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Endocrinology & Metabolism
Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D).
- hepatokines
- myokines
- adipokines
- metabolic disease
1. Introduction
Over the past few decades, the rates of obesity and type 2 diabetes (T2D) have increased worldwide [1]. It is well-known that obesity is an established contributor to T2D, as well as a core component of metabolic syndrome [2,3]. Sedentary lifestyle and the consumption of high-calorie diets are associated with increased risks of obesity and metabolic syndrome, ultimately leading to T2D [1,4,5,6]. At the same time, the level of sedentariness and diet quality are affected by various factors, including stress [7,8]. In this regard, numerous studies have shown that elevated psychological distress is associated with physical inactivity and a high consumption of unhealthy foods, such as foods with a high glycemic index, ultra-processed foods, and snack-type foods, as well as a low consumption of meat, fish, fruits, and vegetables [8,9]. These lifestyle risk factors heavily increase the risks of obesity, metabolic syndrome, and T2D [1,4,5,6]. Therefore, lifestyle modifications have emerged as an appealing approach to treating obesity and T2D.
To maintain energy homeostasis, a complex and delicate network between organs has evolved in higher organisms. Carbohydrates and lipids are the two critical macromolecules that are key components of intracellular storage products for energy production [10]. The metabolism of these macromolecules is interwoven in insulin-sensitive organs, including the liver, muscle, and adipose tissues [10]. Insulin resistance, fat accumulation, and inflammation in these tissues characterize metabolic diseases, such as T2D and obesity. Recently, obesity and T2D have been considered multifactorial and complex metabolic diseases resulting from alterations in the metabolic interorgan crosstalk [11,12]. Interorgan crosstalk can be defined as the broad effects of secreted factors from tissues that may trigger physiological responses in other tissues, affecting homeostasis or the development of diseases [11,13]. Interorgan crosstalk is known to be governed by hormones and metabolites. Nevertheless, recent evidence suggests that organokines are crucial factors in interorgan crosstalk [14,15,16]. Organokines (including myokines, adipokines, and hepatokines) are proteins prominently secreted from specific organs and have been known to have endocrine or paracrine actions [17].
2. Hepatokines
2.1. α2-HS-Glycoprotein (Fetuin-A)
Fetuin-A is a circulating glycoprotein that is abundantly synthesized and secreted from the adipose tissue and the liver [33]. It is a multifaceted molecule functioning in various molecular pathways, including insulin resistance, inflammation, and calcium and bone metabolism [34]. Accumulating epidemiologic evidence suggests that elevated Fetuin-A is associated with obesity [35] and T2D [36]. Reportedly, hyperenergetic, high-fat diet consumption leads to Fetuin-A mRNA synthesis in rats [37] and elevated Fetuin-A in healthy men [38]. Furthermore, palmitate treatment stimulates nuclear factor- κB binding to the promoter region of Fetuin-A [39]. Fetuin-A is a critical inhibitor of insulin receptor tyrosine kinase autophosphorylation, which impairs insulin signaling [40,41]. Many studies observed a positive association between serum Fetuin-A and insulin resistance, risk of T2D, and impaired glucose tolerance [36,42,43]. In mice, the deletion of fetuin led to enhanced insulin sensitivity and glucose clearance with insulin-stimulated phosphorylation of insulin receptor kinase and downstream signaling pathways such as MAPK and Akt in skeletal muscle and liver tissues [44]. Apart from its impact on insulin receptor kinase, Fetuin-A is known to propagate a pro-inflammatory state, promoting insulin resistance. In both monocytes and adipocytes, Fetuin-A treatment significantly increased the expression of pro-inflammatory cytokines with a significant reduction in adiponectin expression [39,45]. Moreover, Fetuin-A is an endogenous ligand that directly binds to toll-like receptor (TLR) 4 and promotes the TLR4-mediated inflammatory signaling pathway [46]. These results suggest that targeting Fetuin-A is a potential therapeutic strategy for treating insulin resistance and T2D.
2.2. Fibroblast Growth Factor 21 (FGF21)
FGF21, predominantly expressed and synthesized in the liver, is suggested as a stress-responsive metabolic regulator [47]. Triglyceride (TG) has been suggested to be a key driver of FGF21 expression in the liver [48]. In humans, plasma levels of FGF21 are known to be increased with insulin resistance in the liver and muscles [49]. Similarly, patients with T2D exhibited an increased level of FGF21 [50], which may be due to the compensatory response for insulin deficiency. Endogenous FGF21 is induced in obese mice and humans in response to elevated cellular stress. Despite high levels of FGF21 in metabolic disease states in the body, exogenous FGF21 administration has been demonstrated to be beneficial in correcting dysregulated metabolism [51]. Intensive research uncovered that systemic administration of high doses of FGF21 strongly prevents or treats metabolic diseases [52,53,54,55]. Similar studies utilizing transgenic mice overexpressing FGF21 mice or FGF21 analog-treated mice showed improvements in multiple metabolic parameters, such as body weight gain, blood glucose, circulating inflammatory cytokines, and adipokines [52,56].
Furthermore, long-term production of FGF21 via administration of AAV8-pAAT-FGF21 targeting the liver reversed the hallmarks of obesity and T2D in high-fat diet-fed mice [50]. A recent clinical trial showed that FGF21 analog treatment for 12 weeks significantly improved lipid profiles with increased adiponectin levels in patients with obesity and T2D [57]. FGF21 improves obesity and insulin resistance by regulating several molecular mechanisms. FGF21 activates the AMPK signaling pathway, suppressing de novo lipogenesis and enhancing fatty acid oxidation, thereby inhibiting TG accumulation in adipose tissues [58]. FGF21 increases browning of WAT by up-regulating uncoupling protein 1 (UCP1) and promotes TG turnover [59]. Notably, FGF21 accelerates TG-derived free fatty acid uptake by tissues by up-regulating low-density lipoprotein receptor (LDLR) expression [60]. There are several known downstream targets of FGF21, such as AMPK and SIRT1 [58]. However, future studies are required to elucidate the downstream targets of FGF21, which possesses the potential of therapeutic targets to treat obesity and T2D.
2.3. Leukocyte Cell-Derived Chemotaxin 2 (LECT2)
Leukocyte cell-derived chemotaxin 2 (LECT2) is a recently discovered hepatokine that plays crucial roles in various diseases, such as obesity [61], T2D [62], liver fibrosis [63], and hepatocellular carcinoma [64]. Studies have reported that hepatic and serum levels of LECT2 are known to be strongly associated with BMI and liver fat in humans [62] and mice [65]. A recent mechanistic study showed that LECT2 treatment markedly suppressed insulin signaling by decreasing the levels of insulin receptor substrate (IRS) and p-Akt in differentiated 3T3-L1 cells [66]. Moreover, LECT2 treatment led to a significant increase in lipid accumulation and inflammation markers, such as NF-κB in 3T3-L1 cells [66]. LECT2 also targets skeletal muscle and causes insulin resistance by activating the c-Jun N-terminal kinase (JNK) pathway in obesity [62]. Conversely, LECT2 knockout mice are strongly protected from developing obesity and liver inflammation following high-fat diet feeding [61]. Additionally, LECT2 knockout mice exhibited a significantly higher level of muscle endurance compared with that in control mice [62]. These studies suggest that LECT2 can be a molecular target to enhance insulin signaling in multiple tissues, such as WAT and muscles.
2.4. Selenoprotein P
Selenoprotein P (SeP) is a widely present extracellular glycoprotein [67,68], and its levels are found to be increased in individuals with conditions, such as NAFLD, T2D, and visceral obesity [69,70]. The liver is the primary site of SeP production, and it is subsequently released into the bloodstream. Studies involving patients with T2D have shown that hepatic SeP expression is associated with insulin resistance [71]. Moreover, when SeP was administered to mice, it hindered insulin signaling and inhibited AMPK activation in the liver. Conversely, depleting SeP in mice resulted in improved insulin sensitivity and glucose tolerance [72].
3. Myokines
3.1. IL-6
Interleukin-6 (IL-6), which is secreted into the bloodstream during muscle contractions, was the first myokine discovered [73]. It is primarily produced by skeletal muscle and its release into the blood increases significantly during exercise, reaching levels up to 100-fold higher than that at rest [74]. Interestingly, IL-6 exerts varying and diverse effects in the body. It promotes myogenic differentiation within skeletal muscle itself and increases glucose uptake by facilitating the translocation of glucose transporter type 4 (GLUT4), a glucose transporter [75,76]. IL-6 also activates 5′ AMP-activated protein kinase (AMPK), an enzyme involved in energy metabolism, leading to increased fatty acid oxidation in both skeletal muscle and adipose tissue [77,78,79]. Of note, IL-6 secretion influences hepatic glucose production, specifically in the regulation of gluconeogenesis, by inducing the expression of PCK1 [80]. In addition, IL-6 secretion is inversely related to plasma glucose levels, suggesting its role in inducing glycogenolysis in the liver under conditions such as overnight fasting when circulating glucose is limited [80]. The effect of IL-6 on glucose production depends on the metabolic state. Notably, mice lacking IL-6 exhibit obesity and glucose intolerance, indicating the beneficial role of muscle-derived IL-6 in metabolic regulation [81].
Another important aspect is the muscle–liver crosstalk, where the exercise-induced expression of CXCL1 is dependent on IL-6 secretion from skeletal muscles [80]. IL-6 plays a crucial role in liver homeostasis. However, its secretion by activated Küpffer cells in the liver is mostly associated with the acute phase of infection [82]. Some studies have shown that IL-6 can impair insulin signaling and disrupt glucose homeostasis through signaling pathways such as JNK1, STAT3, and SOCS3 [83,84,85]. In addition to its metabolic effects, IL-6 also functions as an anti-inflammatory factor by inhibiting the production of tumor necrosis factor (TNF) [81,86,87]. Conversely, in the absence of IL-6, the levels of TNF are elevated. These findings suggest that muscle-derived IL-6 plays a beneficial role in the regulation of metabolic disorders, affecting glucose production during exercise [88].
3.2. Irisin
Irisin is a myokine that acts as a transcriptional co-activator of PGC1α, a master regulator of muscle energy metabolism that is involved in mitochondrial biogenesis, glucose uptake, and fiber-type switching [90,91,92]. The levels of circulating irisin levels have been positively associated with muscle mass, and negatively associated with fat mass, indicating the role of irisin in exercise-induced metabolic adaptation [90]. Following the cleavage of FNDC5, irisin is released from the muscle and circulates in the bloodstream, where it targets white adipocytes in WAT, inducing their transformation into beige cells, and hence leading to increased energy expenditure and potential weight loss [90,93]. The adipose tissue has been recently identified as a source of irisin secretion, with individuals with obesity tending to have higher levels of circulating irisin [94,95,96]. Furthermore, the levels of circulating irisin in humans have been positively correlated with adiposity parameters and insulin resistance markers [96]. Irisin reduces insulin resistance by inhibiting gluconeogenesis and promoting glycogenesis via the PI3K/AKT/FOXO1 pathway in hepatocytes [97]. In conclusion, irisin has multifaceted effects on liver metabolism, including reducing insulin resistance, lipogenesis, and oxidative stress, while promoting glycogenesis and fatty acid oxidation. However, its impact on humans and its role in various metabolic conditions require further investigation to clarify its therapeutic potential and clinical application.
3.3. FGF21
FGF21 is a myokine produced by skeletal muscles that exerts various metabolic functions, particularly in the liver [98,99,100]. It enhances glucose uptake and increases the expression of GLUT1 in skeletal muscle [101]. Activation of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT1) signaling pathway, which is linked to muscle hypertrophy, leads to increased muscle mass, reduced fat mass, and improved overall energy metabolism. Insulin infusion and exercise have been shown to increase the expression and secretion of muscular FGF21 [98,99]. Additionally, the induced expression of FGF21 in muscles has been associated with increased lipolysis, decreased blood glucose levels, enhanced fatty acid oxidation, and WAT browning [102]. Another piece of evidence reinforcing the idea that FGF21 is a myokine was shown to be the increased expression of FGF21 in mice with skeletal muscle-specific overexpression of UCP1 [103]. These findings supported the role of FGF21 as a myokine, which has potential therapeutic implications in T2D and obesity.
3.4. IL-15
IL-15, which is a member of the IL-2 superfamily, is putative myokine produced by skeletal muscles, exhibiting anabolic effects in this tissue [104]. Its levels increase in both muscles and serum after strength training [105,106,107,108]. IL-15 is involved in skeletal muscle growth and has been closely associated with obesity and T2D [109,110]. It enhances glucose uptake in skeletal muscle by increasing the transcription and membrane translocation of GLUT4 through JAK3/STAT3 signaling [111,112]. IL-15 also enhances the activity of PPARδ and PGC-1α, promoting mitochondrial biogenesis and fatty acid oxidation (FAO) in skeletal muscle [113,114,115]. In addition, it has been shown to decrease lipid deposition in preadipocytes and overall WAT mass [104]. Although its presence in the plasma has not been observed, IL-15 might act as a myokine, regulating WAT homeostasis [116,117]. This hypothesis is supported by studies showing an inverse correlation between IL-15, adipose tissue mass, and abdominal adiposity in humans [117]. Overexpression of IL-15 in mouse muscles was reported to reduce visceral fat mass without affecting subcutaneous fat mass [117]. Elevated plasma levels of IL-15 significantly decreased body fat mass without affecting lean body mass or other cytokine levels in mice [117]. These findings indicated that muscle-secreted IL-15 reduces visceral fat mass through the endocrine system, highlighting the role of the muscle–fat crosstalk.
3.5. FSTL
Follistatin (FSTL) is a member of the TGF-β superfamily that serves as a natural inhibitor of myostatin in skeletal muscles [118]. In a mouse model, swimming exercise significantly increased the levels of follistatin in both the plasma and liver tissue. Elevated levels of circulating follistatin were reported to play a role in regulating myostatin levels in skeletal muscles [119]. FSTL-1 is one of the secreted glycoproteins belonging to the follistatin family [120]. Myogenic AKT, a key factor in blood vessel growth and muscle growth, plays a significant role in regulating FSTL-1 [121]. Overexpression of AKT, specifically in the muscle, was shown to lead to increased intramuscular and circulating serum levels of FSTL-1 in both intramuscular and circulating serum. Elevated FSTL-1 levels enhanced endothelial function and revascularization by activating the AKT-eNOS signaling pathway. In human primary skeletal muscle cells, the expression and secretion of FSTL-1 were found to be increased in a differentiation-dependent manner [120]. Furthermore, exercise has been shown to increase the circulating levels of FSTL-1, with the secretion of FSTL-1 being stimulated by IFNγ and IL-1β [120].
4. Adipokines
4.1. Leptin
Leptin is a well-known adipokine primarily secreted by adipocytes into the bloodstream. The levels of leptin in the body have been directly associated with fat mass [122]. In individuals with obesity, the levels of leptin positively correlate with adipose tissue mass, suggesting leptin as a marker of obesity [123]. For instance, Ob/ob mice exhibit characteristics such as increased food intake, decreased energy expenditure, dyslipidemia, obesity, and insulin resistance [124,125]. Leptin also promotes inflammation by enhancing the production of inflammatory cytokines, such as TNF and IL-6 by monocytes, stimulating the generation of reactive oxygen species (ROS), and inducing cell proliferation and migration in monocytes [123,126,127]. In macrophages, leptin activates the JAK2/STAT3 signaling pathway, leading to the production of CC-chemokine ligands [128]. Chronic inflammation and elevated TNFα levels in individuals with obesity and leptin resistance contribute to hyperleptinemia [129,130].
4.2. Adiponectin
Adiponectin is a hormone secreted by mature adipocytes that is inversely correlated with fat mass [131]. Unlike leptin, higher levels of adiponectin have been associated with lower fat mass [131]. The plasma levels of adiponectin are found to be reduced in individuals with obesity, type II diabetes, and insulin resistance, exhibiting an inverse correlation between the levels of adiponectin and BMI [132,133,134]. Adiponectin signaling is involved in increasing insulin sensitivity and has various beneficial effects on metabolism, including reducing adiposity, inflammation, and atherosclerosis [135,136,137]. It affects different target organs, such as the liver, where it decreases gluconeogenesis and insulin resistance [138,139]; skeletal muscle, where it enhances fatty acid oxidation, glucose uptake, and mitochondrial biogenesis [140,141]; and the brain, where it stimulates energy expenditure [136]. Adiponectin also plays a role in enhancing glucose uptake and fatty acid oxidation in skeletal muscle and suppressing glucose production in the liver through the activation of AMPK [141,142]. Moreover, adiponectin stimulates insulin secretion, whereas its deficiency leads to dysfunction of pancreatic β-cells [143]. The expression of adiponectin by adipocytes is decreased in individuals with obesity, while it is also inhibited by pro-inflammatory cytokines, such as TNF and IL-6, as well as conditions such as hypoxia and oxidative stress [144,145,146].
4.3. TNFα
Tumor necrosis factor-α (TNFα) is an inflammatory cytokine predominantly produced by monocytes and macrophages. In individuals with obesity, the macrophage-infiltrated visceral fat becomes a major source of TNFα production [147,148]. Increased expression of TNFα has been observed in the adipose tissue of humans and mouse models of obesity and T2D [149,150]. In ob/ob mice, deletion of TNFα or obesogenic diet leads to a reduction in insulin resistance and improvement in insulin signaling in the WAT and muscles [150]. Furthermore, this cytokine has been associated with reduced insulin sensitivity and decreased levels of anti-inflammatory cytokines in visceral fat obesity [151,152]. Patients with diabetes often exhibit elevated levels of TNFα in their plasma and muscles [153,154,155]. TNFα negatively affects insulin signaling by attenuating the insulin-stimulated tyrosine phosphorylation of the insulin receptor and insulin receptor substrate 1 (IRS1) in the WAT and muscles, leading to insulin resistance [153,154,155,156]. Increased levels of TNFα can stimulate fatty acid uptake in the liver, contributing to fat accumulation and the production of ROS [157,158]. Moreover, TNFα promotes the incorporation of fatty acids into diacylglycerol (DAG), suggesting its role in inducing insulin resistance in skeletal muscle [156]. In summary, TNFα is an inflammatory cytokine produced by monocytes and macrophages, and it is involved in the development of insulin resistance by impairing insulin signaling in the WAT and muscles, with visceral fat obesity being a significant site of its production in individuals with obesity. TNFα also influences hepatic fatty acid uptake, leading to fat accumulation and the production of ROS in the liver. Interestingly, its effects on insulin resistance extend to skeletal muscles.
4.4. IL-6
Interleukin-6 (IL-6) exhibits both pro-inflammatory effects as an adipokine and anti-inflammatory effects as a myokine [126,159,160]. The dual functions of IL-6 in different organs can be attributed to different inducers and signaling pathways that stimulate its expression. As a myokine, IL-6 is primarily secreted by skeletal muscles in response to exercise. Muscle-derived IL-6 regulates glucose and lipid metabolism by enhancing the insulin signaling pathway [159]. Conversely, elevated levels of circulating IL-6 have been observed in individuals with T2D, obesity, and insulin resistance [161,162]. As an adipokine, IL-6 has been positively correlated with BMI, with approximately one-third of circulating IL-6 originating from the adipose tissue. Notably, visceral adipose tissue is a significant source of IL-6 in relation to obesity [163,164,165]. In the adipose tissue, IL-6 expression is predominantly produced by macrophages, with its expression being induced by the activation of the NF-κB signaling pathway [163]. Furthermore, IL-6 hampers insulin signaling and reduces insulin-dependent glucose uptake by inhibiting the expression of GLUT4 and IRS1 in adipocytes [166,167]. In summary, IL-6 exerts distinct roles as an adipokine and myokine. Its myokine activity contributes to metabolic improvements, whereas its adipokine activity, particularly in the visceral adipose tissue, is associated with insulin resistance and metabolic disorders. However, further investigations are required to elucidate the underlying mechanisms and potential therapeutic implications of IL-6.
4.5. RBP4
Retinol binding protein 4 (RBP4) is primariily secreted by hepatocytes and functions as a carrier for transporting retinol from the liver to peripheral tissues [168]. However, it has also been identified as an adipokine secreted by adipocytes and macrophages [169,170].The levels of circulating serum RBP4 are elevated under insulin-resistant conditions. Visceral adipose tissue is a major source of increased levels of serum RBP4, which have been associated with a higher BMI [171,172]. Moreover, elevated levels of serum RBP4 have been linked to adverse health effects including increased blood pressure and plasma levels of cholesterol and triglycerides [171,173]. Consequently, RBP4 is considered as a marker of intra-abdominal fat accumulation and inflammation associated with obesity. Adipocyte-derived RBP4 acts in an autocrine or paracrine manner to inhibit the insulin-induced phosphorylation of IRS1 [170,174]. Studies showed that adipocyte-specific Glut4 knockout mice exhibited increased expression levels of RBP4 in the WAT, contributing to glucose intolerance and insulin resistance [170,171].
5. Organokines and Dietary Interventions
5.1. Caloric Restriction
Caloric restriction (CR) is defined as reducing calorie intake below energy demands without eliminating of essential nutrients [175,176,177]. CR has emerged as a popular approach to treating T2D and obesity. Extensive studies have reported the effectiveness of CR in regulating organokines (hepatokines, myokines, and adipokines), thereby ameliorating the pathophysiology of obesity and T2D. In patients with T2D, CR intervention for 12 weeks significantly down-regulated circulating fetuin-A concentrations, resulting in improved blood pressure, plasma glucose, visceral fat, and lipid profiles [178]. FGF21 is a fasting-induced hepatokine that is gaining attention as a metabolic regulator [52]. A methionine-restricted diet was shown to increase hepatic FGF21 [179]. In addition, in a preclinical study, Fgf21-/- mice exhibited increased high-fat (HF) diet-induced inflammation in the WAT and the liver compared with that in wild-type (WT) mice, while a methionine-restricted diet reduced inflammation in an FGF21-dependent manner [180]. This suggests that the methionine-restricted diet restored endogenous FGF21 and protected against HF diet-induced inflammation in the WAT and liver. Likewise, it was demonstrated that a leucine-deprived diet markedly reduced body weight and induced browning in WAT by increasing hepatic FGF21 gene expression in mice [181]. Despite these beneficial effects of methionine and leucine-restricted diets, prolonging one essential amino acid-deficient diet can jeopardize the animal’s health [182,183]. Methionine has been reported to be crucial for normal metabolic processes [184] and immunity, such as T-cell activation and differentiation [185,186]. Recent studies showed that methionine restriction aggravated tumor progression by repressing T-cell activation [187] and impaired the protein synthesis of translation-initiation machinery and antioxidant enzymes in mice [188]. Furthermore, long-term leucine deprivation led to dramatic weight loss, dysregulation of energy homeostasis, and increased prenatal and neonatal mortalities in mice [182,183]. These studies suggest the importance of seeking the optimal amount of dietary amino acids and an experimental period that can faithfully reproduce the beneficial metabolic effects of methionine and leucine-restricted diets. It is also necessary to consider other factors, such as disease state, to drive the therapeutic benefits of methionine and leucine-restricted diets.
Moreover, information from nutritional studies has indicated that CR can improve organokines in relation to inflammation. Other studies showed that circulating levels of amyloid A protein, interferon-gamma (IFN-γ), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) were prominently reduced in patients with obesity by CR [189,190]. Notably, a randomized controlled trial of CR showed that CR significantly enhanced T-cell proliferation (TP) and prostaglandin E2 production [191] while reducing serum CRP levels [192] compared with the levels before CR. These results indicate that CR potentially affects pro-inflammation marker reduction and enhances innate immunity. There are several underlying molecular mechanisms by which CR reduces the inflammatory response. First, CR increases adiponectin, which may affect down-regulates phosphatidylinositol 3-kinase (PI3K)/NF-κB pathways and inhibit the NLRP3 inflammasome [193,194,195]. A CR-mediated increase in adiponectin can also inhibit macrophage differentiation and induce macrophage polarization from the M1 to M2 state [196,197,198]. Moreover, CR increases circulating ketone bodies such as β-hydroxybutyrate (BHB), which is known to block NLRP3 inflammasome-mediated inflammatory responses [199,200].
These studies show that CR, including amino acid restriction, is an appealing approach for combating obesity and T2D. However, there are some limitations. The findings from preclinical studies may be less applicable to humans. For example, the methionine-restricted diets used in preclinical studies included 0.17% methionine. Animal studies showed high adherence to this diet, while clinical studies showed high withdrawal rates due to poor palatability [201]. This review considered the positive effects of CR on improving metabolic profiles. However, several studies produced conflicting results that CR negatively impacts bone health, wound healing, and immune responses [202].
5.2. Dietary Fiber
Dietary fiber consists of highly complex substances such as nondigestible carbohydrates and lignin that cannot be digested in the upper gut [203]. For example, whole-grain, vegetables, legumes, and fruits contain different types of dietary fiber [203]. Accumulating evidence showed that dietary fiber consumption is associated with a low risk of obesity and T2D [203,204]. The fermentation of dietary fiber by the gut microbiome produces high amounts of microbial metabolites, including short-chain fatty acids (SCFAs), succinate, lactate, and branched-chain fatty acids (BCFAs) [205,206]. Several studies demonstrated a link between SCFAs intake and improvements in metabolic phenotypes [207,208]. In subjects with obesity, consumption of vinegar containing 1.5 g of SCFAs (acetic acid), led to a significant decrease in BMI, body weight, waist circumference, and serum triglycerides, demonstrating the role of SCFAs in body weight control [207]. Another intervention study showed that inulin propionate ester intake over 24 weeks significantly decreased weight gain and prevented deterioration in insulin sensitivity in adults who were overweight [208]. Notably, SCFAs have been reported to stimulate the adipose-tissue-derived satiety hormone leptin in mice [209] and humans [210]. The obesity insulin-resistant state is intimately related to chronic inflammation in adipose tissue. Treatment with butyrate, one of the SCFAs, markedly inhibited secretion of pro-inflammatory cytokines, such as IL-6, TNF-α, and MCP-1 in the co-incubation of murine 3T3-L1 adipocytes and RAW264.7 macrophages [211]. Furthermore, propionate treatment of adipose tissue explants obtained from patients who were overweight significantly downregulated inflammatory cytokines such as CCL5 and TNF-α [212]. These results indicate the beneficial role of SCFAs, obtained by fiber intake in preventing obesity and T2D.
5.3. ω3 Polyunsaturated Fatty Acids (PUFAs)
A diet enriched in ω3 polyunsaturated fatty acids (PUFAs) is known to exert beneficial effects on metabolic health in humans. Studies in rodents revealed that ω3 PUFAs contributed to obesity phenotype improvements, including WAT inflammation, insulin sensitivity, glucose tolerance, and colonic inflammation, by targeting gut microbiota [213,214]. Moreover, ω3 PUFA supplementation reportedly improves dyslipidemia and hyperglycaemia [215]. Recent evidence suggests that PUFAs supplementation targets adipose tissues; PUFAs enhanced brown adipose tissue recruitment and WAT browning by increasing uncoupling protein-1 levels and mitochondrial oxidative capacity [216,217,218,219]. Notably, ω3 PUFAs are known to affect several organokines. A recent study showed that ω3 PUFA supplementation (1250 mg thrice/day) markedly increased serum irisin levels in patients with T2D [220]. ω3 PUFA supplementation also led to a reduction in FBS and HbA1C in these patients [220]. In mice, ω3 PUFAs markedly increased FGF21 secretion from brown or beige adipocytes, thereby inducing brown and beige differentiation via GFP120 activation [221]. ω3 PUFAs strongly inhibit inflammatory cytokine secretion in the adipose tissue. In addition, treatment with ω3 PUFAs (DHA and EPA) effectively inhibited inflammatory signaling pathways and improved insulin sensitivity, potentially through GPR120, in obese mice [222].
5.4. Selenium
Selenium is an essential micronutrient for human health [223] and is a crucial constituent in selenoproteins, which have diverse biological functions, including anti-inflammation and antioxidation [223]. Selenoproteins P plays an important role in regulating T2D. A study utilizing selenoprotein P-neutralizing antibodies demonstrated that glucose metabolism is significantly improved in high-energy diet-induced mice [224]. However, low or high selenium supplementation increases insulin resistance by up- or down-regulating selenoproteins in body, suggesting that moderate intake of selenium is crucial [223,225]. Furthermore, selenium supplementation dramatically improved plasma levels of IGF-1, FGF-21, adiponectin, and leptin levels, protecting against diet-induced obesity in mice [226].
5.5. Vitamins
5.5.1. Vitamin D
Vitamin D insufficiency results from inadequate vitamin D intake, high vitamin D catabolism, inadequate exposure to sunlight, and inefficient production in the skin [227]. Vitamin D insufficiency plays a significant role in the pathogenesis of a wide range of metabolic diseases such as T2D and obesity [228,229]. Specifically, vitamin D has been demonstrated to enhance insulin release and decrease insulin resistance in T2D [230]. Vitamin D supplementation has been shown to increase muscle irisin levels and FDNC5 gene expression with increasing serum vitamin D levels in the streptozotocin-diabetic rats [231]. In addition, a recent clinical study showed that 6 months of vitamin D supplementation increased serum irisin levels [232]. The anti-inflammatory effects of vitamin D in various diseases are well-reported [233,234,235,236,237]. For example, 1,25(OH)2D3 markedly inhibits IL-6, leptin, and nuclear factor-κB in human adipocytes [238]. Furthermore, 25-hydroxyvitamin D3 [(25(OH)D3)], but not vitamin D3, effectively suppressed adipokine expression in human adipose tissues [238]. Notably, vitamin D receptor (VDR) deletion from human adipose tissue up-regulated inflammatory signaling activity, suggesting that the anti-inflammatory effects of vitamin D on adipose tissues are mediated by VDR [238]. These results suggest that vitamin D supplementation may improve obesity-associated metabolic complications by inhibiting inflammation in the adipose tissues.
5.5.2. Vitamin A
Retinoic acid, the carboxylic acid form of vitamin A (retinol), has beneficial effects on energy metabolism [239,240]. All-trans retinoic acid (ATRA) is known to modulate gene expressions via retinoid X receptors (RXRs) and the retinoic acid receptors (RARs). Several studies reported that ATRA supplementation reduced leptin expression in the adipose tissues [241], and inhibited body weight gain and adiposity [242]. ATRA regulates the secretion of signaling proteins from adipose tissues, such as leptin and retinol-binding protein 4 (RBP4), to maintain energy balance and insulin sensitivity [243,244,245,246]. Furthermore, ATRA treatment of C2C12 myoblasts increases irisin secretion in a dose-dependent manner [247]. β-Carotene, known as a provitamin A carotenoid, inhibits oxidative stress-mediated inflammation by increasing the secretion of adiponectin in 3T3-L1 preadipocytes, highlighting its role in remodeling of oxidative stress-mediated dysregulated adipokines [248]. Lycopene, a non-provitamin A carotenoid typically found in tomatoes and tomato products, suppresses pro-inflammatory markers in the WAT of rodents and humans [249]. Notably, apo-10′-lycopenoic acid, a metabolite of lycopene, possesses anti-inflammatory effects in WAT via RAR [250]. A recent study utilizing non-target metabolite analysis of tomato revealed that β-carotene and lycopene improved the adiponectin signaling pathway in C2C12 myotubes [251]. Carotenoids, including lycopene and β-carotene, are prominently stored in the WAT [252].This dominant carotenoid and lycopene accumulation in the adipose tissue, followed by diet intervention, can explain the strong anti-inflammatory effects of carotenoids in WAT.
5.5.3. Vitamin B12 and Folate
Vitamin B12 and folate are crucial cofactors for transforming homocysteine to methionine [254,255]. Vitamin B12 deficiency is highly prevalent among patients with T2D [256]. Mounting evidence revealed that vitamin B12 and folate supplementation improved obesity and insulin sensitivity in T2D [257]. Vitamin B12 and folate deficiency can reportedly disrupt adipokine expression [258,259], possibly leading to an increased risk of obesity and cardiovascular diseases. An animal study showed that vitamin B12 and folic acid treatment increased adiponectin and decreased leptin concentration [260]. Furthermore, a recent study showed that early supplementation with vitamin B12 and folic acid improved leptin concentration and the leptin-adiponectin ratio, suggesting the possibility of increased insulin sensitivity [261].
This entry is adapted from the peer-reviewed paper 10.3390/metabo13090979
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