. This limitation may have clinical implications as the human adults have diminished BAT content, particularly over ageing. Equally unclear is whether the uptake of sEVs in heart is a targeted and regulated process or a purely passive event. In fact, heart tissue also secrets its own sEVs actively. While it is plausible to speculate that dynamic secretion and uptake of sEVs serves as an active mechanism to achieve organ-organ crosstalk, the regulatory mechanism governing the specificity of such exchange is still a total mystery. Although authors observed that cultured myocytes in vitro can readily uptake sEVs prepared from other organs (WAT or BAT), the in vivo evidence presented here is still not sufficient to conclude that myocytes are the only cardiac cells responsible for the observed protective benefits from the endogenous or the injected sEVs, and potential contributions from nonmyocyte in heart, including fibroblasts, endothelium and immune cells remain to be determined.

Despite of the limitations, the clinical implications of these observations remain promising ^{13, 14}. For sEVs produced from the “bad” fat (WAT under diabetic condition), targeted inhibition of the payload miRs may attenuate the detrimental effect in heart and serve as a potential therapeutic strategy to treat cardiac injury under obesity condition. For sEV produced from the “good” fat (BAT after long-term exercise), the beneficial miRs may also be developed as therapeutic agents. It is tempting to speculate that combining both strategies by blocking the pathogenic miRs while delivering the protective miRs through exogenous sEVs may achieve maximal therapeutic benefits. However, this concept remains preliminary at this time since the current published studies only provided limited proof-of-concept evidence for clinical translation. If fat derived sEVs are to be developed as therapeutic targets or reagents for heart failure therapies, much work remains to be done and optimized, including the best therapeutic window, delivery route and optimal dosages. Long-term benefits and risks still need to be demonstrated and the molecular mechanisms should be better established. Finally, the findings of FAT derived sEVs in cardio-protection may also offer a potential clue for the long-standing puzzle of “obesity paradox”. It is clear fat is not only equipped with capacity to store/release energy needed to sustain vital function under varies nutrient conditions, but also holds many potent messengers which can be delivered through circulation to exert profound impact in remote organs. The efforts to decode these messengers, like reported here, are just the beginning to uncover the full potential of intercepting these cross-talks for the benefit of human health.