Research update on the association between SFRP5, an anti‐inflammatory adipokine, with obesity, type 2 diabetes mellitus and coronary heart disease

Abstract Secreted frizzled‐related protein 5 (SFRP5), an anti‐inflammatory adipokine secreted by adipocytes, has been demonstrated to exert its anti‐inflammatory effect via antagonizing the non‐canonical wingless‐type family member 5A (WNT5A) signalling pathways. The WNT5A protein, as a potent pro‐inflammatory signalling molecule, is strongly involved in a variety of inflammatory disorders such as obesity, type 2 diabetes mellitus (T2DM) and atherosclerosis. In this review, we systematically outlined the current understanding on the roles of SFRP5 in the pathogenesis of three inflammatory diseases including obesity, T2DM and coronary heart disease (CHD). Our review might stimulate future research using SFRP5 as a promising novel therapeutic target for the treatment of obesity, T2DM and CHD.

and myocardial inflammation secondary to ischaemia/reperfusion injury 32 or transverse aortic constriction. 33 As an endogenous inhibitor of WNT5A signalling pathways, SFRP5 has been suggested to play vital roles in obesity, 12 T2DM 12 and CHD. 34 Given obesity and T2DM have been well recognized as two major risk factors of CHD, there must be several inflammatory mediators linking obesity, T2DM to CHD. However, as a novel anti-inflammatory adipokine, it remains unclear whether SFRP5 could be a member of these inflammatory mediators. This review summarizes the roles of SFRP5 in these three inflammatory disorders, respectively. Furthermore, we discussed how SFRP5 may represent a novel link between obesity, T2DM and CHD.

| ROLE S OF S FRP5 IN OB E S IT Y
As a public health issue, obesity, which is characterized by excess of body fat, especially excessive visceral adipose tissue accumulation, is a multifactorial disorder, involving genetics, hormones, diets and environments, and is considered as a state in which chronic low-grade inflammation occurs within adipose tissue. 35 Ouchi et al 12 have observed that in leptin-deficient (ob/ob) mice, Zucker diabetic fatty mice and wild-type mice fed a high-fat, high-sucrose diet for 24 weeks, obesity contributed to lower levels of SFRP5 expression, higher levels of WNT5A expression and an increase in the ratio of pro-inflammatory WNT5A to anti-inflammatory SFRP5. They also measured SFRP5 F I G U R E 1 SFRP5 at the crossroad between obesity, T2DM and CHD. As a member of the non-canonical WNT family of proteins, WNT5A mainly activates WNT5A/Ca 2+ and WNT5A/JNK signalling pathways. One branch of the non-canonical signalling pathways involves the activation of small GTPases Rho and Rac. After WNT5A binds to FzR, activated DSH integrates Rho and Rac into it, respectively. Then, the DSH-Rho and DSH-Rac complexes activate JNK to regulate the PCP pathway. In addition, WNT5A can also bind to Ror2 to directly activate JNK to mediate the PCP pathway. This signalling branch has been shown to regulate cell orientation. Another branch, when activated, leads to PLC-mediated increase in intracellular Ca 2+ levels, which further activates CAMKII and PKC. This signalling branch has been demonstrated to mediate cell proliferation, migration and adhesion. Inflammation plays an important role in this process, which is from obesity, IR and ED to atherosclerosis. As we know, CHD has been regarded as an atherosclerosis-related disease and the development of T2DM is significantly correlated with insulin resistance. Therefore, we propose that SFRP5, as an anti-inflammatory adipokine, might link obesity, T2DM to CHD. Abbreviations: AS, atherosclerosis; CAMKII, Ca 2+ /calmodulin-dependent protein kinase II; CD, cytoplasmic domain; CHD, coronary heart disease; CRD, cysteine-rich domain; DSH, dishevelled; EC, endothelial cell; ED, endothelial dysfunction; FzR, Frizzled receptor; IR, insulin resistance; JNK, C-jun N-terminal kinase; Mac, macrophage; NTR, netrin-like domain; PCP, planar cell polarity; PKC, protein kinase C; PLC, phospholipase C; Ror2, receptor tyrosine kinase-like orphan receptor 2; SFRP5, secreted frizzled-related protein 5; SMC, smooth muscle cell; T2DM, type 2 diabetes mellitus; WNT5A, wingless-type family member 5A expression in visceral fat biopsy specimens of obese patients and found that patients with adipose tissue inflammation showed a decrease in SFRP5 transcript expression compared with obese patients without adipose tissue inflammation. These results suggested that regulation of SFRP5 expression is related to obesity.
Recently, multiple clinical studies demonstrated the relationship between anti-inflammatory SFRP5 and obesity (Table 1) anti-inflammatory SFRP5 level was not significantly altered. These findings provided a novel regulatory system of chronic low-grade inflammation in obesity, which could be affected by nutritional intervention or weight loss.
As mentioned above, pro-inflammatory WNT5A and anti-inflammatory SFRP5 both play pivotal roles in the development of obesity. Therefore, we propose that SFRP5 may exert a protective role in the pathogenesis of adipose tissue inflammation and obesity via non-canonical WNT5A signalling pathway. Importantly, the specific mechanisms remain to be elucidated through a series of basic studies.

| S FRP5 IN THE PATHOGENESIS OF T2DM
Insulin resistance has been identified as one of the important characteristics of T2DM and also been considered as an indispensable factor underlying the pathogenesis of T2DM, which usually precedes the onset of this disease. 42 It has been demonstrated that the development of insulin resistance is linked to a macrophagemediated inflammation of adipose tissue [43][44][45] and is associated with chronic low-grade inflammation. 46 Therefore, it is boldly speculated that SFRP5, which is a novel anti-inflammatory adipokine and also an endogenous inhibitor of WNT5A signalling pathways, might prevent macrophage-mediated inflammation of adipose tissue by antagonizing the WNT5A protein to improve the insulin sensitivity, consequently playing a protective role in the pathogenesis of T2DM.
Intriguingly, a study conducted by Ouchi et al 12

| S FRP5 CONTRIBUTING TO CHD
Atherosclerosis is the basic pathological foundation of CHD. Multiple mechanisms are linked to the pathogenesis of atherosclerosis, including endothelial dysfunction, which is characterized by an imbalance between endothelium-dependent vasorelaxation and vasoconstriction, 52 the migration and proliferation of vascular smooth muscle cells. 53,54 Breton-Romero et al 17  As for clinical studies (Table 1)

| S FRPAT THE CROSS ROAD B E T WEEN OB E S IT Y, T2DM AND CHD
There are multiple papers focusing on the crucial roles of adipokines in constituting a critical link between the obesity, T2DM and atherosclerosis or cardiovascular diseases. 11,56,57 SFRP5, as a novel anti-inflammatory adipokine, might be at the crossroad between obesity, T2DM and CHD (Figure 1). It is known that obesity, especially the central obesity, mainly participates in the formation and development of insulin resistance by affecting the sensitivity of insulin. Moreover, it has been demonstrated that improving endothelial function could ameliorate insulin resistance, whereas improving insulin sensitivity could ameliorate endothelial dysfunction, which suggesting the reciprocal relationships between insulin resistance and endothelial dysfunction. 58 Endothelial dysfunction has been identified as the primary and a crucial step of the development of atherosclerosis. 52,59,60 In addition, inflammation plays an important role in this process, which is also the common disease feature of obesity, insulin resistance and endothelial dysfunction. Therefore, we propose that SFRP5, as an antiinflammatory adipokine, might link obesity, T2DM to CHD.

| CON CLUS I ON S AND PER S PEC TIVE S
In this review, we summarized the indispensable roles of SFRP5, a novel anti-inflammatory adipokine, in the pathogenesis of these three inflammatory disorders, namely obesity, T2DM and CHD. Taken together, we propose that SFRP5 binds to WNT5A and blocks the non-canonical WNT5A signalling pathways, consequently reducing chronic inflammation and exerting its protective effect on reducing/retarding obesity, insulin resistance and atherosclerosis. SFRP5, as an anti-inflammatory adipokine, might link obesity, T2DM-CHD. Thereby, this hypothesis might be of clinical relevance since SFRP5 can be a promising candidate for future treatments of these three inflammatory disorders. Despite ongoing and available research, further studies are required to investigate whether WNT5A non-canonical signalling pathways are the only one to participate in the development of these three inflammatory disorders or not. This is because WNT5A mainly acts on the non-canonical signalling pathways; however, it can also activate the canonical β-catenin signalling pathway in virtue of the receptor availability. 14 In summary, inflammation is the common disease feature of these three inflammatory disorders-obesity, T2DM and CHD, which makes it possible for SFRP5 to be at the crossroad between obesity, T2DM and CHD. Further exploration of the biological functions of SFRP5 may pave the way for it to serve as a potential novel treatment option for obesity, T2DM and CHD.

ACK N OWLED G EM ENTS
Our work was supported by 81670321, 81871105 and 81870270 from the National Natural Science Foundation of China (NSFC).

CO N FLI C T O F I NTE R E S T
The authors confirm that there are no conflicts of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author upon reasonable request.