Metabolic syndrome (MetS) is a cluster of metabolic disturbances including abdominal obesity (elevated waist circumference), hypertension, hypertriglyceridemia, reduced high-density lipoprotein cholesterol (HDL-C) and hyperglycemia, which are some of the major risk factors for developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) [1]. For MetS to be clinically diagnosed, one must have at least three of those metabolic disturbances [1,2,3,4,5]. The occurrence of non-alcoholic fatty liver disease (NAFLD), which is defined by an excessive hepatic accumulation of triglycerides and cholesterol gallstone disease, are two main manifestations of MetS in the liver [1,6]. Moreover, insulin resistance (IR) is one of the crucial factors involved in the etiology of MetS and its comorbidities due to the important role of insulin in regulating energy, glucose, and lipid metabolism [1,7,8]. Therefore, IR is also involved in the pathogenesis of NAFLD, T2DM, obesity and CVD [9]. These conditions are connected by low-grade inflammation, which is a key pathophysiological process in the pathogenesis and growth of disturbances associated with MetS [10]. In that context, the release of pro-inflammatory cytokines and adipokines by immune cells and adipose tissues mediate the state of inflammation in the body leading to IR, exacerbation of NAFLD and development of CVD [9,10].

Microalgae are unicellular and photosynthetic microscopic algae that live in fresh or saltwater which comprise eukaryotic microalgae and prokaryotic cyanobacteria [15,16]. From the human consumption perspective, microalgae are cultivated commercially for application in the food and cosmetic industries. Microalgae biomass and their extracts, such as pigments, carotenoids, fatty acids and proteins, have been incorporated as additives or ingredients in food products such as biscuits, bread, cookies, snacks, milk, yogurt, and pasta [17,18,19,20]. Microalgae are emerging sources of bioactive components such as polysaccharides (especially β-1,3-glucan), carotenoids, pigments and water extracts in cosmetic products namely lotions, creams, shampoos, and soaps that are marketed with anti-aging, UV protective and moisturizing properties [20,21,22,23]. Eukaryotic microalgae such as Chlorella sp., Dunaliella salina, Haematococcus pluvalis, Crypthecodinium cohnii and Shizochytrium, and prokaryotic cyanobacteria such as Arthrospira plantesis and Aphanizomenon flos-aquae are the most popular microalgae species used for human consumption but many other species are yet to be explored [20,24,25].

A cell model representing MetS is yet to be reported in the literature, probably because some MetS criteria are improbable to be measured in a cell-based study. Interestingly, a study has assessed the microalgae-derived products in several cell models that closely recapitulate some MetS criteria in a well-designed study that compared with the positive control drugs (Table 1).

The Peroxisome proliferator-activated receptors (PPARs) such as PPARγ and PPARα, are types of nuclear receptors found in the human liver and adipose tissue, respectively. These are ligand-activated receptors that heterodimerize with retinoid X receptors (RXRs) to regulate gene expression by acting as transcriptional factors [38]. Activated PPARγ modulates the growth and differentiation of adipocytes through the upregulation of lipogenesis and lipid storage genes, and functions to regulate insulin sensitivity by promoting the synthesis of adiponectin and leptin, and improvement of hyperglycemia [39,40,41,42]. In contrast, activated PPARα is involved in the uptake, activation, and oxidation of fatty acids in the liver [41]. Impairment in these PPARs is related to obesity, IR and diabetes mellitus, which are some of the conditions associated with MetS [40]. PPAR agonists such as thiazolidinedione (targets PPARγ) and fibrates (targets PPARα) have been proven to improve insulin sensitivity and hyperlipidemia, respectively [39,40,41,42].

Long-chain fatty acids such as oxo-fatty acids (oFAs) are involved in different physiological processes that appear to be connected to the pathophysiological state caused by obesity such as IR, diabetes, and cardiovascular diseases [43,44,45]. A study has found that oFAs produced by gut bacteria exhibited PPARγ ligand activity which may be used to modulate the host’s energy metabolism [45]. In line with this, (7E)-9-oxohexadec-7-enoic acid [(7E)-9-OHE] and (10E)-9-oxohexadec-10-enoic acid [(10E)-9-OHE], which are two novel oxo-fatty acids identified from the microalgae C. karianus, have been reported to exhibit considerable PPARα/γ agonist activity [41]. Another study found that OFAs produced by gut bacteria have previously been shown to promote the secretion of cholecystokinin (CCK) to improve postprandial glycemia, lipidemia, and appetite but its PPAR agonist activity was not assessed [46].

Sæther et al. investigated the potential of oFAs, [(7E)-9-OHE] and [(10E)-9-OHE] from C. karianus in activating PPAR in hepatocytes and adipocytes [38]. Preliminarily, the dose-dependent effects of both oFAs were studied in COS1 cells (a fibroblast-like cell line derived from African green monkey kidney) treated with (7E)-9-OHE, (10E)-9-OHE, pirinixic acid, rosiglitazone, or palmitic acid for 18 h. The results show that both oFAs produce considerable dose-dependent PPAR agonist activity. In that context, both oFAs demonstrated similar potency as pirinxic acid, which is a positive control, in activating the PPARα receptor. As for PPARγ activation, the oFAs had lower potency and efficacy compared to rosiglitazone which is another positive control but the PPRAγ activation was still higher compared to palmitic acid being the negative control. To determine the endogenous PPAR target genes activated by the oFAs in the liver, Huh-7 was treated with (7E)-9-OHE or (10E)-9-OHE. The results showed that the oFAs treatment was able to activate fatty acid catabolism in hepatocytes. In that context, the oFAs upregulated the expressions of CPT1A and ANGPTL4 due to the activation of the PPARα receptor. Moreover, ACSL3 and PLIN1 genes were significantly upregulated by treating the cells with (7E)-9-OHE and (10E)-9-OHE, respectively. CPT1A gene functions to synthesize the CPT1 enzyme, which is the rate-limiting enzyme for fatty acid β-oxidation, and the ACSL3 gene encodes for acyl-CoA synthetases that convert FAs into fatty acyl-CoA esters which participate in β-oxidation [47,48]. Besides that, the ANGPTL4 gene functions to modulate TG and energy homeostasis according to body state [48,49,50]. ANGPTL4 expression has been shown to improve glucose tolerance and hyperglycemia in diabetic mice which suggests that it can improve glucose metabolism [51]. Lastly, PLIN1 is involved in modulating lipolysis depending on energy requirement, so these genes also regulate lipid metabolism in the liver [52]. The endogenous PPAR target genes activation by the oFAs was also determined in SGBS adipocytes. The SGBS cells were originally pre-adipocytes that were differentiated in an adipogenic medium for 8 days. At day 8, the SGBS cells were stimulated with (7E)-9-OHE, (10E)-9-OHE or rosiglitazone medium for 24 h. The results show that both oFAs induce fatty acid catabolism in adipocytes by upregulating CPT1A expression. In adipose tissue, CPT1A improves fatty acid-induced IR and reduces TG accumulation [47]. Moreover, in SGBS cells treated with (10E)-9-OHE, ANGPTL4 expression was upregulated. Apart from its effect on TG metabolism, ANGPTL4 also functions as an adipokine in inducing adipocyte differentiation and adipose tissue expansion [49]. Overall, the findings suggest that oFAs play a role in regulating adipocyte metabolism but are not as efficacious as the drug, rosiglitazone.

Next, the study compared the adipogenic potentials of the oFAs with rosiglitazone. Here, the SGBS cells were differentiated in a medium containing (7E)-9-OHE, (10E)-9-OHE or rosiglitazone for 12 days in which the medium was renewed every 4 days. The results show that both oFAs increased the number of adipocyte-like cells and total volume of lipid droplets upon Oil-Red-O staining but not as profound as rosiglitazone-treated cells. The author stated that the RNA analysis suggests that the oFAs were able to promote the regulation of fatty acid metabolism, transport, storage, adipokine signaling and browning. In that context, the oFAs upregulated PPARG, CEBPA, CEBPB, PLIN1, FABP4, CD36 and SCD1 gene expressions. CEBPB promotes the expression of PPARG and CEBPA, being the key event in adipocyte differentiation [53]. Meanwhile, the FABP4 gene functions to maintain adipocyte homeostasis [54], while the CD36 gene may play a role in modulating adipocyte hyperplasia and hypertrophy [55]. SCD1 gene produces the rate-limiting enzyme in the synthesis of MUFAs involved in lipogenesis [56]. So, the upregulation of these genes favors adipogenesis. However, these gene expressions were 5 to 10-fold higher with rosiglitazone. The author suggested that with oFAs treatment, only temporary upregulation of crucial adipogenic genes such as PPARG and C/EBPa genes was possible but a more stable expression is exhibited when treated with rosiglitazone. Furthermore, the oFAs upregulate UCP1 gene expression, although not as profoundly as rosiglitazone. The UCP1 gene is crucial in the event of adipose tissue (AT) browning [53]. Adipose tissue can be divided into white and brown. White adipose tissues (WAT) function to store excess energy as TG and release adipokines that are involved in the regulation of energy metabolism. Moreover, brown adipose tissue (BAT) functions as a thermogenic organ and protects against obesity and certain metabolic disturbances. Therefore, adipose tissue dysfunction and/or imbalance in their composition can lead to metabolic derangements [57,58]. Hence, these oFAs have the potential to induce adipose tissue browning that is associated with improvement in dyslipidemia and obesity.

To further reveal the difference between the oFAs and rosiglitazone in stimulating adipocyte differentiation, adipocyte transcriptomic analyses were included in this work. As a result, it was shown that the adipogenic effects of the oFAs were considerable but still lower compared to rosiglitazone. This may not appear ideal since fatty acid uptake and adipogenesis are important effects exerted by PPARγ agonists in the attempt to alleviate dyslipidemia. However, considering the side effects of thiazolidinediones (rosiglitazone) such as weight gain and edema [40], oFAs are still potential substitutes. Furthermore, the oFAs were able to upregulate the expressions of leptin and the insulin-sensitizing adipokine adiponectin (ADIPOQ) genes. Moreover, PPARγ activation by the oFAs is associated with the suppression of pro-inflammatory cytokines gene expressions such as IL-6, TNFa, CXCL1, CXCL5 and IL-1B. Additionally, the expression of IRS1 and SLC2A4 genes was increased. Increased expression of IL-1B is linked to the downregulation of IRS1 and SLC2A4 genes which leads to reduced adipose insulin sensitivity. Therefore, these oFAs are termed as semi-potent dual PPARα/γ agonists and activate anti-diabetic gene programs via suppressing pro-inflammatory cytokines and increasing insulin-sensitive adipokines. As such, dual PPARα/γ agonists activity of the oFAs has the potential to alleviate hyperglycemia and dyslipidemia which are crucial components of MetS.

Many studies have reported the effects of microalgae on the individual components of MetS using obese, diabetic and hypertension animal models. However, these models might not be the best to represent MetS because the status of other components was not evaluated or might not be affected by the component-specific models. Hence, the actual therapeutic potential of microalgae on MetS is difficult to appreciate. Therefore, this section will only include those studies that have established the MetS models by measuring most if not all the parameters that are sufficient to define the presence of MetS and discuss the effects of microalgae on these components (Table 2).