Background

Metabolic syndrome is a cluster of non-communicable diseases includes central obesity, diabetes, insulin resistance, hypertension and dyslipidemia. Prevalence of obesity and diabetes are increasing day by day among children, young and elderly populations both in developed and developing countries [1–3]. A sedentary nature of jobs and high calorie diet mainly western style diet are the main causes of developing obesity and diabetes, consequently metabolic syndrome [1, 4]. Ever increasing obese and diabetes population are causing serious problems for the management of health sector as well as increasing personal health risks [4]. Recent evidence also suggests that increased body fat mass causes cardiovascular diseases and increases morbidity and mortality in human [5, 6]. Dietary modification, for example decreasing the intake of high fat and high carbohydrate could be a possible way of reducing the risk of fat accumulation in the body. In addition, several dietary approaches such as Mediterranean diet or diet containing high amount of fibres, fruits and vegetables would be valuable for the prevention of hypertension, diabetes, dyslipidemia and obesity [7, 8]. Mediterranean diet or fruits and vegetables possess large amount of phenolic or polyphenolic compounds. It is now widely recognized that, phenolic or polyphenolic compounds are strong antioxidant substances and showed anti-inflammatory properties [9, 10]. Some of them are also effective against diabetes, insulin resistance and dyslipidemia [11–15]. Many of them also prevent hypertension and cardiovascular diseases [16]. All these biological activities are mainly regulated by phenolic acid’s ability to scavenge free radicals generated due to excess nutrition supply to the tissues in obesity, or they may regulate the energy homeostasis and inflammatory pathways. This work will thus review the potential health benefit of hydroxycinnamic acid derivatives in obesity and metabolic syndrome and their possible mechanism of action.

Obesity and energy homeostasis, mechanism of fat metabolism

Obesity can be defined as the accumulation of excess fat due to the increased energy intake and lack of energy expenditure. However, World Health Organization uses Body Mass Index (BMI) as a parameter for defining obesity. According to WHO, BMI >30 is considered as moderately obese and BMI > 35 is considered as severely obese in human [17]. Global obesity in young to adult population is increasing tremendously in recent years [18, 19]. Lack of physical movements, sedentary nature of work and consumption of diet containing high carbohydrate and high fat are responsible for the development of obesity [20]. Thus, increased energy expenditure would be a contributing factor to control and manage obesity and related pathophysiological conditions. Mitochondrial biogenesis are the major pathways in various cell types like, liver, adipose tissue, skeletal muscle etc. to increase ATP production and energy expenditure. Decreased mitochondrial function was observed in obesity and metabolic disorder [21–23]. In obese condition, abundance of fuel supply e.g., fatty acid and glucose overwhelm the mitochondrial electron transport chain and increased the superoxide production [24–27]. Mitochondrial biogeneses are regulated via several transcriptional regulatory factors like AMPK, PPAR- γ and PGC-1α [28, 29]. AMPK regulated PPAR-γ and PGC-1α activation stimulated most of the transcriptional signal to increase fatty acid oxidation and mitochondrial function [30–32].

AMPK

AMP-activated protein kinase (AMPK) is a cellular fuel gauge, maintaining intracellular energy balance in mammalian cells [33]. AMPK signalling pathway is activated by elevation of the AMP/ATP ratio due to the decreased ATP synthesis by mitochondria or by increased energy (ATP) expenditure [33]. Glucose deprivation, hypoxia or ischaemia, or metabolic poisons are few factors which may inhibit glycolysis, tricarboxylic acid cycle or oxidative phosphorylation and disturb energy balance by interfering with ATP synthesis, which may trigger activation of AMPK signalling [34]. AMPK activation is necessary for the transcriptional regulation of energy demand. Mice expressing a dominant-negative form of AMPK failed to increase mitochondrial biogenesis in response to energy deprivation in skeletal muscles [35]. In contrast, lipid oxidation and mitochondrial activity was increased in mice over expressing the phosphorylated AMPK [36, 37]. Several ligands such as thiazolidinediones (for example, rosiglitazone) and biguanides (metformin) both activates AMPK [38]. Thiazolidinediones and biguanides inhibits complex I of the mitochondrial respiratory chain and elevates cellular AMP/ATP ratios [39]. Furthermore, mice fed with AMPK agonists increased oxidative gene expression, enhanced endurance capacity and gave protection against metabolic disease [40, 41]. AMPK can also be activated by metabolic stresses such as muscle contraction or hypoxia, and modulated by hormones and cytokines affecting whole-body energy balance such as leptin, adiponectin, resistin, ghrelin and cannabinoids [33].

PPAR- γ

AMPK activation increased the fatty acid oxidation through activating the PPAR-γ and PGC-1α [42]. Peroxisome proliferator activator protein-γ (PPAR- γ) is highly expressed in adipose tissues [43]. The expression of PPARγ in liver is very low compared to the level present in adipose tissue [43–45]. The actions of PPAR-γ are mediated by two protein isoforms, PPARγ1 and PPARγ2 [46]. PPARγ1 is widely expressed while PPARγ2 is restricted to the adipose tissue only [46]. Fatty acids binding activates PPAR-γ [46]. Activation of PPARγ is necessary for adipocyte differentiation and fatty-acid storage [43, 44]. PPAR-γ deficient mice are devoid of adipose tissue and PPAR-γ +/− mice are characterized by a decreased adipose tissue mass [47, 48]. PPAR-γ is also important for anti-inflammatory pathways, lipid metabolism and regulates genes taking part in the release, transport and storage of fatty acids [49, 50]. Moreover, PPARγ is also responsible for the improvement of insulin resistance and plays an important role in glucose homeostasis. Mice lacking PPARγ in fat, muscle, or liver are predisposed to develop insulin resistance [51–54] while mice with increased PPARγ activities are protected from obesity-associated insulin resistance [55]. PPARγ is a ligand activated protein, thiazolidinediones are considered as the activator of PPARγ [56]. However, thiazolidinediones are adipogenic and responsible for moderate weight gain in patients taking thiazolidinediones [50, 57].

PGC-1α

Peroxisome proliferator activator protein-γ co-activator-1α (PGC-1α) is another regulator of lipid and glucose metabolism. AMPK regulates PGC-1α at both gene and protein level [36]. PGC-1α directly co-activates multiple transcriptional factors such as the PPARs or the thyroid hormone receptor, glucocorticoid receptors and estrogen receptors [29, 58]. PGC-1α also increases mitochondrial biogenesis and respiration rates, as well as the uptake and utilization of substrates for energy production [59]. In brown adipose tissue (BAT), cold induces PGC-1α protein expression that controls adaptive thermogenesis [59]. Furthermore, fasting induces hepatic PGC-1α expression and increases gluconeogenesis, whereas in skeletal and cardiac muscle, exercise increases PGC-1α mediated mitochondrial biogenesis and respiration [60]. Phenolic compound resveratrol increased the PGC-1α activity and increased running time and consumption of oxygen in muscle fibers in mice [61]. Moreover, resveratrol increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma co-activator-1α (PGC-1α) activity, increased mitochondrial number, and improved motor function in middle-aged mice fed a high-calorie diet [62].

Inflammation and obesity

Inflammation is a protective response mechanism for tissue injury. Both acute and chronic inflammatory responses are responsible for the development of diabetes and insulin resistance [63, 64]. Recent research findings suggest that chronic low grade inflammation is developed in obese individuals and triggers adipocyte dysfunction [65]. Moreover, adipose tissues are playing a major role in secreting pro-inflammatory and inflammatory cytokines during obesity [66]. Pathologic growth of adipocyte houses many of inflammatory cytokines like TNF-alpha and IL-6 [67]. Inputs into this inflammatory response further stimulate ER stress, adipose tissue hypoxia, and adipocyte death [68–70]. Macrophage numbers in adipose tissues are also increased with obesity where they mainly scavenge the dead adipocytes [71, 72]. Macrophages are also responsible for the cytokine production in obese adipose tissues [73].

Hydroxycinnamic acid derivatives overview

Hydroxycinnamic acid derivatives (Fig. 1) comprise a large group of simple phenolic acids, found mainly in cereals, fruits and vegetables. A review has been published recently describing the occurrence, biosynthesis, and pharmacokinetics of hydroxycinnamic acid derivatives [74]. Ferulic acid, caffeic acid, p-coumaric acid, chlorgenic acid, sinapic acid, curcumin, and rosmarinic acid belongs to this important phenolic acid group. Hydroxycinnamic acids are abundant in fruits, vegetables and cereals and seeds of fruits [74]. In plant, hydroxycinnamic acid derivatives are synthesized by following the mavolonate and shikimate pathways where phenylalanine and tyrosine are two starter precursor molecules [74, 75]. Following several intermediate enzymatic process, shikimate pathways produced cinnamic acid, p-coumaric acid, caffeic acid, ferulic acid, sinapic acid to various complex lignin molecules [74, 75]. Hydroxycinnamic acid derivatives are also serving as precursor molecules for the stilbenes, chalcons, flavonoids, lignans, and anthocyanins [74].

Fig. 1
figure 1

Structures of hydroxyl cinnamic acid derivatives. Cinnamic acid, p-caumaric acid, ferulic acid, caffeic acid, chlorgenic acid, rosemarinic acid

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HCAs are absorbed easily from the stomach and intestine depending on their structure and compared to other complex phenolic compounds [76]. Ferulic acid and p-coumaric acid are also absorbed from intestine, jejunum, ileum and colon of rats [74]. However, chlorgenic acid, ester of caffeic and quinic acid, first hydrolysed and free caffeic acid is absorbed from the intestine [76]. In Caco-2 cell monolayers, caffeic acid demonstrated that monocarboxylic acid transporters (MCTs), a transport system present across the intestinal epithelial cells, may be involved in the absorption process [77, 78]. p-Coumaric acid and ferulic acid also followed the same monocarboxylic acid transporter (MCT) system to cross the intestinal epithelium [77, 78]. However, passive diffusion mechanism is also important and not ignored for the absorption of ferulic acid in the stomach and Caco-2 cells [75, 79]. In addition, involvement of a Na+-dependent, carrier-mediated transport process are also involved in the uptake of cinnamic acid and ferulic acid across the brush border membrane of rat jejunum [80]. Bioavailability of cinnamic acid derivatives are reviewed recently [74, 76]. Various cinnamic acid derivatives can be found in plasma immediately after the oral administration and may show various health benefit in different diseases (Fig. 2).

Fig. 2
figure 2

Health benefit of cinnamic acid derivatives in various diseases

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Effect of Hydroxycinnamic acid derivatives on various parameters of Metabolic syndrome

Effect of hydroxycinnamic acid derivatives in Inflammation

Hydroxycinnamic acid derivatives showed anti-inflammatory properties both in vitro and in vivo [81]. Ferulic acid prevented the production of TNF-alpha and decreased Macrophage inflammatory protein-2 (MIP-2) levels in lipopolysaccharide (LPS)-stimulated RAW264.7 cells [82]. The transcription factor nuclear factor kappa B (NF-κB) plays a critical role in stress, immune, and inflammatory responses. Ferulic acid in cereals inhibits NF-kB activation [83]. Salt of ferulic acid, ferulate, exhibited antioxidant action by maintaining redox regulation, suppressing NF-κB activation and modulating the expression of NF-κB-induced, proinflammatory COX-2, iNOS, VCAM-1 and ICAM-1 in aged Sprague–Dawley rats [84]. NF-kB suppression by ferulate is mediated via suppressing the activation of NIK/IKK and MAPKs [84].

p-Coumaric acid prevented the increased cell-mediated immune responses and macrophage phagocytic index in rats [85].p- Coumaric acid also decrease in the expression of inflammatory mediator TNF-α and circulating immune complexes in adjuvant induced arthritic rats [85]. p-Coumaric acid also inhibited the TNF-α-induced changes in levels of monocyte chemoattractant protein-1 (MCP-1), plasminogen activator inhibitor-1 (PAI-1), and intracellular reactive oxygen species (ROS) in 3 T3-L1 adipocytes [86]. Furthermore, p-coumaric acid increased the secretion and concentration of adiponectin, superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GPx), and glutathione S-transferase (GST) in TNF-α-treated 3 T3-L1 adipocytes [86].

Caffeic acid phenetyl ester (CAPE) non-selectively inhibited the activities of baculovirus-expressed hCOX-1 and hCOX-2 enzymes and inhibits prostaglandin synthesis and COX 2 in the rat carrageenan air pouch model of inflammation [87]. Caffeic acid and some of its derivatives such as caffeic acid phenetyl ester (CAPE) and octyl caffeate showed anti-inflammatory activity both in vitro and in vivo [88]. Caffeic acid derivatives suppressed the iNOS expression and prevented the production of NO from RAW macrophage cells. Moreover, butyl, octyl and CAPE derivatives of caffeic acid inhibited carrageenan-induced paw edema and prevented the increase in IL-1β levels in the mouse paw [88]. Butyl, octyl and CAPE derivatives also prevented carrageenan-induced neutrophil influx in the mouse paw [88]. Caffeic acid supplementation reduced the inflammatory cytokines interleukin (IL)-beta, IL-6, tumor necrosis factor (TNF)-alpha and monocyte chemoattractant protein (MCP)-1 concentration in diabetic mice [16].

Chlorogenic acid, the ester of caffeic acid with quinic acid blocked UVB- or TPA-induced transactivation of AP-1 and NF-κB in JB6 P+ cells [89]. CGA inhibited lipopolysaccharide (LPS)-induced inflammatory response in RAW 264.7 cells mediated by decreasing cyclooxygenase (COX-2) at protein and mRNA levels and decreased the secretion of prostaglandin E2 (PGE2) [90]. Chlorogenic acid also inhibited LPS induced inflammation of liver in mice and prevented the mRNA expression of toll-like receptor 4 (TLR4), TNF-α and NF-κB p65 subunit [91].

Effect of hydroxycinnamic acid derivatives on lipid and fat metabolism

Elevated plasma concentrations of total cholesterol (TC) and low density lipoprotein (LDL) cholesterol (and/or reduced high-density lipoprotein [HDL]) are commonly seen in dyslipidemia and strongly associated with cardiovascular disease, peripheral vascular disease and stroke [92]. High fat diet feeding in laboratory animals showed dyslipidemic condition similar to human dyslipidemia. Several plant based compounds e.g., plant stanols and sterols, tea-based catechins and theaflavins showed improvement in lowering plasma lipid profiles; however the clinical efficacy of many of these substances are not well studied [93]. Most of the hydroxycinnamic acid derivatives are effective against fat deposition and lowered plasma lipid profile and increases fat metabolism in liver (Table 1). Polyphenol rich red wine improved plasma lipid profiles by increasing HDL cholesterol levels, improve LDL oxidation [94] and improved the antioxidant status by reducing the oxidative stress in patients [95].

Table 1 Lipid lowering effect of hydroxycinnamic acid derivatives
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Cinnamic acid derivative supplementation lowered the plasma and liver triglycerides and cholesterol concentrations in high cholesterol fed rats [96]. Ferulic acid supplementation also lowered plasma lipid and cholesterol concentrations in various model of dyslipidemia such as C57BL/6 mice fed with high fat diet [97], Golden syrian hamsters fed with chow-based hypercholesterolemic diet [98], stroke-prone spontaneously hypertensive rats [99], apolipoprotein E-deficient (apo E−/−) mice fed Western diet [100, 101] and in streptozotocin induced diabetes rats [102]. Chlorogenic acid infusion in diabetic Zucker rats lowered the fasting plasma cholesterol and triacylglycerol concentrations significantly [103]. Chlorogenic acid also lowered the plasma cholesterol in ICR mice fed with high fat diet [15] and lipid, free fatty acids and triglycerides in Streptozotocin (STZ)–nicotinamide (NA)-induced type 2 diabetic rats [104].

Cholesterol lowering effect is attributed to the inhibition of the cholesterol synthesis and utilization of the free fatty acids in liver. HMG-CoA reductase is the rate regulating enzymes found in liver which is responsible for the cholesterol biosynthesis. Several statins selectively inhibited the HMG-CoA reductase in liver and lowered plasma cholesterol in hyperlipidemic patients [105, 106]. Hepatic ACAT is other type of enzymes that increased the utilization of fatty acid for cholesterol biosynthesis. Cinnamic acid derivatives such as cinnamic acid, ferulic acid, chlorgenic acid reduced the HMG-CoA reductase and ACAT activity in experimental animals [96, 101, 15, 104]. Ferulic acid decreased hepatic acyl-coenzyme A: cholesterol acyltransferase activity [100, 101] and down regulates the genes involved in lipid metabolism [99]. Moreover, Chlorgenic acid increased beta-oxidation and lypolitic lipase activity in diabetic animal [15, 104].

Effect of hydroxycinnamic acid derivatives on body weight and obesity

Hydroxycinnamic acids are also effective against body weight gain, fat deposition and dysfunction of the adipocytes due to high fat diet feeding in animal model (Table 2). Adipocyte proliferation and differentiation plays critical role on adipose tissue deposition and dysfunction. 3 T3-L1 preadipocytes are excellent cell lines for studying the anti-obesity effect of various therapeutic agents. Addition of phenolic acids to the growth medium decreased the cell population of 3 T3-L1 preadipocytes in vitro [107]. Chlorogenic acid, o-coumaric acid, and m-coumaric acid caused cell cycle arrest in the G1 phase in 3 T3-L1 preadipocytes [107]. Ferulic acid prevented the body weight gain in high fat diet fed mice and decreased the plasma and liver lipids, triglycerides and total cholesterol [97]. Ferulic acid also decreased the activity of hepatic lipogenic enzymes, such as G6PD, ME, and FAS which are responsible for the cholesterol and fatty acid synthesis [97]. Chlorogenic acid showed anti-obesity effect on mice fed with a high fat diet [15]. Chlorogenic acid also lowered the visceral fat mass and plasma leptin and insulin levels compared to the high-fat control group [15]. Caffeic acid and chlorogenic acid significantly inhibited fatty acid synthase, 3-hydroxy-3-methylglutaryl CoA reductase and acyl-CoA:cholesterol acyltransferase activities, while they increased fatty acid β-oxidation activity and peroxisome proliferator-activated receptors α expression in the liver compared to the high-fat group [15].

Table 2 Effect of hydroxycinnamic acid derivatives on obesity and adipocyte dysfunction
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Effect of hydroxycinnamic acid derivatives on diabetes and insulin resistance

Hyperglycemia and insulin resistance are commonly seen in obesity [108–110]. Polyphenolic compounds showed prevention of metabolic disorder associated with hyperglycemia and diabetes. The mechanisms behind these benefits have multiple targets. Some molecules prevented the beta cell destruction in pancreas thereby increasing the insulin secretion. Others include inhibition of carbohydrate digestive enzymes, increased glycogen synthesis, increased glucose uptake in muscle tissues and adipocytes by phosphorylation of AMPK and increased GLUT4 content as well as increasing glucose metabolism. Hydroxycinnamic acid derivatives also showed considerable hypoglycaemic activities in experimental condition (Table 3). Cinnamic acid improved glucose intolerance and insulin resistance in STZ induced diabetic rats [13]. Cinnamic acid also increased the expression of glycogen synthase, whereas the expression of glycogen synthase kinase and phosphorylation of glycogen synthase at Ser641 in TNF-α-treated insulin-resistant mouse hepatocytes was decreased [111]. Rice bran fraction and ferulic acid reduced the blood glucose concentrations and increased the insulin in plasma of diabetic C57BL/KsJ db/db mice [112]. Glucose lowering effect by ferulic acid was also seen in KK-Ay mice [14] and STZ induced diabetic mice [14]. Ferulic acid also increased glucokinase activity [112] and decreased glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities in liver [113]. Moreover, ferulic acid prevented lipid peroxidation and improved the antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT) [114].

Table 3 Effect of hydroxycinnamic acid derivatives on diabetes
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Caffeic acid has been studied extensively in experimental diabetes and related complications. Caffeic acid lowered blood glucose level in C57BL/KsJ-db/db mice [115] and Streptozotocin (STZ)-induced diabetic rats [116]. Caffeic acid also improved insulin level in plasma of male Balb/cA mice [11] and improved glucose intolerance in high fat diet fed male mice [117]. Caffeic acid improved insulin resistance by promoting insulin receptor tyrosyl phosphorylation, up-regulate the expression of insulin signal associated proteins, including insulin receptor, phosphatidylinositol-3 kinase, glycogen synthase, and glucose transporter-2, increase the uptake of glucose in tumor necrosis factor-α induced insulin resistant mouse liver FL83B cells [118]. Other studies showed that caffeic acid decreased the inflammatory cytokines [119] and reduced the induction of the inflammatory pathway, c-jun-N- terminal kinase, the nuclear factor kappa B, and cyclooxygenase-2 expression [11]. Furthermore, Caffeic acid increased increased phosphorylation of AMPKs and increased glucose uptake and GLUT4 content in L6-GLUT4myc cells [120]. Chlorogenic acid also follows the similar mechanism for improving insulin resistance and diabetes. Chlorogenic acid stimulates glucose transport in skeletal muscle via the GLUT 4 translocation and phosphorylation of AMPK and Akt in db/db mice [121].

Conclusion

Recent research has provided the scientific benefit of these phenolic acids and confirmed the important role of phenolic acids in the prevention and treatment of obesity, diabetes and associated disorders. Phenolic acids could favourably affect most of the leading aspects of obesity including diabetes, including insulin resistance, hyperglycemia, hyperlipidemia, and adepocyte dysfunction and inflammation (Fig. 3). Despite the potential benefits of these natural products in preclinical studies, scanty literatures have been found on any beneficial effect from clinical trials of phenolic acids so far. Studies are thus required in humans to confirm the potential benefit of phenolic acids in limiting obesity and other associated disorders. Furthermore, multiple approaches are also needed to overcome limited solubility and poor bioavailability of phenolic acids. These include synthesis of phenolic acids derivatives and development of novel drug delivery system and formulations such as nanoparticles, liposomal encapsulation, emulsions, and sustained released tablets. Therefore, enhanced bioavailability and convinced clinical trial results of phenolic acids could bring these promising natural products to the forefront of therapeutic agents for obesity.

Fig. 3
figure 3

Hypothetical representation of fat metabolism in response to hydroxycinnamic acid derivatives

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