Cardiac-to-adipose axis in metabolic homeostasis and diseases: special instructions from the heart

Adipose tissue is essential for maintaining systemic metabolic homeostasis through traditional metabolic regulation, endocrine crosstalk, and extracellular vesicle production. Adipose dysfunction is a risk factor for cardiovascular diseases. The heart is a traditional pump organ. However, it has recently been recognized to coordinate interorgan cross-talk by providing peripheral signals known as cardiokines. These molecules include specific peptides, proteins, microRNAs and novel extracellular vesicle-carried cargoes. Current studies have shown that generalized cardiokine-mediated adipose regulation affects systemic metabolism. Cardiokines regulate lipolysis, adipogenesis, energy expenditure, thermogenesis during cold exposure and adipokine production. Moreover, cardiokines participate in pathological processes such as obesity, diabetes and ischemic heart injury. The underlying mechanisms of the cardiac-to-adipose axis mediated by cardiokines will be further discussed to provide potential therapeutic targets for metabolic diseases and support a new perspective on the need to correct adipose dysfunction after ischemic heart injury.


Introduction
Adipose tissue, which is the most vital organ that regulates and coordinates systemic metabolism [1], is responsible for lipid storage, energy homeostasis, and whole-body insulin sensitivity [2].Recent evidence has shown that various remote organs are involved in regulating adipose function in endocrine manners, including weight gain [3], fat mass, adipocyte size, lipid metabolism (lipolysis [4] and lipogenesis) and glucose metabolism [3] (glucose level control and insulin sensitivity), adipogenesis [5,6], adipose inflammation [3] and adipokine biosynthesis [7,8].There are currently many secretory components with endocrine regulatory effects, including traditional cytokines and secretory peptides [5], as well as recently discovered extracellular vesicles and their cargoes [9].
The heart is a conventional pump organ that continuously supplies blood to other tissues.Since the discovery of atrial natriuretic peptide (ANP), the heart has been redefined as an endocrine organ that regulates the functions of other organs or tissues by producing and releasing specialized molecules into circulation.In addition to ANP, cardiac tissues also secrete atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), follistatin like (FSTL) 1, angiotensin II (Ang II) and tumor necrosis factor-α (TNF-α), which are known as cardiokines, emphasizing their source.Cardiokines participate in cell growth and death, myocardial hypertrophy, fibrosis and remodeling through autocrine or paracrine regulation [10,11], such as bidirectional endothelial-myocardial sympathetic interactions [12].However, the communication mediated by cardiokines between the heart and peripheral tissues remains unclear.
The past decade's research has increased comprehension of the adipose tissue's role in cardiovascular disease.A large number of studies have confirmed that adipokines (cytokines specifically releasing from adipose tissue) exert protective or deleterious effects on cardiac functions [13,14], especially current fascinating adiposederived extracellular vesicles (EVs) and their cargoes in cardiac regulation (Table 1) .Among them, the most concerned is adiponectin (APN), a well-known metabolic regulatory/cardioprotective adipokine [49].Meanwhile, emerging evidence supports the existence of the "heart-adipose axis" in the human body [11].It has been confirmed that ANP, which is a well-known cardiokine, regulates cardiac lipid metabolism through ANP receptors in cardiac tissue, including lipolysis, energy expenditure, and adipokine synthesis and secretion [50].Under physiological conditions, baseline cardiokines contribute to maintaining metabolic homeostasis [51].Under pathological conditions, damaged cardiac tissuederived cardiokines contribute to metabolic disorders [52], such as heart failure [50], coronary heart disease [53], obesity and diabetes [54].These data suggest bidirectional regulation between heart tissue and adipose tissue.Therefore, this review focuses on the current advances in cardiac-to-adipose communication to provide a novel therapeutic avenue for metabolic disorders caused by adipose dysfunction.

The classification and endocrine manner of cardiokines
Hundreds of cardiokines that can be cardioprotective in an autocrine manner [55] or transferred to various peripheral organs [56], such as the spleen, kidney and skeletal muscle, have been identified, and dozens mediate interorgan interactions between the heart and adipose tissue.Cardiokines can be classified according to different standards.First, cardiokines can be produced and released by several cell types in cardiac tissue, including cardiomyocytes, fibroblasts, endothelial cells, cardiac progenitor cells, adipocytes and cardiac telocytes [57].Among these, cardiomyocyte-derived cardiokines, which are known as cardiomyokines, are the most abundant, followed by fibroblasts and endothelial cell-derived cardiokines.Second, based on their different molecular structures, cardiokines can be divided into peptides, proteins, microRNAs, etc.Recently, extracellular vesicles (EVs) have been demonstrated to be involved in cardiac-adipose communication [58], and their cargos constitute cardiokines.Common cardiac peptides include natriuretic peptides, such as ANP and BNP [59].Cardiac proteins have been studied frequently , including mediator complex subunit 13 (MED13), C1q/TNF-related proteins (CTRPs) [60], fibroblast growth factor 21 (FGF21) [61], FSTL1 and Mitsugumin 53 (MG53), which play vital roles in cardiac-adipose communication.Interestingly, micro-RNAs (miRNAs or miRs) [62], which are small noncoding RNAs that regulate gene expression, have been newly defined as cardiokines because of their enrichment in the heart.Common cardio-enriched miRNAs include miR-208a, miR-22-3p, miR-1956, miR-21-3p, and miR-409-3p [63].Importantly, miRNA-mediated communication typically occurs in an EV-dependent manner.Common cardiokines with different molecular structures and cell sources are detailed in Table 2.
After synthesis and secretion in heart tissue, including cardiomyocytes and cardiac fibroblasts, cardiokines are thought to play roles in situ, in adjacent cells, or even over a long distance to maintain metabolic homeostasis and regulate metabolic disorders such as myocardial infarction (MI) and heart failure (HF) [64][65][66].Here, we mainly discuss the endocrine effects of cardiac tissue and investigate the regulatory effects on adipose tissue; therefore, we focus on how cardiokines are transported to adipose tissue.Cardiokines are released into the blood and can be transported to terminal adipose tissue through the circulation, and an increase in circulating levels of cardiokines has been revealed [67].Then, cardiokines are taken up by adipose tissue, especially adipocytes.Depending on the molecular types, cardiokines are accepted in different ways.Peptides and proteins such as NPs and FGF21 often bind with their specific receptors in adipose tissue, thus mediating subsequent cellular signaling [68,69].Micro-RNAs are typically encapsulated in EVs and can be captured and endocytosed by adipocytes through membrane fusion [58].Consequently, microRNAs are released into the cytoplasm and bind to the 3′UTR of specific mRNAs, resulting in the direct regulation of protein expression in adipose tissue [69].

Cardiokines-mediated physiological and pathological communication
Cardiokines are transported to peripheral organs through the circulation and have various effects on physiological and pathological processes.These cardiokines include previously known adipokines and myokines, such as CTRP9, FGF21 and MG53.CTRPs and FGF21 were first discovered as adipocytokines with powerful regulatory effects on adipose metabolism.In recent years, CTRPs and FGF21 have been newly discovered in cardiac tissue, and there is evidence that these factors can be synthesized and secreted by cardiomyocytes (Fig. 1).Enhancing myocardial oxygen metabolism [27] Decreasing LSG function and neural activity [40] Suppressing ventricular arrhythmia [41] Adipose tissue Adipocyte omentin1 MI-induced HF Ameliorating cardiac function, cardiac hypertrophy, infarct size and cardiac pathological features [28] Increasing

Cardiokines maintain metabolic homeostasis
Under physiological conditions, cardiokine levels remain at baseline to maintain metabolic homeostasis, which is the physiological function of cardiokines, including regulation of lipolysis, adipogenesis, energy expenditure, and thermogenic activity in response to cold exposure and adipokine biosynthesis.

Enhancing adipose energy expenditure
Energy expenditure is essential for cellular energy homeostasis and prevents excessive nutrient accumulation that could lead to pathological conditions such as obesity and type 2 diabetes [70].Cardiokines have been reported to modulate energy expenditure in adipose tissue which involves the proteins ANP, BNP and MED [71].ANP improves energy expenditure, including oxygen utilization, by activating the AMPK pathway [72].Moreover, cardiac-specific overexpression of MED13 enhances oxygen consumption and carbon dioxide production by upregulating multiple metabolic genes in the fatty acid β-oxidation pathway and the Krebs cycle, such as Slc27a2 and DLAT [67].These results suggest that cardiac tissue physiologically regulates lipid metabolism and promotes systemic energy expenditure in adipose tissue through cardiokines.

Promoting lipolysis
Lipolysis is the hydrolysis of triacylglycerols (TGs), and adipose tissue is the most extensive storage site of TGs, suggesting that adipose tissue is the leading site for lipolysis [73].Natriuretic peptides have been shown to regulate lipolysis in adipose tissue [51].As a classical cardiomyokine, ANP modulates physiological lipid metabolism and oxygen utilization in adipose tissue, especially adipocytes [72,74].Beneficial effects on adipose metabolism, including increased lipolysis and mitochondrial oxidative capacity, are mediated by ANP in both human and mouse adipocytes, indicating the promotion of adipose metabolism in physiological situations.

Regulating adipogenesis
When nutrient and calorie intake exceeds energy expenditure, excess calories are stored in the adipose tissue through hyperplasia and hypertrophy.Hyperplasia, which is also known as adipogenesis, is a normal physiological process that promotes the conversion of perivascular preadipocytes into adipocytes [2].Cardiac tissue has been observed to regulate adipogenesis in adipose tissue through these cardiac-derived proteins.Adipogenesis is stimulated by Ang II and suppressed by ANP at physiological concentrations [75].
MEDs are also involved in the regulation of adipogenesis.MED14 participates in PPARγ-dependent adipogenesis in mouse embryonic fibroblasts [76].Moreover, MED23 and its transcription factor ELK1 regulate adipogenesis, and knockdown or antagonization of Med23 or Elk1 inhibits adipogenesis [77].The newly identified cardiokine FSTL1-mediated adipogenesis was verified by its differential expression in preadipocytes and adipocytes [70].Therefore, baseline adipogenesis could be physiologically regulated by cardiokines.

Strengthening adipose browning
Browning of adipose tissue refers to the switch of white adipocytes to brown fat cells, which are also known as beige cells [78], and these cells play a crucial role in regulating thermogenic activity and energy expenditure in adipose tissue.Cardiac tissue is reported to promote adipose browning through cardiokines and is associated with elevated levels of thermogenic gene expression and the consequent enhanced thermogenic activity.Cardiac FSTL1, especially glycosylated FSTL1, might play a major role in adipose browning in maintaining physiological thermogenic activity by activating the adrenergic receptor signaling pathway [79].
Although direct evidence of heart-specific deletion is lacking, cardiokines-mediated cardiac instruction is essential for physiological adipose tissue browning.In CHD models, the cardiomyocyte-derived BNP leads to metabolic disorder and abnormal adiponectin secretion in adipose tissue.At the same time, adipokines in obesity and diabetes play a vital role in insulin resistance, systemic metabolism, lipid metabolism in AT, adipocyte cell size, adipogenesis, adipose tissue browning, the anti-contractile effect, adipose inflammation and angiogenesis in BAT

Enhancing adipokine biosynthesis
Adipokine biosynthesis is crucial for maintaining systemic metabolism.Emerging evidence has revealed the regulatory effects of cardiokines on adipokine synthesis and secretion.NPs increase the synthesis and secretion of adipokines in adipocytes [80,81], indicating metabolic potency of cardiokines in adipose tissue.Both ANP and BNP enhanced the expression of adiponectin transcripts and it secretion in dose-dependent manners [82], and the high molecular-weight (HMW)adiponectin levels in healthy subjects were elevated by ANP infusion [83].All the regulations should be mediated by high-affinity transmembrane NP receptors, which expressed at high levels on adipocytes [81].But the underling molecular mechanism need to be further elucidated.

Cardiokines are involved in metabolic disorders
Contrary to physiological conditions, dysfunctional or injured cardiac tissue synthesizes and secretes abnormal levels of cardiokines, thus leading to disorders in adipose tissue, which are pathological effects of cardiokines under conditions such as obesity, diabetes, myocardial infarction, and coronary heart disease.These abnormal cardiokines include FGF21, miRNAs, EVs and the cargo released from injured cardiac tissue.

Cardiokines in obesity and diabetes
Obesity and type 2 diabetes are often caused by an overload of nutrients and calories, thus leading to subsequent multiorgan dysfunction.Several cardiokines derived from cardiac tissue have been reported to regulate systemic metabolism [84] and insulin resistance and affect adipocyte metabolic and endocrine functions.
(1) Insulin resistance Insulin resistance and systemic metabolic disorder are the common manifestations of obesity and diabetes, which can be regulated by cardiokines.High-fat diet (HFD)-fed mice show significant insulin resistance and increased accumulation of lipid droplets in adipose tissue.Cardiomyokines such as ANP and CTRP9 attenuate HFD-induced glucose intolerance and insulin resistance, which are evaluated by IPGTT and ITT in mice, thus playing a protective role in HFD-induced obesity [85,86].Furthermore, the recently identified cardiokine MG53 might be deleterious to insulin resistance and metabolic syndrome and has a relatively high level in obesity and diabetes by promoting ubiquitindependent degradation of insulin receptor or insulin receptor substrate-1 [54].The detrimental effect of MG53 on insulin resistance is confirmed by the worsening of insulin resistance after cardiac-specific overexpression of MG53 and improvements after treatment with the MG53-specific monoclonal antibody [87].These results suggest the regulatory effects of cardiokines on insulin resistance and systemic metabolic syndrome and provide potential therapeutic directions in obesity and diabetes.(2) Adipocyte hypertrophy Adipocyte hypertrophy is more significant in obesity and diabetes, and there is increased accumulation of lipid droplets, suggesting impaired lipid metabolism in adipocytes.MED13 participates in pathological adipocyte hypertrophy, and lower MED13 level has been observed in obesity and diabetes.In addition, cardiac-specific ablation of MED13 increases susceptibility to obesity [88], while cardiac overexpression of MED13 leads to a lean phenotype [67], which shows the crucial role of MED13 in obesity.MiR-208a is a heart-specific miRNA that acts as a cardiokine [89], in addition to cardiac miR-378 and miR-378* [90].Its expression increases with adipocyte hypertrophy and obesity, and it plays a role in adipose regulation by inhibiting MED13 expression [91].However, a decrease in miR-208a expression increases body weight gain, WAT mass and adipocyte size in adipocytes [92].These conflicting results may be attributed to the differences in target molecules of miR-208a, which are MED13 dependent or independent [89].Therefore, targeting MED13 and its upstream regulators might be beneficial for inhibiting pathological adipocyte hypertrophy in obesity and diabetes.(3) Impaired adipogenesis Significantly impaired adipogenesis has been observed in obesity and diabetes, and CTRP6 and FSTL1 are involved in pathological adipogenesis.Elevated CTRP6 expression is observed in adipose tissue during obesity, which is accompanied by inhibited adipogenesis [93].CTRP6-mediated adipogenesis involves in the inhibition of adipocyte differentiation after CTRP6 overexpression and the restoration after CTRP6 ablation in a PPAR-γ-dependent manner, indicating the possible protective effects of CTRP6 on obesity and diabetes, although CTRP6 depletion is not cardiac specific.In contrast, cardiac FSTL1 has the opposite effect as CTRP6, and an increase in FSTL1 promotes preadipocyte-toadipocyte conversion [94] and enhances adipogenesis in obesity and diabetes [95].A decrease in FSTL1 expression is associated with a reduction in adipogenesis in severe obesity, which is accompanied more severe senescence in preadipocytes and increased apoptosis in adipocytes [96], which conflicts with previous results.A possible explanation may be that FSTL1 is exhausted by the significant senescence of the accumulated preadipocytes in extreme obesity, which leads to exacerbated apoptosis in adipocytes.(4) Limited adipose browning Recent studies have demonstrated that impaired adipose tissue browning in obesity and type 2 diabetes while promoting adipose tissue browning can attenuate pathological changes [78].UCP1 is highly specific in brown adipose tissue and indicates a change in adipose browning.Cardiomyocyte-derived ANP and fibroblast-derived miR-21-3p are involved in the rebrowning of adipose tissue in HFD-fed mice.ANP attenuates HFD-induced BAT whitening by promoting UCP1 expression through activation of the p38 MAPK or GPR120 pathway [85,97], while miR-21-3p, which directly targets FGFR1 in adipose tissue, inhibits adipose rebrowning by repressing UCP1 expression in HFD [69].Consequently, further ANP administration and specific antagonism of miR-21-3p or blockade of miR-21-3p-FGFR1 binding might be effective approaches to promote adipose browning and ameliorate HFD-induced pathological processes.(5) Adipose inflammation Chronic systemic inflammation is an essential feature of obesity and type 2 diabetes and can manifest as adipose inflammation [19], which is modulated by cardiac tissue in an endocrine manner.Cardiokines such as FSTL1 and miR-22-3p exhibit high pathological levels in obesity and diabetes, leading to an abundant proinflammatory profile including IL-6, TNF-α and MCP-1 [95,98].In contrast, in addition to its adipogenic properties, CTRP6 is a proinflammatory cardiomyokine in obese adipose tissue, and an increase in CTRP6 induces the expression of inflammatory genes such as Tnf-α, Ccl2 and Il6, which is further evidenced by gain-and loss-offunction experiments [93].Therefore, inhibiting proinflammatory cardiokines or promoting antiinflammatory cardiokines might be beneficial to adipose homeostasis and would be a novel therapeutic strategy in obesity and diabetes.

Cardiokines derived from ischemic hearts induce adipose dysfunction
Clinical studies have shown that patients with heart failure have local and systemic metabolic disorders, which are characterized by progressive wasting, adipocyte size alternation, and adipokine biosynthesis disorders.Ventricular assist device implantation to restore cardiac function significantly corrects metabolic disorders and adipose dysfunction, indicating cardiac instruction to adipose tissue under pathological conditions [52].The most striking phenomenon is the change of adiponectin (APN) biosynthesis after ischemic heart disease.Lower plasma APN levels were observed in patients with coronary artery disease and acute myocardial infarction, correlated with worse cardiac functional recovery after MI with reperfusion [99][100][101], indicating adipocyte endocrine dysfunction and impaired APN secretion occurred after acute cardiac injury.However, the hypoadiponectinemia usually accompany with heart failure, and hyperadiponectinemia is associated with poor cardiac function and increased mortality in these patient populations [102,103].The mechanism involved in the regulation of adiponectin biosynthesis after acute and chronic ischemic heart disease has not been clearly explained.Recently, our group demonstrated myocardial miR-23-27-24 contributed to the reduced circulating APN levels after MI/R [58], which provided the first evidence that cardiac factors directly lead to adipocyte endocrine dysfunction after ischemic heart injury, and supported the importance of cardiac-to-adipose communication.
In addition, increased serum levels of FGF21 have been observed in patients with acute myocardial infarction (AMI), along with higher serum fatty acid binding protein-4 (FABP4) and saturated fatty acid levels [104].In coronary heart disease patients with heart failure, higher serum BNP levels are commonly associated with higher circulating adiponectin levels [53].Additionally, FGF21 expression is elevated in cardiomyocytes after cardiac endoplasmic reticulum (ER) stress [105], which is accompanied by defective lipolysis and disturbed energy homeostasis [106].These results suggest that adipose dysfunction are closely related with ischemic heart injury, while cardiokines are responsible for heart-to-adipose communication.

Regulatory signaling pathways of cardiokines
Presently, the signaling pathway of cardiokines-mediated heart-adipose tissue communication is not fully understood.Herein, we describe recent research investigating the underlying mechanisms of cardiokines such as ANP, BNP, FGF21, MED13, FSTL1 and miRNAs (Fig. 2), including the cell proliferation-and differentiation-associated, autophagy-associated, inflammation-associated, and exocytosis-associated signaling pathways.

Cell proliferation-associated signaling pathways
Adipocyte proliferation, which is also named adipogenesis, is predominant in the pathological process of obesity and obesity-related diseases, and MED13 levels are negatively correlated with adipocyte proliferation in HFD-induced obesity [91].Kruppel-like factor 5 (KLF5) can upregulate MED13, as it can directly bind to the Med13 promoter and promote MED13 expression.Furthermore, miRNA-208a downregulates MED13 by binding with the MED13 mRNA 3′UTR [89,107] in obesity and diabetes.However, little is known about the relationship between KLF5 and miRNA-208a in regulating MED13-mediated adipocyte proliferation and whether they interact with each other or exert their effects independently.In addition, the EC-derived cardiokine miR-409-3p plays an essential role in EC-BAT crosstalk and inhibits angiogenesis in BAT through the ZEB1/MAP4K3 pathway [108].

Cell differentiation-associated signaling pathways
Adipocyte differentiation, which contributes to adipose browning, regulates the metabolic and endocrine functions of adipose tissue, and PPARγ is a prominent signaling pathway [109].Recently, there have been several upstream regulators of PPARγ, including FGF21 and FSTL1.First, elevated levels of FGF21 in ischemic heart injury, including myocardial infarction, inhibit the phosphorylation of PPARγ, which is the active form of PPARγ, thus suppressing adipose browning in WAT [91].Additionally, the regulatory effect of FGF21 is partly dependent on cardiomyocyte-derived KLF5, as evidenced by cardiomyocyte-specific KLF5-knockout mice.Moreover, cardiac fibroblast-derived miR-21-3p can negatively regulate the expression of FGFR1, the molecule that binds to FGF21, by binding to the 3′UTR of Fgfr1 mRNA [69].This FGF21-FGFR1 mismatch eventually leads to adipose dysfunction.Second, apart from promoting adipogenesis in adipose tissue, N142-glycosylated FSTL1 is essential for PPARγ activation and subsequently leads to adipocyte differentiation into brown adipose tissue [110].In addition, the biological effects of glycosylated FSTL1 might Fig. 2 Underlying upstream and downstream mechanisms of cardiokines that mediate the heart-to-adipose tissue communication.Under physiological conditions, cardiomyocytes are the primary source of cardiokines, including the cardiomyocyte-derived ANP and BNP.Autophagy and cardiac corin regulators ANP synthesis and secretion in cardiomyocytes.When exposed to cold temperatures, ANP down-regulates LDL metabolism by decreasing adipocyte LDLR through the PCSK1 pathway.Meanwhile, cardiomyocyte-derived BNP increases mTORC1 expression and promotes the phosphorylation of S6K1 and S6 through the PKG/p-PKG signaling pathway.While in pathological conditions, cardiokines are derived from cardiomyocytes, cardiac fibroblasts and endothelial cells.EC-mediated miR-409-3p inhibits PLGF expression and angiogenesis in BAT through ZEB1 and MAP4K3 activation.Fibroblast-mediated miR-21-3p suppresses the FGFR1 in adipocytes and impairs the combination of FGF21-FGFR1 through direct binding with FGFR1 mRNA.In addition, the cardiomyocyte-derived FSTL1 inhibits the phosphorylation of PPARγ through the integrin β1-FAK/ERK signaling by the N-glycosylation of FSTL1 in the N142 site.Cardiomyocyte-derived miR-208a decreases MED13 expression by inhibiting MED13 mRNA translation through miR-208a-MED13 mRNA combination rely on the integrin β1-FAK/ERK pathway, but the present evidence is limited, and further research is needed.

Autophagy-associated signaling pathway
Autophagy plays a central role in cardiokine-mediated myocardial-adipose crosstalk in physiological and pathological situations.On the one hand, cardiac autophagy, especially cardiomyocyte-specific autophagy, regulates the physiological synthesis and secretion of cardiokines such as ANP and BNP [111].On the other hand, cardiokines can activate the mTOR signaling pathway via the phosphorylation of S6K1 and S6, which are the downstream targets of mTOR, which is essential for autophagy inhibition [112].Thus, baseline autophagy maintains baseline levels of cardiokines under physiological homeostasis.In general, MAPK acts as an important upstream regulator of cardiac autophagy and subsequent cardiokine-mediated thermogenesis through activation of the p38-MAPK/Ppp1r3c pathway [85].Moreover, there are several downstream regulators of autophagy, including PCSK9, the alpha2 subunit of AMPK, and phosphorylated PKG, that regulate lipoprotein metabolism, lipolysis and adipose browning in adipose tissue [72,112,113].

Inflammation-associated signaling pathways
Excessive adipose inflammation is a vital feature of obesity and type 2 diabetes, and the SIRT1 pathway is essential in adipose inflammation.Moreover, clinical and experimental studies have demonstrated that overexpression of the cardiokine miR-22-3p might upregulate SIRT1 inhibition in a severely inflamed profile in diabetes [98].Unfortunately, gain-and loss-of-function models are lacking, and further research is needed.

Exocytosis-associated signaling pathways
Aberrant exocytosis promotes interorgan crosstalk via vesicle content release through the fusion of the vesicle membrane with the plasma membrane, which depends on cytosolic Ca 2+ concentrations.The high glucoseinduced increase in the expression of the SNARE-binding protein synaptotagmin 7 (Syt7), which is an important Ca 2+ sensor, is responsible for the higher levels of cytosolic Ca 2+ and the increased release of glucose-triggered MG53 via exocytosis [54].

Extracellular vesicle-mediated heart-to-adipose communication
Extracellular vesicles (EVs) are systemic messengers that deliver signaling molecules that mediate intracellular and intraorgan communication.Exosomes and microvesicles, which have different biogenesis pathways and are collectively known as small EVs (sEVs), are two of the most important EV types.sEV biogenesis is greatly enhanced after heart injury [114].Our group demonstrated that small extracellular vesicles (sEVs) from injured mouse cardiomyocytes after myocardial ischemia/reperfusion (MI/R), which exert cardiokine-like effects, induced adipocyte ER stress and adipokine biosynthesis disorders in adipose droplets [58].Inhibition of cardiac sEV biogenesis by GW4869 administration alleviates adipocyte ER stress and restores adipose metabolic and endocrine functions.Further analysis indicates that miR-23-27-24 is an effective molecule in cardiomyocyte-derived sEVs after MI/R that induces adipose dysfunction by suppressing EDEM3 expression.Moreover, cardiac sEVs carrying miR-1956 from the ischemic heart stimulate adiposederived mesenchymal stem cell-mediated proangiogenic paracrine signaling by suppressing Notch-1.These results suggest that EVs, which are essential components of the myocardial secretome, affect adipose function by delivering messengers (cardiokines) from the heart to adipose tissue.In addition, with the progress in sEV isolation and research technology, more powerful evidence will be obtained on the regulation of cardiac sEV generation, cargo sorting and packaging, and vesicle orientation intervention.

Cardiokine-mediated clinical therapy
Although numerous animal experiments have investigated the regulatory effects of various kinds of cardiokines on metabolic and endocrine functions in adipose tissue, limited clinical data are available for cardiokine-mediated therapy in patients.Natriuretic peptides, including ANP and BNP, are the only cardiokines under clinical investigation.NPs enhance lipid metabolism and energy expenditure both in healthy individuals [115] and in heart failure (HF) patients [116], indicating their advantages in maintaining metabolic homeostasis and improving pathological metabolic disorders.Moreover, endocrine function is associated with human ANP administration in patients with congestive heart failure (CHF), which is characterized by a significantly increase in adiponectin in plasma after ANP management in CHF patients [82].There are two main reasons why NPs are the only cardiokines used in the clinic to date.First, NPs are well known, as many animal models have been examined; thus, they could be applied in the clinic.Second, natriuretic peptide receptors (NPRs) are found in human adipose tissue [117], and inhibiting natriuretic peptide clearance receptors seems beneficial to diabetic patients [118], which demonstrates the pivotal role of NPRs in adipose regulation.However, the present clinical studies are limited, and more research regarding other cardiokines is needed.

Conclusion and prospects
In conclusion, cardiokines widely participate in metabolic and endocrine regulation of adipose tissue, including weight gain, systemic metabolism (glucose level, insulin sensitivity, lipolysis), fat mass, adipocyte size, adipogenesis, preadipocyte to adipocyte conversion, adipose browning, and the synthesis and secretion of adipokines.Unfortunately, these studies have focused almost exclusively on the roles of cardiokines on classical white and brown adipose depots, ignoring the adipose tissue with special locations, such as epicardial adipose tissue, pericardial adipose tissue and perivascular adipose tissue.Due to its complex structure and numerous component cell types, their biological roles vary greatly.Therefore, the future studies should fucus on revealing the effect of cardiokines on these special adipose depots.Moreover, we supported that cardiokines played essential roles in adipose metabolism in populations with obesity, type 2 diabetes mellitus (T2DM) and other metabolic-associated diseases, and feedback exacerbated ischemic heart injury through adipokine-mediated instruction [121], forming a vicious cycle.Supplementation or inhibition of specific cardiokines may change the metabolic status in individuals with obesity and diabetes, thus providing a promising treatment strategy.Moreover, in the treatment of heart diseases, blocking cardiokine-mediated adipose dysfunction has a positive effect on reducing cardiac injury and improving prognosis.However, these conclusions are based only on studies in animal models.More research, especially clinical research, is needed in the future.

Fig. 1
Fig. 1 Cardiokines-mediated communication in physiological and pathological conditions.Cardiokines can be divided into peptides, proteins, miRNAs and sEVs.The physiological regulation of adipose tissue includes lipolysis, adipogenesis, energy expenditure, browning of adipose tissue, and the synthesis and secretion of adipokines.While in pathological situations, cardiokine-mediated adipose regulation differs in several diseases.The cardiomyocyte-derived miR-23-27-24 impairs adipose tissue's metabolism and endocrine function by exacerbating adipose ER stress in AMI.In CHD models, the cardiomyocyte-derived BNP leads to metabolic disorder and abnormal adiponectin secretion in adipose tissue.At the same time, adipokines in obesity and diabetes play a vital role in insulin resistance, systemic metabolism, lipid metabolism in AT, adipocyte cell size, adipogenesis, adipose tissue browning, the anti-contractile effect, adipose inflammation and angiogenesis in BAT