Abstract
Fibroblast growth factors (FGFs) are a superfamily of 22 proteins related to cell proliferation and tissue repair after injury. A subgroup of three proteins, FGF19, FGF21, and FGF23, are major endocrine mediators. These three FGFs have low affinity to heparin sulfate during receptor binding; in contrast they have a strong interaction with the cofactor Klotho/β-Klotho. FGF21 has received particular attention because of its key role in carbohydrate, lipids, and energy balance regulation. FGF21 improves glucose and lipids metabolism as well as increasing energy expenditure in animal models and humans. Conditions that induce human physical stress such as exercise, lactation, obesity, insulin resistance, and type 2 diabetes influence FGF21 circulating levels. FGF21 also has an anti-oxidant function in human metabolic diseases which contribute to understanding the FGF21 compensatory increment in obesity, the metabolic syndrome, and type 2 diabetes. Interestingly, energy expenditure and weight loss is induced by FGF21. The mechanism involved is through “browning” of white adipose tissue, increasing brown adipose tissue activity and heat production. Therefore, clinical evaluation of therapeutic action of exogenous FGF21 administration is warranted, particularly to treat diabetes and obesity.
Introduction
Fibroblast growth factors (FGFs) are a superfamily of 22 proteins associated with cell proliferation, differentiation, migration, and tissue repair after injury [1–4]. A subgroup of three proteins, FGF19, FGF21, and FGF23, showed endocrine effects [5]. FGF19 (FGF15 in mice) is associated with cholesterol and bile acid synthesis [6], FGF21 regulates glucose and lipid metabolism [7]; and FGF23 control phosphorus circulating levels [8]. They were therefore grouped in an endocrine superfamily with particular features [9]. First, in comparison to the remaining FGFs, this endocrine superfamily showed low affinity to heparin sulfate during receptor binding which conferred their endocrine function [10]. Secondly, reduction in the heparin-binding affinity is compensated with a cofactor interaction named Klotho/β-Klotho (Figure 1). This cofactor binds together with the endocrine FGF and its receptor, achieving proper signal transduction at their target tissues [10, 11]. Finally, such factors have been related to clinical consequences after being overexpressed or knocked out in different artificially created animal models or when evaluated in human disease [7, 12–14]. FGF21 has received particular attention because of its key role in carbohydrates, lipids, and energy balance regulation [12, 15], protection against oxidative stress [16], and “browning” of white adipose tissue (WAT) increasing energy expenditure and weight loss [17–19]. Our group was the first to report increased FGF21 levels after intense physical activity in sedentary young women, which was significantly and independently correlated with noradrenaline levels and FFAs, suggesting that increase sympathetic activity and lipolysis was the mechanism that induce FGF21 augmentation [20]. The effect of exercise in FGF21 levels were consistent with other studies [21, 22], as well as the key role of adrenergic activity to induce FGF21 expression [23]. Conditions with high FFAs mobilization or under increased chronic inflammation such as lactation, patients under growth hormone treatment, insulin resistance, heart ischemic disease, hypothyroidism, and kidney failure associated with preeclampsia have higher circulating FGF21 levels [15, 25–29].
Role of FGF21 on energy balance.
Modulators of FGF21 synthesis are prolonged fasting, carbohydrates, protein restriction, increase in oxidative stress and sympathetic activity. Different stimuli that cause supraphysiologic free fatty acid (FFAs) levels, like exercise, increase FGF21 circulating levels. Peroxisome-proliferator-activated receptor-α (PPAR-α) activity is induced by fasting and FFAs. Carbohydrates increase FGF21 promoter expression through carbohydrate response element-binding protein (ChREBP). Protein restriction increases the activity of general control nonderepressible 2 (GCN2)-eukaryotic initiation factor 2 (eIF2) α pathways activating the transcription factor 4 (ATF4) and the transcriptional coactivator protein of PPAR-γ (PGC)-1 α. Oxidative stress markers interact directly with a FGF21 response element increasing FGF21 synthesis. After FGF21 is released into circulation, interacts with its receptor (FGFR) particularly subtype 1c (FGFR1c). However, FGFR is tissue specific. Cell functional response is induced and FGF21 promotes lipid oxidation and ketogenesis as energy source in low glucose environment because starvation. Also, FGF21 increase glucose uptake in periphery and has an important anti-oxidative effect in multiple organs such as liver and kidney. Finally, FGF21 induces “browning” of white adipose tissue (WAT) to brown adipose tissue (BAT), increasing heat production and energy expenditure. This is also induced by brain sympathetic activity and cathecolamines (adrenaline) release.
FGF21 has a similar structure to other FGFs. However, currently it is not considered a FGR as it does not have activity in fibroblasts, and does not promote growth in vivo [30]. Nowadays, FGF21 is considered a key hormone for human energy homeostasis. Also, the pathophysiological role of FGF21 in human diseases such as metabolic syndrome, diabetes, dyslipidemias, and obesity with a potential role as therapeutic target has been suggested. This review focuses specifically on interventions that modulate FGF21 circulating levels and actions in glucose and lipid metabolism as well as energy expenditure. The consequences of different human metabolic diseases and oxidative stress on FGF21 expression is also reviewed. Finally, an update in novel FGF21-based pharmacotherapy is briefly summarized.
Fibroblast growth factor 21 (FGF21)
FGF21 is a 209 amino acid protein in humans which regulates glucose and lipids metabolism. It is synthetized mainly in liver [31] but also in white [32] and brown [18] adipose tissue, skeletal muscle [33], heart [34], and β cells [12]. Action of FGF21 is through cell membrane receptor FGFR1c and β-Klotho interaction (Figure 1) [35–37]. Intracellular signaling is then activated through phosphorylation of FGFR substrate 2 α (FRS2 α), extracellular response kinase 1/2 (ERK1/2), and Akt (protein kinase B) pathways [38, 39].
Conditions that influence human energy balance and physical stress modify FGF21 synthesis and secretion with measurable changes in circulating FGF21 plasma levels. The response elements involved in the regulation of FGF21 expression are shown in Table 1. Because they are numerous and highly interrelated, the regulation of FGF21 secretion is complex and critical for the energy balance.
Relevant transcription factors acting at FGF21 gene promoter.
| Transcription factor | Name | Concise function | Clinical significance |
|---|---|---|---|
| PPAR-γ | Peroxisome proliferator-activated receptor γ | Nuclear receptor regulating fatty acid storage, and glucose metabolism | Physiopathology of cancer, obesity, type 2 diabetes, vascular atherosclerosis |
| PPAR-α | Peroxisome proliferator-activated receptor α | Controls lipid metabolism at liver and is mainly activated under energy deprivation | Metabolic disruption including hypoglycemia, low ketone bodies, and fatty liver |
| MyoD | Myogenic D factor | Regulates muscle differentiation and p21 expression. Induces fast-twitch muscle fiber phenotype. | No clear clinical association. Probably related to muscle-related diseases (i.e. cachexia). |
| STAT3 | Signal transducer and activator of transcription 3 | Transcription activator activated by growth factors and cytokines in response to inflammation or cell proliferation | Hyperimmunoglobulin E syndrome with recurrent infections, bone disorders, auto-inmmune diseases, human cancer, and acromegaly |
| AP-2 α, β, γ | Transcription factor family activating enhancer binding protein 2 | Recruits transcription machinery. It is induced by retinoic acid mainly at liver | Branchio-oculo-facial syndrome (α); Char syndrome (β); early development with fetal death (γ) |
| AP-4 | Activating enhancer binding protein 4 | Repressor and an activator of multiple genes | Unknown |
| CREB | AMPc response element binding protein | Transduction of intracellular signaling associated with AMPc in multiple tissues | Huntington’s disease; Rubinstein-Taybi syndrome; insulin resistance physiopathology, cognition, circadian rhythms |
| Nrf-2 | Nuclear factor (erythroid-derived 2)-like 2 | Expression of antioxidant proteins such as FGF21. | Protects against oxidative damage. |
| SREBP | Sterol regulatory element-binding protein | Cholesterol biosynthesis and uptake of fatty acids | Physiopathology of different lipid abnormalities |
| ChREBP | Carbohydrate-responsive element-binding protein | Binds to DNA in a glucose-dependent manner | Williams-Beuren syndrome |
| NR3C1 | Glucocorticoid nuclear receptor response element | Transactivation and transrepression of target genes | Familial glucocorticoid resistance; neuroendocrine integration; depression; post-traumatic stress disorder; Cushing’s disease |
| ATF4 | Activating transcription factor 4 | Encodes cAMP-response element binding protein 2 (CREB2) | Bone mineralization; reduces oxidative stress. |
| AAREs | Amino acid response element | Enhances ATF2 and ATF4 activity to control mammalian gene transcription | Unknown |
Interventions that modulates FGF21 synthesis and secretion
Fasting
Prolonged fasting was one of the first stimuli to be associated with an important increment on FGF21 liver synthesis in animal models [40, 41]. Prolonged fasting induces lipolysis and free fatty acids (FFAs) release from WAT. Then, FFAs increases peroxisome-proliferator-activated receptor-α (PPAR-α) activity (Figure 1). PPAR-α is a nuclear receptor that response to endogenous signaling ligands such as FFAs, increasing their oxidation and ketone bodies formation as energy source in a carbohydrate deprivation state caused by fasting. The FGF21 promoter has PPAR-α response element which is activated after FFAs/PPAR-α/retinoid X receptor (RXR) interaction (Table 1) [40, 42]. Therefore, increase PPAR-α activity also increases FGF21 liver synthesis and release to circulation in order to improve energy production, increase ketogenesis, gluconeogenesis, appetite, and systemic glucose uptake as adaptive responses to starvation [43, 44].
However, regulation of glucose levels during fasting seems to be different in humans than in animal models. In mice, FGF21 is rapidly induced by fasting whereas in humans, fasting does not consistently increase FGF21 [44–46]. In one recent study, a notable surge in FGF21 occurred after 7–10 days of fasting, and did not drive starvation-mediated ketogenesis like in mice [46]. Also, in humans FGF21 increment was stimulated after decreased thermogenesis, reduction in adiponectin levels, and tissue breakdown markers like transaminases elevation rather than changes in FFAs [46]. Nevertheless, several clinical studies have shown increment in FGF21 levels after other well-known inducers of supraphysiological concentrations of circulating FFAs different than prolonged fasting. Lactation [25], milk ingestion in neonates [17], growth hormone therapy [26, 47], and intensive physical activity [20] increased FGF21 circulating levels, probably through liver PPAR-α activation as well [43, 44] (Figure 1). Mechanisms associated with higher FGF21 expression are inhibition of histone deacetylase 3 enzyme (HDAC3) by sodium butyrate. HDAC3 usually suppress PPAR-α activity by removing acetyl groups. Inhibition of HDAC3, therefore, permits expression of PPAR-α and in turn higher expression of FGF21 [48]. The thyroid hormone receptor β (TR-β) [49], retinoic acid receptor β (RAR-β) [50], retinoic acid receptor-related orphan receptor α (ROR-α) [51], and the cyclic AMP response element-binding protein H (CREBH) [52], mediate liver responses regulating FGF21 expression. FGF21 is a mechanism involved in the cross talk between liver and brain to maintain glucose homeostasis during prolonged fasting. Liver-derived FG21 exerts its action in the FGFR1 of hypothalamic neurons inducing liver gluconeogenesis, the so-called “liver-brain” axis [53]. FGF21 induces direct activation of hypothalamic mitogen-activated protein kinase extracellular signal-related kinase 1/2 (ERK1/2), thus increasing the expression of corticotropin-releasing hormone (CRH) by activation of the transcription factor cAMP response element binding protein (CREB) [54]. CRH increase corticotropin (ACTH) release from anterior corticotroph pituitary cells, which in turn will increase cortisol release from adrenal cortex. Cortisol stimulates liver gluconeogenesis and glucose release, correcting glucose homeostasis. FGF21 and glucocorticoids regulate each other production in a feed-forward loop. Glucocorticoids induce FGF21 expression in liver through glucocorticoid nuclear receptor response element located in fgf21 transcription site (Table 1) [54]. FGF21, in turn, induces glucocorticoids synthesis and release in adrenal gland in response to ACTH. This loop bypasses the negative feedback of glucocorticoids in the hypothalamic-pituitary-adrenal axis in order to sustain gluconeogenesis in liver during starvation [54]. Recently, it has been reported that FGF21 expression is regulated by activating transcription factor 4 (ATF4), a transcription factor activated by various stimuli such as endoplasmic reticulum (ER) stress [55]. ATF4 binds to the amino acid response element (AARE), a binding site for ATF4, in the promoter region of the target genes. The two response elements for ATF4 (AARE1 and AARE2) have been reported in the promoter region of FGF21 gene [55].
Carbohydrates
Carbohydrates also influence FGF21 gene expression. FGF21 increases to overcome the insulin resistance induced by prolonged fasting, but also remains active during early refeeding, therefore maximizing glucose uptake [56]. Then, liver-derived FGF21 expression and release is modulated by carbohydrates through the carbohydrate response element-binding protein (ChREBP) in liver (Figure 1) [57], and ChREBP and PPAR-γ interaction in adipocytes [32, 58]. ChREBP is a central regulator of glycolysis and de novo FFAs synthesis in liver [59]. The beneficial effects on insulin sensitivity observed upon ChREBP overexpression may be due to FGF21 induction [59]. Fructose ingestion also increased circulating FGF21 levels in humans [60]. Recent report also showed metabolic benefit by FGF21 in the liver, modulating the nutrient flux through both carbohydrate [mediated by suppression of a hepatic pyruvate dehydrogenase (PD) complex through PD kinase 4 activity] and fat (mediated by deactivation of acetyl-CoA carboxylase) metabolism [61]. In humans after resting or exercising, FGF21 was regulated depending on splanchnic bed blood flow which in turn modified glucagon-to-insulin ratio stimulating splanchnic FGF21 secretion [22].
Proteins
In addition to starvation, FGF21 expression is regulated by nutritional status such as complete (fasting) or partial deprivation (50% food restriction), when nutrients are over consumed, and also depending on diet amino acid composition [62]. Food restriction causing malnutrition induced FGF21 levels in mice, however, role of the FGF21 increment is not clear since metabolic changes were similar in Fgf21–/– and Fgf21+/+ models under caloric restriction [63], except for the finding that Fgf21 knockout model were resistant to malnutrition-induced reduction of bone growth [64]. In some studies, when caloric restriction did not caused malnutrition, FGF21 was not induced neither in mouse or human subjects [63, 65]. A potential theory therefore is that FGF21 is regulated by specific macronutrients rather than caloric status. As the effect of fasting and ketogenic diet in mice showed impressive induction of liver FGF21 synthesis and secretion, proteins have been studied as FGF21 regulators. In fact, recent reports suggested that reduced protein intake was an important regulator of liver FGF21 production [66]. FGF21 promoter has amino-acid response elements (AAREs) inducing its expression [55, 67, 68]. After amino acid deprivation the general control non-derepressible 2 (GCN2)-eukaryotic initiation factor 2 (eIF2) α pathway is activated inducing binding of activating transcription factor 4 (ATF4) and the transcriptional coactivator protein of PPAR-γ PGC-1 α [45, 67, 68]. PGC-1 α also is induced with exercising. In both conditions liver FGF21 expression is increased [16]. Amino acid composition also changes FGF21 expression. Methionine restriction in mice showed higher FGF21 expression in liver, lower fat mass and better insulin sensitivity [69, 70]. The effects of low protein diet on FGF21 induction was not overcome by carbohydrates suggesting the primarily role of protein intake rather than the reduced carbohydrate ingestion. Also, increment of FGF21 may be influenced by subsequent changes in energy expenditure and decrease in fat mass with protein restriction.
Lipids
FGF21 induces fatty acid oxidation to increase energy production by different substrates than carbohydrates, increasing ketogenesis [43, 71]. As further described below, FGF21 exogenous administration consistently causes reduction in plasma triglycerides suggesting increased metabolism induced by treatment [72, 73]. Lipids utilization is induced by FGF21 in liver and adipose tissue [74–76]. The mechanisms involve are the fatty acids production by adipose tissue which in turn are transformed in triglycerides-rich lipoproteins like very low density lipoproteins (VLDL-c) by the liver, and chylomicrons by the intestine. These particles are metabolized by lipoprotein lipase (LPL) in peripheral organs such as skeletal muscle and adipose tissue. Recent information suggests that FGF21 increase LPL activity in brown adipose tissue (BAT) to induce clearance of such high-triglycerides particles. Also, CD36, a fatty acid scavenger, is induce to improve this process. FGF21 reduced VLDL secretion by liver, increase lipid influx to BAT reducing the lipid flux to other organs, and all this through LPL and CD36 overexpression after FGF21 stimulation, lowering serum triglycerides and increasing their catabolism [77].
Oxidative stress
High carbohydrate or fat diet, obesity, and insulin resistance impairs energy balance increasing reactive oxygen species such as peroxides and free radicals that damage proteins, lipids, and DNA. Interestingly, FGF21 expression increase importantly in conditions related to high oxidative stress. FGF21 expression in heart [34, 78], and skeletal muscle [79, 80], occurs mainly and may be only after mitochondrial dysfunction, exerting cardioprotective effects attenuating heart remodeling, inflammation, and oxidative stress [81]. FGF21 has an anti-oxidant function in animal models and human metabolic diseases related to increase pro-inflammatory proteins and oxidative stress. These recent results contribute to understand the FGF21 increment in humans with obesity, the metabolic syndrome and type 2 diabetes. Furthermore, FGF21 seems to play an important role to reduced lipotoxicity and glucotoxicity to reduce cell dysfunction and apoptosis.
FGF21 expression and synthesis is induced with liver [82–84] and kidney disease [24, 85–87]. Higher FGF21 synthesis and release has been reported in patients with liver resection. Also, FGF21 is induced after lipid load and high hepatocyte intracellular lipid content is demonstrated [82, 83, 88, 89]. FGF21 correlates with genetic markers and serum proteins associated with oxidative stress. Serum markers of oxidative stress in humans are serum anti-oxidative activity, isoprostane, reactive oxygen species, malondialdehyde, and oxidized low-density lipoprotein (LDLox) [90]. Treatment with LDLox in endothelial cells caused mRNA FGF21 and protein overexpression up to 20-fold [91]. FGF21 was then correlated with the nuclear factor erythroid 2-related factor (Nrf2). Nrf2 is a transcription factor that has emerged as a key regulator of cell detoxification when oxidative stress is present [92–94]. The Nrf2 system regulates the cell baseline anti-oxidative capacity and cell response under acute oxidative stress challenge. In vitro studies of multiple human and mice cell cultures have shown increase gene expression of several proteins related to cell protection under oxidative stress challenge. Such genes are activated through Nrf2 transcription activity [95]. In contrast, a Nrf2 knock-out mice model (Nrf2-KO) caused increase cell oxidative stress, high cancer incidence and lung disease among other inflammatory conditions [96, 97]. Nrf2 have shown important functions for cell adaptation to metabolic distress too, for example, after caloric restriction or lipid metabolism with high carbohydrates and fat diet [98]. Nrf2-KO mice also have impairment in adipocyte cell differentiation, reduced adipogenesis, and resistance to diet-induced obesity [99]. Interestingly, overexpression of Nrf2 caused FGF21 gene promoter repression with FGF21 protein synthesis suppression [100]. The Nrf2-KO mice are the only animal model, until now, with increase insulin sensitivity but high FGF21 liver expression and serum levels [100]. These findings contrasted with previous results showing a FGF21 serum levels reduction after insulin sensitivity improvement [7]. A possible explanation has been related to the specific FGF21 gene promoter that has specific transcription factor response elements that are activated after oxidative stress [16]. In one side, the Nrf2-KO mice showed better metabolic profile with resistance to diet-induced obesity, in the other, Nrf2 absence eliminates oxidative-stress protection. Therefore, it is hypothesized that in absence of Nrf2, repression of FGF21 is also eliminated in order to increase FGF21 synthesis and protect against oxidative stress [100]. The Nrf2-FGF21 loop could be a key regulation in human metabolic diseases related to oxidative stress such as insulin resistance, obesity and type 2 diabetes but also in complications such as liver steatosis or diabetic nephropathy. Recent evidence showed, for example, that FGF21 pharmacologic effect corrected diabetic nephropathy in mice, reduced albuminuria, suppress pro-inflammatory proteins with important reduction in oxidative stress markers [85, 101]. Consistently, mitochondrial damage induced by critical illness and inflammatory stress response caused overexpression of fgf21 gene inducing higher serum FGF21 [102]. Moreover, skeletal muscle-specific deletion of ATG7 (encoding autophagy-related 7) caused mitochondrial dysfunction and increased FGF21 expression through induction of ATF4 [63]. The term “mitokine” has been proposed to refer to proteins like FGF21 that showed important over expression with mitochondrial dysfunction [63].
FGF21 role in energy expenditure
FGF21 improves insulin sensitivity through increasing translocation of glucose transporter 1 (GLUT1) to cell membrane in adipose tissue. The consequence is higher glucose uptake with an additive effect to glucose uptake through GLUT4 induced by insulin [7, 103]. In addition to this increment in insulin sensitivity, such a mechanism has also been associated with higher energy expenditure and weight loss [104]. FGF21 overexpression in transgenic mice model was resistant to weight gain after high-fat and high-carbohydrate diet-induced obesity [7]. Exogenous administration of FGF21 as pharmacological treatment reduced weight and fat mass in animal models with obesity and insulin resistance such as ob/ob and db/db mice [104]. Moreover, when FGF21 couldn’t interact with its receptor in the β-Klotho knock-out mice model, overexpression of FGF21 cause less weight reduction [105]. Increased glucose and lipid metabolism with impressive weight reduction were showed in obese monkeys treated with monoclonal antibody directed to β-Klotho/FGFR1c receptor complex confirming FGF21 metabolic benefits on energy balance [106]. Higher adiponectin levels, improvement of insulin sensitivity and lipid profile with higher high-densitiy lipoproteins (HDL) and lower triglycerides was also previously reported with exogenous administration of FGF21 in diabetic monkeys [7]. The mechanism of weight reduction in these different animal models was higher energy expenditure induced by FGF21 rather than less caloric consumption or higher physical activity [104, 107].
“Browning” of WAT
The next question to be responded was how FGF21 induced increment in energy expenditure. The answer was found in BAT activation. BAT is usually present in small mammals and neonates. Then, a progressive loss of BAT in human adults results in a small proportion of BAT (50–80 g) in the organism in comparison of WAT. Human BAT involution was associated with non-significant role in adult human physiology. However, active BAT plays an important role in energy expenditure in humans burning 100 kcal/day equivalent of 5 kg of fat loss per year [108–110]. Positron emission tomography (PET) assays using [18F]-fluorodeoxyglucose revealed the presence of metabolically active adipose tissue in neck and shoulder areas [108–110]. BAT activity is higher in women, induced with cold temperature, lower in obesity, and decrease with aging [111]. Like in mice, human BAT is able to express FGF21, FGFR1c, and β-Klotho, with good correlation with mitochondrial uncoupling protein-1 (UCP1) expression [23, 112, 113]. UCP1 is a key protein to use lipids and glucose for heat production [113]. Mice models knocked-out for UCP1 expression developed obesity as well as overexpression of UCP1 cause diet-induced obesity resistance [114]. Recent studies showed that FGF21 targets BAT to increase heat production activating the oxidative phosphorylation pathway (respiration) and glucose oxidation [17]. Also, genes of those enzymes needed to improve these pathways were induced by FGF21 administration [17, 19, 107]. FGF21 also induce expression of GLUT1 in BAT [17]. After chronic stimulation with FGF21 or hypothermia, BAT developed hyperplasia and if stimulation persists, transformation of WAT to BAT was activated, the so-called “browning” process (Figure 1). There is evidence that FGF21 promotes the transformation of WAT to “beige” and then BAT, particularly in subcutaneous adipose tissue [115].
UCP1 in BAT is necessary to FGF21 energy expenditure promotion. However, when UCP1 is absent in UCP1-null mice, FGF21 decrease appetite and food intake resulting in weight loss as well [61, 116]. Interestingly, UCP1-null mice showed impressive increment in FGF21 levels with very high expression in BAT and WAT [61, 117]. Therefore, FGF21 is an important compensatory mechanism when UCP1 mechanism is diminished, and anti-obesity effect do not necessarily involve the generation of brown adipocytes in WAT and UCP1 activity in mice [116]. Actually, a diet-induced obesity model treated with FGF21-analog showed that significant “browning” of WAT by FGF21 is indeed temperature dependent present only in a cold (21 °C) environment [116]. Under 30 °C temperature, mice also reduce weight and improve glucose metabolism after FGF21-analog treatment but without increasing BAT and UCP1 expression, suggesting other mechanisms different to UCP1 for energy expenditure induced by FGF21 [118]. Consistent with this finding, novel mechanisms were described such as, first, expression of the mitochondrial gene, Ppargc1 that was increased [116], second, increment of the exercise-induced myokines irisin and FGF21 under cold exposure, which in turn increased shivering, thermogenesis, and browning of fat [119]; third, mitochondrial dysfunction because of skeletal muscle–specific deletion of ATG7 that decreased fat mass, accompanied by increased fatty acid oxidation and browning of WAT [63]; fourth, FGF21 induction of PGC-1-α which exerts strong effect on “browning” of WAT [19, 107]. Then, this “new” BAT becomes the target of FGF21 and also a site of FGF21 synthesis and secretion [18, 100]. Further mechanisms proposed are through hypothalamic adrenergic activation by FGF21 to induce BAT thermogenesis activating adenosine monophosphate (AMP) kinase (AMPK) and Sirt-1 (sirtuin protein 1) pathways [58, 120–123]. Patients with pheochromocytoma and very high adrenergic action occasioned by high catecholamine release by tumor showed higher proportion of beige cells in omental WAT with higher expression of FGF21 and UCP1 [23]. Finally, browning of WAT by FGF21 may be related to perilipin 5 (PLIN5). PLIN5 is highly expressed in oxidative tissues and skeletal muscle, in order to increase energy metabolism. Overexpression of PLIN5 increased “browning” factors in adipose tissue through 80-fold higher FGF21 gene expression in muscle with the subsequent increase in serum FGF21 concentration [124].
FGF21 and adiponectin
Initially, mice treated with exogenous FGF21 showed higher adiponectin serum levels [7] and such increment was confirmed in further studies done in monkeys [125]. FGF21 acts in adipose tissue with a key function in glucose and lipid metabolism. First, increase GLUT1 translocation to rise glucose uptake [7]. In addition, FGF21 induces PPAR-γ activation which in turn increased adiponectin expression, particularly after high-fat diet [76, 126]. Adiponectin is a key adipokine consider today the mediator of the favorable metabolic actions of FGF21 [76, 127]. This was confirmed in lipodystrophic mice who showed lack of FGF21 metabolic effects as adiponectin expression is absent [123, 128, 129]. Importantly, FGF21 regulated adiponectin secretion in adipose tissue, but adiponectin does not regulate FGF21 secretion.
FGF21 to combat obesity in humans
Humans with obesity, metabolic syndrome, and type 2 diabetes have higher levels of serum circulating FGF21 levels [12, 112, 130, 131]. This paradox may reflect a FGF21 compensatory response in humans to metabolic disruptions induced mainly by weight increment such as hyperinsulinemia, higher levels of FFAs, increased oxidative stress, and a lower amount of BAT. Unfortunately, this FGF21 elevation in patients with obesity or type 2 diabetes suggests low benefit of exogenous therapeutic FGF21 administration. Nevertheless, FGF21 actions in glucose and lipids metabolism as well as its effects in BAT with potential energy expenditure justifies an opportunity as novel treatment for human metabolic diseases. Multiple different engineering approaches have successfully improved manufacturing of a FGF21 with higher plasma half-life, stability and solubility [132, 133]. PEGylated FGF21 [134, 135], FGF21-antibody conjugates [136], and antibody-based activation of the FGFR/β-Klotho complex [137] are under study. Also, the FGF21 analogs LY2405319 and PF05231023 were tested in two different pilot studies in humans [138, 139]. LY2405319 was administered subcutaneously once daily for 4 weeks in patients with diabetes and obesity. PF-05231023 was administered intravenously in patients with type 2 diabetes. Both drugs showed improvement of glucose levels, lipid profile and weight loss [138, 139]. Administration of PF-05231023 to obese cynomolgus monkeys or in a placebo-controlled, clinical trial in humans with type 2 diabetes showed that ascending doses caused significant decrease in body weight, improved lipoprotein profile, and increased adiponectin level but there were no significant changes in hyperglycemia control [140]. Also, an increased concentrations of bone resorption markers and insulin-like growth factor 1 (IGF-1) was reported. Other FGF21 analogs with potential therapeutic utility are under study, however, development status is unclear [72, 73, 141].
Integrative view of the FGF21 regulation and actions
Initial impression with FGF21 studies in different animal models suggested it main role in glucose uptake at adipose tissue [7]. Then, important energy balance regulation was shown by FGF21 in mice under different conditions such as hypothermia or starvation [41, 43]. Further actions have emerged to date, associating FGF21 as an integrative hormone for multiple actions in mammals’ organism, such as a regulator of insulin, glucagon, leptin, adiponectin, growth hormone, IGF-1, and most recently glucagon-like peptide 1 (GLP1) [142] and their metabolic processes. Recent studies seem to integrate FGF21 actions in the regulation of mitochondrial function which is interesting as it explains multiple if not all the associations between FGF21 and weight, glucose and lipid metabolism, and heat production involving actions in BAT activity as well as human resting or exercising. Also, when these metabolic mechanisms are disrupted by obesity, insulin resistance or type 2 diabetes among others, FGF21 seems to compensate in humans by increasing its circulating levels against oxidative stress. Diseases with higher oxidative stress which are characterized by mitochondrial dysfunction affect FGF21 expression. The clinical translation is that FGF21 is associated with many biochemical, clinical, and tissue parameters associated with energy balance such as the ones summarized here in this review. Today, FGF21 should be seen as a key energy balance regulator acting at a cell mitochondrial function level.
Highlights
The FGF21-β-Klotho pathway switches to oxidative metabolism during fasting and starvation. Currently FGF21 is considered a link between nutrition, heat production, and energy expenditure with human fat mass, body weight, glucose and lipid metabolism.
FGF21 improves glucose and lipids metabolism as well as increases energy expenditure in animal models and humans.
The action of FGF21 is at central and systemic levels, modifying human physiology from brain to periphery at adipose tissue, liver, and skeletal muscle.
Conditions that induce human physical stress such as exercise, lactation, obesity, insulin resistance, and type 2 diabetes influence in FGF21 circulating levels and action.
FGF21 has an anti-oxidant function in animal models and human metabolic diseases which contribute to understanding of FGF21 compensatory increment in humans with obesity, the metabolic syndrome, and type 2 diabetes.
FGF21 has a key role in human metabolism inducing “browning” of WAT, increasing BAT activity and heat production.
As a FGF21 response to different human stressors such as starvation, nutrient excess, autophagy deficiency, mitochondrial stress, exercise, and cold exposure, it has been proposed as a “mitokine” and as a “stress” hormone.
Clinical evaluation of the therapeutic action of exogenous FGF21 administration as novel molecules, analogs, or through antibody-based activation of the FGFR/β-Klotho complex is warranted, particularly to treat diabetes and obesity.
References
1. Gospodarowicz D. Localisation of a fibroblast growth factor and its effect alone and with hydrocortisone on 3T3 cell growth. Nature 1974;249:123–7.10.1038/249123a0Search in Google Scholar PubMed
2. Galzle ZK, Smith JA. Fibroblast growth factors and their receptors. Biochem Cell Biol 1997;75:669–85.10.1139/o97-091Search in Google Scholar
3. Powers CJ. Fibroblast growth factors, their receptors and signaling. Endocrinol Relat Cancer 2000;7:165–97.10.1677/erc.0.0070165Search in Google Scholar PubMed
4. Ornitz DM, Itoh N. Fibroblast growth factors. Biology 2001;2:3005.1–3005.12.10.1016/B0-12-370879-6/00155-1Search in Google Scholar
5. Kuro-o M. Endocrine FGFs and Klothos: emerging concepts. Trends Endocrinol Metab 2008;19:239–45.10.1016/j.tem.2008.06.002Search in Google Scholar PubMed
6. Tomlinson E, Fu L, John L, Hultgren B, Huang X, Renz M, Stephan JP, Tsai SP, Powell-Braxton L, French D, Stewart TA. Transgenic mice expressing human fibroblast growth factor 19 display increased metabolic rate and decreased adiposity. Endocrinology 2002;143:1741–7.10.1210/endo.143.5.8850Search in Google Scholar PubMed
7. Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005;115:1627–35.10.1172/JCI23606Search in Google Scholar PubMed PubMed Central
8. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, Fujita T, Nakahara K, Fukumoto S, Yamashita T. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004;19:429–35.10.1359/JBMR.0301264Search in Google Scholar PubMed
9. Zhang F, Yu L, Lin X, Cheng P, He L, Li X, Lu X, Tan Y, Yang H, Cai L, Zhang C. Minireview: roles of fibroblast growth factors 19 an d21 in metabolic regulation and chronic diseases. Mol Endocrinol 2015;29:1400–13.10.1210/me.2015-1155Search in Google Scholar PubMed PubMed Central
10. Goetz R, Beenken A, Ibrahimi OA, Kalinina J, Olsen SK, Eliseenkova AV, Xu C, Neubert TA, Zhang F, Linhardt RJ, Yu X, White KE, Inagaki T, Kliewer SA, Yamamoto M, Kurosu H, Ogawa Y, Kuro-o M, Lanske B, Razzaque MS, Mohammadi M. Molecular insights into the klotho-dependent, endocrine mode of action of fibroblast growth factor 19 subfamily members. Mol Cell Biol 2007;27:3417–28.10.1128/MCB.02249-06Search in Google Scholar PubMed PubMed Central
11. Kurosu H, Kuro-o M. The Klotho gene family as a regulator of endocrine fibroblast growth factors. Mol Cell Endocrinol 2009;299:72–8.10.1016/j.mce.2008.10.052Search in Google Scholar PubMed
12. Zhang X, Yeung DC, Karpisek M, Stejskal D, Zhou ZG, Liu F, Wong RL, Chow WS, Tso AW, Lam KS, Xu A. Serum FGF21 levels are increased in obesity and are independently associated with the metabolic syndrome in humans. Diabetes 2008;57:1246–53.10.2337/db07-1476Search in Google Scholar PubMed
13. Reyes García R, García-Martín A, García-Fontana B, Morales-Santana S, Rozas-Moreno P, Muñoz-Torres M. FGF23 in type 2 diabetic patients: relationship with bone metabolism and vascular disease. Diabetes Care 2014;37:e89–90.10.2337/dc13-2235Search in Google Scholar PubMed
14. Potthoff M, Kliewer SA, Mangelsdorf DJ. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev 2012;26:312–24.10.1101/gad.184788.111Search in Google Scholar PubMed PubMed Central
15. Cuevas-Ramos D, Aguilar-Salinas CA, Gómez-Pérez FJ. Metabolic actions of fibroblast growth factor 21. Curr Opin Pediatr 2012;24:523–9.10.1097/MOP.0b013e3283557d22Search in Google Scholar PubMed
16. Schaap FG, Kremer AE, Lamers WH, Jansen PL, Gaemers IC. Fibroblast growth factor 21 is induced by endoplasmic reticulum stress. Biochimie 2013;95:692–9.10.1016/j.biochi.2012.10.019Search in Google Scholar PubMed
17. Hondares E, Rosell M, Gonzalez FJ, Giralt M, Iglesias R, Villarroya F. Hepatic FGF21 expression is induced at birth via PPARalpha in response to milk intake and contributes to thermogenic activation of neonatal brown fat. Cell Metab 2010;11: 206–12.10.1016/j.cmet.2010.02.001Search in Google Scholar PubMed PubMed Central
18. Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, Villarroya F. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011;286:12983–90.10.1074/jbc.M110.215889Search in Google Scholar PubMed PubMed Central
19. Fisher FM, Kleiner S, Douris N, Fox EC, Mepani RJ, Verdeguer F, Wu J, Kharitonenkov A, Flier JS, Maratos-Flier E, Spiegelman BM. FGF21 regulates PGC-1a and browning of white adipose tissues in adaptive thermogenesis. Genes Dev 2012;26:271–81.10.1101/gad.177857.111Search in Google Scholar PubMed PubMed Central
20. Cuevas-Ramos D, Almeda-Valdes P, Meza-Arana CE, Brito-Córdova G, Gómez-Pérez FJ, Mehta R, Oseguera-Moguel J, Aguilar-Salinas CA. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS One 2012;7:e38022.10.1371/journal.pone.0038022Search in Google Scholar PubMed PubMed Central
21. Kim KH, Kim SH, Min YK, Yang HM, Lee JB, Lee MS. Acute exercise induces FGF21 expression in mice and in healthy humans. PLoS One 2013;8:e63517.10.1371/journal.pone.0063517Search in Google Scholar PubMed PubMed Central
22. Hansen JS, Clemmesen JO, Secher NH, Hoene M, Drescher A, Weigert C, Pedersen BK, Plomgaard P. Glucagon-to-insulin ratio is pivotal for splanchnic regulation of FGF-21 in humans. Mol Metab 2015;4:551–60.10.1016/j.molmet.2015.06.001Search in Google Scholar PubMed PubMed Central
23. Hondares E, Gallego-Escuredo JM, Flachs P, Frontini A, Cereijo R, Goday A, Perugini J, Kopecky P, Giralt M, Cinti S, Kopecky J, Villarroya F. Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism 2014;63:312–7.10.1016/j.metabol.2013.11.014Search in Google Scholar PubMed
24. Lin Z, Zhou Z, Liu Y, Gong Q, Yan X, Xiao J, Wang X, Lin S, Feng W, Li X. Circulating FGF21 levels are progressively increased from the early to end stages of chronic kidney diseases and are associated with renal function in Chinese. PLoS One 2011;6:e18398.10.1371/journal.pone.0018398Search in Google Scholar PubMed PubMed Central
25. Schoenberg KM, Giesy SL, Harvatine KJ, Waldron MR, Cheng C, Kharitonenkov A, Boisclair YR. Plasma FGF21 is elevated by the intense lipid mobilization of lactation. Endocrinology 2011;152:4652–61.10.1210/en.2011-1425Search in Google Scholar PubMed
26. Yu J, Zhao L, Wang A, Eleswarapu S, Ge X, Chen D, Jiang H. Growth hormone stimulates transcription of the fibroblast growth factor 21 gene in the liver through the signal transducer and activator of transcription 5. Endocrinology 2012;153:750–58.10.1210/en.2011-1591Search in Google Scholar PubMed
27. Lin Z, Wu Z, Yin X, Liu Y, Yan X, Lin S, Xiao J, Wang X, Feng W, Li X. Serum levels of FGF-21 are increased in coronary heart disease patients and are independently associated with adverse lipid profile. PLoS One 2010;5:e15534.10.1371/journal.pone.0015534Search in Google Scholar PubMed PubMed Central
28. Lee Y, Park YJ, Ahn HY, Lim JA, Park KU, Choi SH, Park do J, Oh BC, Jang HC, Yi KH. Plasma FGF21 levels are increased in patients with hypothyroidism independently of lipid profile. Endocrine J 2013;60:977–83.10.1507/endocrj.EJ12-0427Search in Google Scholar PubMed
29. Stepan H, Kley K, Hindricks J, Kralisch S, Jank A, Schaarschmidt W, Schrey S, Ebert T, Lössner U, Kratzsch J, Blüher M, Stumvoll M, Richter J, Fasshauer M. Serum levels of the adipokine fibroblast growth factor21 are increased in preeclampsia. Cytokine 2013;62:322–6.10.1016/j.cyto.2013.02.019Search in Google Scholar PubMed
30. Kharitonenkov A, Larsen P. FGF21 reloaded: challenges of a rapidly growing field. Trends Endocrinol Metab 2011;22:81–6.10.1016/j.tem.2010.11.003Search in Google Scholar PubMed
31. Nishimura T, Nakatake Y, Konishi M, Itoh N. Identification of a novel FGF, FGF-21, preferentially expressed in the liver. Biochim Biophys Acta 2000;1492:203–6.10.1016/S0167-4781(00)00067-1Search in Google Scholar
32. Muise ES, Azzolina B, Kuo DW, El-Sherbeini M, Tan Y, Yuan X, Mu J, Thompson JR, Berger JP, Wong KK. Adipose fibroblast growth factor 21 is up-regulated by peroxisome proliferator-activated receptor gamma and altered metabolic state. Mol Pharmacol 2008;74:403–12.10.1124/mol.108.044826Search in Google Scholar PubMed
33. Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt-regulated myokine. FEBS Lett 2008;582:3805–10.10.1016/j.febslet.2008.10.021Search in Google Scholar PubMed PubMed Central
34. Planavila A, Redondo I, Hondares E, Vinciguerra M, Munts C, Iglesias R, Gabrielli LA, Sitges M, Giralt M, van Bilsen M, Villarroya F. Fibroblast growth factor 21 protects against cardiac hypertrophy in mice. Nat Commun 2013;4:2019.10.1038/ncomms3019Search in Google Scholar PubMed
35. Ming AY, Yoo E, Vorontsov EN, Altamentova SM, Kilkenny DM, Rocheleau JV. Dynamics and distribution of Klothoβ (KLB) and fibroblast growth factor receptor-1 (FGFR1) in living cells reveal the fibroblast growth factor-21 (FGF21)-induced receptor complex. J Biol Chem 2012;287:19997–20006.10.1074/jbc.M111.325670Search in Google Scholar PubMed PubMed Central
36. Adams AC, Cheng CC, Coskun T, Kharitonenkov A. FGF21 requires βklotho to act in vivo. PLoS One 2012;7:e49977.10.1371/journal.pone.0049977Search in Google Scholar PubMed PubMed Central
37. Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M. Tissue-specific expression of betaKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 2007;282:26687–95.10.1074/jbc.M704165200Search in Google Scholar PubMed PubMed Central
38. Yang C, Jin C, Li X, Wang F, McKeehan WL, Luo Y. Differential specificity of endocrine FGF19 and FGF21 to FGFR1 and FGFR4 in complex with KLB. PLoS One 2012;7:e33870.10.1371/journal.pone.0033870Search in Google Scholar PubMed PubMed Central
39. Wente W, Efanov AM, Brenner M, Kharitonenkov A, Köster A, Sandusky GE, Sewing S, Treinies I, Zitzer H, Gromada J. Fibroblast growth factor-21 improves pancreatic beta-cell function and survival by activation of extracellular signal-regulated kinase 1/2 and Akt signaling pathways. Diabetes 2006;55:2470–8.10.2337/db05-1435Search in Google Scholar PubMed
40. Oishi K, Uchida D, Ishida N. Circadian expression of FGF21 is induced by PPARalpha activation in the mouse liver. FEBS Lett 2008;582:3639–42.10.1016/j.febslet.2008.09.046Search in Google Scholar PubMed
41. Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPAR-alpha mediated induction of FGF21. Cell Metab 2007;5:415–25.10.1016/j.cmet.2007.05.003Search in Google Scholar PubMed
42. Lundàsen T, Hunt MC, Nilsson LM, Sanyal S, Angelin B, Alexson SE, Rudling M. PPARalpha is a key regulator of hepatic FGF21. Biochem Biophys Res Commun 2007;360:437–40.10.1016/j.bbrc.2007.06.068Search in Google Scholar PubMed
43. Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPAR-alpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007;5:426–37.10.1016/j.cmet.2007.05.002Search in Google Scholar PubMed
44. Gälman C, Lundåsen T, Kharitonenkov A, Bina HA, Eriksson M, Hafström I, Dahlin M, Amark P, Angelin B, Rudling M. The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPAR-alpha activation in man. Cell Metab 2008;8:169–74.10.1016/j.cmet.2008.06.014Search in Google Scholar PubMed
45. Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC-1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 2009;106:10853–8.10.1073/pnas.0904187106Search in Google Scholar PubMed PubMed Central
46. Fazeli PK, Lun M, Kim SM, Bredella MA, Wright S, Zhang Y, Lee H, Catana C, Klibanski A, Patwari P, Steinhauser ML. FGF21 and the late adaptive response to starvation in humans. J Clin Invest 2015;125:4601–11.10.1172/JCI83349Search in Google Scholar PubMed PubMed Central
47. Chen W, Hoo RL, Konishi M, Itoh N, Lee PC, Ye HY, Lam KS, Xu A. Growth hormone induces hepatic production of fibroblast growth factor 21 through a mechanism dependent on lipolysis in adipocytes. J Biol Chem 2011;286:34559–66.10.1074/jbc.M111.285965Search in Google Scholar PubMed PubMed Central
48. Li H, Gao Z, Zhang J, Ye X, Xu A, Ye J, Jia W. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes 2012;61:797–806.10.2337/db11-0846Search in Google Scholar PubMed PubMed Central
49. Adams AC, Astapova I, Fisher FM, Badman MK, Kurgansky KE, Flier JS, Hollenberg AN, Maratos-Flier E. Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner. J Biol Chem 2010;285:14078–82.10.1074/jbc.C110.107375Search in Google Scholar PubMed PubMed Central
50. Li Y, Wong K, Walsh K, Gao B, Zang M. Retinoic acid receptor β stimulates hepatic induction of fibroblast growth factor 21 to promote fatty acid oxidation and control whole-body energy homeostasis in mice. J Biol Chem 2013;288:10490–504.10.1074/jbc.M112.429852Search in Google Scholar PubMed PubMed Central
51. Wang Y, Solt LA, Burris TP. Regulation of FGF21 expression and secretion by retinoic acid receptor-related orphan receptor alpha. J Biol Chem 2010;285:15668–73.10.1074/jbc.M110.102160Search in Google Scholar PubMed PubMed Central
52. Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, Zhang K. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology 2014;155:769–82.10.1210/en.2013-1490Search in Google Scholar PubMed PubMed Central
53. Liang Q, Zhong L, Zhang J, Wang Y, Bornstein SR, Triggle CR, Ding H, Lam KS, Xu A. FGF21 maintains glucose homeostasis by mediating the cross talk between liver and brain during prolonged fasting. Diabetes 2014;63:4064–75.10.2337/db14-0541Search in Google Scholar PubMed
54. Patel R, Bookout AL, Magomedova L, Owen BM, Consiglio GP, Shimizu M, Zhang Y, Mangelsdorf DJ, Kliewer SA, Cummins C. Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol 2015;29:213–23.10.1210/me.2014-1259Search in Google Scholar PubMed PubMed Central
55. Maruyama R, Shimizu M, Li J, Inoue J, Sato R. Fibroblast growth factor 21 induction by activating transcription factor 4 is regulated through three amino acid response elements in its promoter region. Biosci Biotechnol Biochem 2016;24:1–6.10.1080/09168451.2015.1135045Search in Google Scholar PubMed
56. Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, Mohammadi M, Potthoff MJ. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014;63:4057–63.10.2337/db14-0595Search in Google Scholar PubMed PubMed Central
57. Uebanso T, Taketani Y, Yamamoto H, Amo K, Ominami H, Arai H, Takei Y, Masuda M, Tanimura A, Harada N, Yamanaka-Okumura H, Takeda E. Paradoxical regulation of human FGF21 by both fasting and feeding signals: is FGF21 a nutritional adaptation factor? PLoS One 2011;6:e22976.10.1371/journal.pone.0022976Search in Google Scholar PubMed PubMed Central
58. Wang H, Qiang L, Farmer SR. Identification of a domain within peroxisome proliferator-activated receptor gamma regulating expression of a group of genes containing fibroblast growth factor 21 that are selectively repressed by SIRT1 in adipocytes. Mol Cell Biol 2008;28:188–200.10.1128/MCB.00992-07Search in Google Scholar PubMed PubMed Central
59. Filhoulaud G, Guilmeau S, Dentin R, Girard J, Postic C. Novel insights into ChREBP regulation and function. Trends Endocrinol Metab 2013;24:257–68.10.1016/j.tem.2013.01.003Search in Google Scholar PubMed
60. Dushay JR, Toschi E, Mitten EK, Fisher FM, Herman MA, Maratos-Flier E. Fructose ingestion acutely stimulates circulating FGF21 levels in humans. Mol Metab 2014;8:51–7.10.1016/j.molmet.2014.09.008Search in Google Scholar PubMed PubMed Central
61. Samms RJ, Murphy M, Fowler MJ, Cooper S, Emmerson P, Coskun T, Adams AC, Kharitonenkov A, Ebling FJ, Tsintzas K. Dual effects of fibroblast growth factor 21 on hepatic energy metabolism. J Endocrinol 2015;227:37–47.10.1530/JOE-15-0334Search in Google Scholar PubMed
62. Kim KH, Lee MS. FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes Metab J 2014;38:245–51.10.4093/dmj.2014.38.4.245Search in Google Scholar PubMed PubMed Central
63. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, Kim SS, Kim do H, Hur KY, Kim HK, Ko T, Han J, Kim HL, Kim J, Back SH, Komatsu M, Chen H, Chan DC, Konishi M, Itoh N, Choi CS, Lee MS. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med 2013;19:83–92.10.1038/nm.3014Search in Google Scholar PubMed
64. Kubicky RA, Wu S, Kharitonenkov A, De Luca F. Role of fibroblast growth factor 21 (FGF21) in undernutrition-related attenuation of growth in mice. Endocrinology 2012;153:2287–95.10.1210/en.2011-1909Search in Google Scholar PubMed
65. Lips MA, de Groot GH, Berends FJ, Wiezer R, van Wagensveld BA, Swank DJ, Luijten A, van Dijk KW, Pijl H, Jansen PL, Schaap FG. Calorie restriction and Roux-en-Y gastric bypass have opposing effects on circulating FGF21 in morbidly obese subjects. Clin Endocrinol (Oxf) 2014;81:862–70.10.1111/cen.12496Search in Google Scholar PubMed
66. Laeger T, Henagan TM, Albarado DC, Redman LM, Bray GA, Noland RC, Münzberg H, Hutson SM, Gettys TW, Schwartz MW, Morrison CD. FGF21 is an endocrine signal of protein restriction. J Clin Invest 2014;124:3913–22.10.1172/JCI74915Search in Google Scholar PubMed PubMed Central
67. De Sousa-Coelho AL, Marrero PF, Haro D. Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation. Biochem J 2012;443:165–71.10.1042/BJ20111748Search in Google Scholar PubMed
68. De Sousa-Coelho AL, Relat J, Hondares E, Pérez-Martí A, Ribas F, Villarroya F, Marrero PF, Haro D. FGF21 mediates the lipid metabolism response to amino acid starvation. J Lipid Res 2013;54:1786–97.10.1194/jlr.M033415Search in Google Scholar PubMed PubMed Central
69. Ables GP, Perrone CE, Orentreich D, Orentreich N. Methionine-restricted C57BL/6J mice are resistant to diet-induced obesity and insulin resistance but have low bone density. PLoS One 2012;7:e51357.10.1371/journal.pone.0051357Search in Google Scholar PubMed PubMed Central
70. Lees EK, Król E, Grant L, Shearer K, Wyse C, Moncur E, Bykowska AS, Mody N, Gettys TW, Delibegovic M. Methionine restriction restores a younger metabolic phenotype in adult mice with alterations in fibroblast growth factor 21. Aging Cell 2014;13:817–27.10.1111/acel.12238Search in Google Scholar PubMed PubMed Central
71. Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, Kharitonenkov A, Schuppan D, Flier JS, Maratos-Flier E. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology 2014;147:1073–83.e6.10.1053/j.gastro.2014.07.044Search in Google Scholar PubMed PubMed Central
72. Gimeno RE, Moller DE. FGF21-based pharmacotherapy – potential utility for metabolic disorders. Trends Endocrinol Metab 2014;25:303–11.10.1016/j.tem.2014.03.001Search in Google Scholar PubMed
73. Kharitonenkov A, DiMarchi R. FGF21 Revolutions: recent advances illuminating FGF21 biology and medicinal properties. Trends Endocrinol Metab 2015;26:608–17.10.1016/j.tem.2015.09.007Search in Google Scholar PubMed
74. Véniant MM, Hale C, Helmering J, Chen MM, Stanislaus S, Busby J, Vonderfecht S, Xu J, Lloyd DJ. FGF21 promotes metabolic homeostasis via white adipose and leptin in mice. PLoS One 2012;7:e40164.10.1371/journal.pone.0040164Search in Google Scholar PubMed PubMed Central
75. Adams AC, Yang C, Coskun T, Cheng CC, Gimeno RE, Luo Y, Kharitonenkov A. The breadth of FGF21’s metabolic actions are governed by FGFR1 in adipose tissue. Mol Metab 2012;2:31–7.10.1016/j.molmet.2012.08.007Search in Google Scholar PubMed PubMed Central
76. Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 2013;17:779–89.10.1016/j.cmet.2013.04.005Search in Google Scholar PubMed
77. Schlein C, Talukdar S, Heine M, Fischer AW, Krott LM, Nilsson SK, Brenner MB, Heeren J, Scheja L. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown dipose tissues. Cell Metab 2016;23:441–53.10.1016/j.cmet.2016.01.006Search in Google Scholar PubMed
78. Planavila A, Redondo-Angulo I, Ribas F, Garrabou G, Casademont J, Giralt M, Villarroya F. Fibroblast growth factor 21 protects the heart from oxidative stress. Cardiovasc Res 2015;106:19–31.10.1093/cvr/cvu263Search in Google Scholar PubMed
79. Tyynismaa H, Carroll CJ, Raimundo N, Ahola-Erkkilä S, Wenz T, Ruhanen H, Guse K, Hemminki A, Peltola-Mjøsund KE, Tulkki V, Oresic M, Moraes CT, Pietiläinen K, Hovatta I, Suomalainen A. Mitochondrial myopathy induces a starvation-like response. Hum Mol Genet 2010;19:3948–58.10.1093/hmg/ddq310Search in Google Scholar PubMed
80. Ribas F, Villarroya J, Hondares E, Giralt M, Villarroya F. FGF21 expression and release in muscle cells: involvement of MyoD and regulation by mitochondria-driven signalling. Biochem J 2014;463:191–9.10.1042/BJ20140403Search in Google Scholar PubMed
81. Tanajak P, Chattipakorn SC, Chattipakorn N. Effects of fibroblast growth factor 21 on the heart. J Endocrinol 2015;227:R13–30.10.1530/JOE-15-0289Search in Google Scholar PubMed
82. Giannini C, Feldstein AE, Santoro N, Kim G, Kursawe R, Pierpont B, Caprio S. Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 2013;98:2993–3000.10.1210/jc.2013-1250Search in Google Scholar PubMed PubMed Central
83. Yang C, Lu W, Lin T, You P, Ye M, Huang Y, Jiang X, Wang C, Wang F, Lee MH, Yeung SC, Johnson RL, Wei C, Tsai RY, Frazier ML, McKeehan WL, Luo Y. Activation of Liver FGF21 in hepatocarcinogenesis and during hepatic stress. BMC Gastroenterol 2013;13:67.10.1186/1471-230X-13-67Search in Google Scholar PubMed PubMed Central
84. Zhang Q, Li Y, Liang T, Lu X, Liu X, Zhang C, Jiang X, Martin RC, Cheng M, Cai L. Loss of FGF21 in diabetic mouse during hepatocellular carcinogenetic transformation. Am J Cancer Res 2015;5:1762–74.Search in Google Scholar
85. Kim HW, Lee JE, Cha JJ, Hyun YY, Kim JE, Lee MH, Song HK, Nam DH, Han JY, Han SY, Han KH, Kang YS, Cha DR. Fibroblast growth factor 21 improves insulin resistance and ameliorates renal injury in db/db mice. Endocrinology 2013;154:3366–76.10.1210/en.2012-2276Search in Google Scholar PubMed
86. Stein S, Bachmann A, Lössner U, Kratzsch J, Blüher M, Stumvoll M, Fasshauer M. Serum levels of the adipokine FGF21 depend on renal function. Diabetes Care 2009;32:126–8.10.2337/dc08-1054Search in Google Scholar PubMed PubMed Central
87. Jian WX, Peng WH, Jin J, Chen XR, Fang WJ, Wang WX, Qin L, Dong Y, Su Q. Association between serum fibroblast growth factor 21 and diabetic nephropathy. Metabolism 2012;61:853–9.10.1016/j.metabol.2011.10.012Search in Google Scholar PubMed
88. Yan H, Xia M, Chang X, Xu Q, Bian H, Zeng M, Rao S, Yao X, Tu Y, Jia W, Gao X. Circulating fibroblast growth factor 21 levels are closely associated with hepatic fat content: a cross-sectional study. PLoS One 2011;6:e24895.10.1371/journal.pone.0024895Search in Google Scholar PubMed PubMed Central
89. Mutanen A, Heikkilä P, Lohi J, Raivio T, Jalanko H, Pakarinen MP. Serum FGF21 increases with hepatic fat accumulation in pediatric onset intestinal failure. J Hepatol 2014;60:183–90.10.1016/j.jhep.2013.09.003Search in Google Scholar PubMed
90. Ho E, Karimi Galougahi K, Liu CC, Bhindi R, Figtree GA. Biological markers of oxidative stress: applications to cardiovascular research and practice. Redox Biol 2013;1:483–91.10.1016/j.redox.2013.07.006Search in Google Scholar PubMed PubMed Central
91. Lü Y, Liu JH, Zhang LK, DU J, Zeng XJ, Hao G, Huang J, Zhao DH, Wang GZ, Zhang YC. Fibroblast growth factor 21 as a possible endogenous factor inhibits apoptosis in cardiac endothelial cells. Chinese Med J 2010;123:3417–21.Search in Google Scholar
92. Calkins MJ, Johnson DA, Townsend JA, Vargas MR, Dowell JA, Williamson TP, Kraft AD, Lee JM, Li J, Johnson JA. The Nrf2/ARE pathway as a potential therapeutic target in neurodegenerative disease. Antioxid Redox Signal 2009;11:497–508.10.1089/ars.2008.2242Search in Google Scholar PubMed PubMed Central
93. Kobayashi M, Yamamoto M. Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 2006;46:113–40.10.1016/j.advenzreg.2006.01.007Search in Google Scholar PubMed
94. Kensler TW, Wakabayashi N, Biswal S. Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 2007;47:89–116.10.1146/annurev.pharmtox.46.120604.141046Search in Google Scholar PubMed
95. Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf2, a multi-organ protector? FASEB J 2005;19:1061–6.10.1096/fj.04-2591hypSearch in Google Scholar PubMed
96. Sykiotis GP, Bohmann D. Stress-activated cap’n’collar transcription factors in aging and human disease. Sci Signal 2010;3:re3.10.1126/scisignal.3112re3Search in Google Scholar PubMed PubMed Central
97. Motohashi H, Yamamoto M. Nrf2-Keap1 defines a physiologically important stress response mechanism. Trends Mol Med 2004;10:549–57.10.1016/j.molmed.2004.09.003Search in Google Scholar PubMed
98. Sykiotis GP, Habeos IG, Samuelson AV, Bohmann D. The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation. Curr Opin Clin Nutr Metab Care 2011;141:41–8.10.1097/MCO.0b013e32834136f2Search in Google Scholar PubMed PubMed Central
99. Pi J, Leung L, Xue P, Wang W, Hou Y, Liu D, Yehuda-Shnaidman E, Lee C, Lau J, Kurtz TW, Chan JY. Deficiency in the nuclear factor E2-related factor-2 transcription factor results in impaired adipogenesis and protects against diet-induced obesity. J Biol Chem 2010;285:9292–300.10.1074/jbc.M109.093955Search in Google Scholar PubMed PubMed Central
100. Chartoumpekis DV, Ziros PG, Psyrogiannis AI, Papavassiliou AG, Kyriazopoulou VE, Sykiotis GP, Habeos IG. Nrf2 represses FGF21 during long-term high-fat diet–induced obesity in mice. Diabetes 2011;60:2465–73.10.2337/db11-0112Search in Google Scholar PubMed PubMed Central
101. Zhang C, Shao M, Yang H, Chen L, Yu L, Cong W, Tian H, Zhang F, Cheng P, Jin L, Tan Y, Li X, Cai L, Lu X. Attenuation of hyperlipidemia- and diabetes-induced early-stage apoptosis and late-stage renal dysfunction via administration of fibroblast growth factor-21 is associated with suppression of renal inflammation. PLoS One 2013;8:e82275.10.1371/journal.pone.0082275Search in Google Scholar PubMed PubMed Central
102. Thiessen SE, Vanhorebeek I, Derese I, Gunst J, Van den Berghe G. FGF21 response to critical illness: effect of blood glucose control and relation with cellular stress and survival. J Clin Endocrinol Metab 2015;100:E1319–27.10.1210/jc.2015-2700Search in Google Scholar PubMed
103. Ge X, Chen C, Hui X, Wang Y, Lam KS, Xu A. Fibroblast growth factor 21 induces glucose transporter-1 expression through activation of the serum response factor/Ets-like protein-1 in adipocytes. Biol Chem 2011;286:34533-41.10.1074/jbc.M111.248591Search in Google Scholar PubMed PubMed Central
104. Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008;149:6018–27.10.1210/en.2008-0816Search in Google Scholar PubMed
105. Ding X, Boney-Montoya J, Owen BM, Bookout AL, Coate KC, Mangelsdorf DJ, Kliewer SA. βKlotho is required for fibroblast growth factor 21 effects on growth and metabolism. Cell Metab 2012;16:387–93.10.1016/j.cmet.2012.08.002Search in Google Scholar PubMed PubMed Central
106. Foltz IN, Hu S, King C, Wu X, Yang C, Wang W, Weiszmann J, Stevens J, Chen JS, Nuanmanee N, Gupte J, Komorowski R, Sekirov L, Hager T, Arora T, Ge H, Baribault H, Wang F, Sheng J, Karow M, Wang M, Luo Y, McKeehan W, Wang Z, Véniant MM, Li Y. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/FGFR1c receptor complex. Sci Transl Med 2012;4:162ra153.10.1126/scitranslmed.3004690Search in Google Scholar PubMed
107. Emanuelli B, Vienberg SG, Smyth G, Cheng C, Stanford KI, Arumugam M, Michael MD, Adams AC, Kharitonenkov A, Kahn CR. Interplay between FGF21 and insulin action in the liver regulates metabolism. J Clin Invest 2014;124:515–27.10.1172/JCI67353Search in Google Scholar PubMed PubMed Central
108. Nedergaard J, Bengtsson T, Cannon B. Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab 2007;293:E444–52.10.1152/ajpendo.00691.2006Search in Google Scholar PubMed
109. Nedergaard J, Bengtsson T, Cannon B. Three years with adult human brown adipose tissue. Ann N Y Acad Sci 2010;1212: E20–36.10.1111/j.1749-6632.2010.05905.xSearch in Google Scholar PubMed
110. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng YH, Doria A, Kolodny GM, Kahn CR. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509–17.10.1056/NEJMoa0810780Search in Google Scholar PubMed PubMed Central
111. Bauwens M, Wierts R, van Royen B, Bucerius J, Backes W, Mottaghy F, Brans B. Molecular imaging of brown adipose tissue in health and disease. Eur J Nucl Med Mol Imaging 2014;41:776–91.10.1007/s00259-013-2611-8Search in Google Scholar PubMed
112. Gallego-Escuredo JM, Gómez-Ambrosi J, Catalan V, Domingo P, Giralt M, Frühbeck G, Villarroya F. Opposite alterations in FGF21 and FGF19 levels and disturbed expression of the receptor machinery for endocrine FGFs in obese patients. Int J Obes (Lond) 2015;39:121–9.10.1038/ijo.2014.76Search in Google Scholar PubMed
113. Townsend KL, Tseng YH. Brown fat fuel utilization and thermogenesis. Trends Endocrinol Metab 2014;25:168–77.10.1016/j.tem.2013.12.004Search in Google Scholar PubMed PubMed Central
114. Feldmann HM, Golozoubova V, Cannon B, Nedergaard J. UCP1 ablation induces obesity and abolishes diet-induced thermogenesis in mice exempt from thermal stress by living at thermoneutrality. Cell Metab 2009;9:203–9.10.1016/j.cmet.2008.12.014Search in Google Scholar PubMed
115. Giralt M, Gavaldà-Navarro A, Villarroya F. Fibroblast growth factor-21, energy balance and obesity. Mol Cell Endocrinol 2015;418(Pt 1):66–73.10.1016/j.mce.2015.09.018Search in Google Scholar PubMed
116. Véniant MM, Sivits G, Helmering J, Komorowski R, Lee J, Fan W, Moyer C, Lloyd DJ. Pharmacologic effects of FGF21 are independent of the “browning” of white adipose tissue. Cell Metab 2015;21:731–8.10.1016/j.cmet.2015.04.019Search in Google Scholar PubMed
117. Keipert S, Kutschke M, Lamp D, Brachthäuser L, Neff F, Meyer CW, Oelkrug R, Kharitonenkov A, Jastroch M. Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion. Mol Metab 2015;4:537–42.10.1016/j.molmet.2015.04.006Search in Google Scholar PubMed PubMed Central
118. Lee P, Brychta RJ, Linderman J, Smith S, Chen KY, Celi FS. Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab 2013;98:E98–102.10.1210/jc.2012-3107Search in Google Scholar PubMed PubMed Central
119. Lee P, Linderman JD, Smith S, Brychta RJ, Wang J, Idelson C, Perron RM, Werner CD, Phan GQ, Kammula US, Kebebew E, Pacak K, Chen KY, Celi FS. Irisin and FGF21 are cold-induced endocrine activators of brown fat function in humans. Cell Metab 2014;19:302–9.10.1016/j.cmet.2013.12.017Search in Google Scholar PubMed PubMed Central
120. Douris N, Stevanovic DM, Fisher FM, Cisu TI, Chee MJ, Nguyen NL, Zarebidaki E, Adams AC, Kharitonenkov A, Flier JS, Bartness TJ, Maratos-Flier E. Central fibroblast growth factor 21 browns white fat via sympathetic action in male mice. Endocrinology 2015;156:2470–81.10.1210/en.2014-2001Search in Google Scholar PubMed PubMed Central
121. Owen BM, Ding X, Morgan DA, Coate KC, Bookout AL, Rahmouni K, Kliewer SA, Mangelsdorf DJ. FGF21 acts centrally to induce sympathetic nerve activity, energy expenditure, and weight loss. Cell Metab 2014;20:670–7.10.1016/j.cmet.2014.07.012Search in Google Scholar PubMed PubMed Central
122. Chau MD, Gao J, Yang Q, Wu Z, Gromada J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway. Proc Natl Acad Sci USA 2010;107:12553–8.10.1073/pnas.1006962107Search in Google Scholar PubMed PubMed Central
123. Bookout AL, de Groot MH, Owen BM, Lee S, Gautron L, Lawrence HL, Ding X, Elmquist JK, Takahashi JS, Mangelsdorf DJ, Kliewer SA. FGF21 regulates metabolism and circadian behavior by acting on the nervous system. Nat Med 2013;19:1147–52.10.1038/nm.3249Search in Google Scholar PubMed PubMed Central
124. Harris LA, Skinner JR, Shew TM, Pietka TA, Abumrad NA, Wolins NE. Perilipin 5-driven lipid droplet accumulation in skeletal muscle stimulates the expression of fibroblast growth factor 21. Diabetes 2015;64:2757–68.10.2337/db14-1035Search in Google Scholar PubMed PubMed Central
125. Kharitonenkov A, Wroblewski VJ, Koester A, Chen YF, Clutinger CK, Tigno XT, Hansen BC, Shanafelt AB, Etgen GJ. The metabolic state of diabetic monkeys is regulated by fibroblast growth factor-21. Endocrinology 2007;148:774–81.10.1210/en.2006-1168Search in Google Scholar PubMed
126. Goetz R. Metabolism: adiponectin – a mediator of specific metabolic actions of FGF21. Nat Rev Endocrinol 2013;9: 506–8.10.1038/nrendo.2013.146Search in Google Scholar PubMed
127. Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC, Volk K, Kuo MS, Gordillo R, Kharitonenkov A, Scherer PE. An FGF21-adiponectin-ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 2013;17:790–7.10.1016/j.cmet.2013.03.019Search in Google Scholar PubMed PubMed Central
128. Owen BM, Mangelsdorf DJ, Kliewer SA. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol Metab 2015;26:22–9.10.1016/j.tem.2014.10.002Search in Google Scholar PubMed PubMed Central
129. Sarruf DA, Thaler JP, Morton GJ, German J, Fischer JD, Ogimoto K, Schwartz MW. Fibroblast growth factor 21 action in the brain increases energy expenditure and insulin sensitivity in obese rats. Diabetes 2010;59:1817–24.10.2337/db09-1878Search in Google Scholar PubMed PubMed Central
130. Cuevas-Ramos D, Almeda-Valdes P, Gómez-Pérez FJ, Meza-Arana CE, Cruz-Bautista I, Arellano-Campos O, Navarrete-López M, Aguilar-Salinas CA. Daily physical activity, fasting glucose, uric acid, and body mass index are independent factors associated with serum fibroblast growth factor 21 levels. Eur J Endocrinol 2010;163:469–77.10.1530/EJE-10-0454Search in Google Scholar PubMed
131. Chavez AO, Molina-Carrion M, Abdul-Ghani MA, Folli F, Defronzo RA, Tripathy D. Circulating fibroblast growth factor-21 is elevated in impaired glucose tolerance and type 2 diabetes and correlates with muscle and hepatic insulin resistance. Diabetes Care 2009;32:1542–6.10.2337/dc09-0684Search in Google Scholar PubMed PubMed Central
132. Zhang J, Li Y. Fibroblast growth factor 21, the endocrine FGF pathway and novel treatments for metabolic syndrome. Drug Discov Today 2014;19:579–89.10.1016/j.drudis.2013.10.021Search in Google Scholar PubMed
133. Kharitonenkov A, Adams AC. Inventing new medicines: the FGF21 story. Mol Metab 2013;3:221–9.10.1016/j.molmet.2013.12.003Search in Google Scholar
134. Ye X, Qi J, Ren G, Xu P, Wu Y, Zhu S, Yu D, Li S, Wu Q, Muhi RL, Li D. Long-lasting anti-diabetic efficacy of PEGylated FGF-21 and liraglutide in treatment of type 2 diabetic mice. Endocrine 2015;49:683–92.10.1007/s12020-014-0503-8Search in Google Scholar
135. Ye X, Qi J, Wu Y, Yu D, Xu P, Li S, Zhu S, Wu Q, Ren G, Li D. Comparison of PEGylated FGF-21 with insulin glargine for long-lasting hypoglycaemic effect in db/db mice. Diabetes Metab 2015;41:82–90.10.1016/j.diabet.2014.09.001Search in Google Scholar
136. Weng Y, Chabot JR, Bernardo B, Yan Q, Zhu Y, Brenner MB, Vage C, Logan A, Calle R, Talukdar S. Pharmacokinetics (PK), pharmacodynamics (PD) and integrated PK/PD modeling of a novel long acting FGF21 clinical candidate PF-05231023 in diet-induced obese and leptin-deficient obese mice. PLoS One 2015;10:e0119104.10.1371/journal.pone.0119104Search in Google Scholar
137. Reitman ML. FGF21 mimetic shows therapeutic promise. Cell Metab 2013;18:307–9.10.1016/j.cmet.2013.08.014Search in Google Scholar
138. Gaich G, Chien JY, Fu H, Glass LC, Deeg MA, Holland WL, Kharitonenkov A, Bumol T, Schilske HK, Moller DE. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab 2013;18:333–40.10.1016/j.cmet.2013.08.005Search in Google Scholar
139. Dong JQ, Rossulek M, Somayaji VR, Baltrukonis D, Liang Y, Hudson K, Hernandez-Illas M, Calle RA. Pharmacokinetics and pharmacodynamics of PF-05231023, a novel long-acting FGF21 mimetic, in a first-in-human study. Br J Clin Pharmacol 2015;80:1051–63.10.1111/bcp.12676Search in Google Scholar
140. Talukdar S, Zhou Y, Li D, Rossulek M, Dong J, Somayaji V, Weng Y, Clark R, Lanba A, Owen BM, Brenner MB, Trimmer JK, Gropp KE, Chabot JR, Erion DM, Rolph TP, Goodwin B, Calle RA. Cell Metab 2016;23:427–40.10.1016/j.cmet.2016.02.001Search in Google Scholar
141. Bailey C, Tahrani AA, Barnett AH. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol 2016;4:350–9.10.1016/S2213-8587(15)00462-3Search in Google Scholar
142. Beiroa D, Imbernon M, Gallego R, Senra A, Herranz D, Villarroya F, Serrano M, Fernø J, Salvador J, Escalada J, Dieguez C, Lopez M, Frühbeck G, Nogueiras R. GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 2014;63:3346–58.10.2337/db14-0302Search in Google Scholar PubMed
©2017 Walter de Gruyter GmbH, Berlin/Boston
