<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a protein highly synthesized in the liver that exerts paracrine and endocrine control of many aspects of energy homeostasis in multiple tissues. In preclinical models of obesity and type 2 diabetes, treatment with FGF<em>21</em> improves glucose homeostasis and promotes weight loss, and, as a result, FGF<em>21</em> has attracted considerable attention as a therapeutic agent for the treatment of metabolic syndrome in humans. An improved understanding of the biological role of FGF<em>21</em> may help to explain why its therapeutic potential in humans has not been fully realized. This review will cover the complexities in FGF<em>21</em> biology in rodents and humans, with emphasis on its role in protection from central and peripheral facets of obesity.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent obesity-related disease that affects large populations throughout the world due to excessive calorie intake and an increasingly sedentary lifestyle. <em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) has recently emerged as a promising therapeutic candidate for the treatment of obesity and diabetes. FGF<em>21</em> is a starvation-induced pleiotropic hormone with various beneficial metabolic effects, and pharmacological treatment in rodents has been shown to improve insulin sensitivity and decrease simple fatty liver disease. However, its effects on reversing the symptoms of advanced liver disease have yet to be validated. Here, we investigated the protective effects of the LY2405319 compound, an engineered FGF<em>21</em> variant, in a non-alcoholic steatohepatitis (NASH) model using leptin-deficient ob/ob mice and a methionine- and choline-deficient (MCD) diet to induce steatohepatitis. LY2405319 treatment in ob/ob mice corroborated previous results showing that improvements in the metabolic parameters were due to increased mitochondrial oxygen consumption rate and fatty acid oxidation. LY2405319 treatment in ob/ob mice on an MCD diet significantly reduced the symptoms of steatohepatitis, as confirmed by Masson's trichrome staining intensity. Serum levels of AST and ALT were also reduced, suggesting an attenuation of liver injury, while detection of inflammatory markers showed decreased mRNA expression of TGF-β1 and type-I collagen, and decreased phosphorylation of NF-kB p65, JNK1/2, and p38. Collectively, these data show that LY2405319 treatment attenuated MCD diet-induced NASH progression. We propose that the LY2405319 compound is a potential therapeutic candidate for the treatment of advanced liver disease.

The aim of the study was to assess serum <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) concentrations in Chinese type 2 diabetic patients with and without retinopathy and to assess the association between FGF<em>21</em> and the severity of retinopathy. 117 diabetic patients were compared with 68 healthy controls. Fasting blood glucose, serum total cholesterol, serum triglycerides, serum insulin, and serum FGF<em>21</em> levels were estimated. FGF<em>21</em> concentrations in the patients were significantly higher than those in control. In the patient group there was a significant positive correlation between FGF<em>21</em>, insulin level, and homeostasis model assessment index. Serum FGF<em>21</em> concentrations in patients with proliferative diabetic retinopathy or nonproliferative diabetic retinopathy were significantly higher than those in patients without diabetic retinopathy. When the presence of diabetes was defined as the final variable in the conditional logistic regression model with the FGF<em>21</em> concentration as the continuous variable, FGF<em>21</em> was significantly involved in the model. This study shows that the increase in serum concentration of FGF<em>21</em> was associated with the severity of diabetic retinopathy and suggests that FGF<em>21</em> may play a role in the pathogenesis of diabetic retinopathy and its degree.

Bile acids (BAs) are signaling molecules controlling energy homeostasis that can be both toxic and protective for the liver. BA alterations have been reported in obesity, insulin resistance (IR), and nonalcoholic steatohepatitis (NASH). However, whether BA alterations contribute to NASH independently of the metabolic status is unclear.

To assess BA alterations associated with NASH independently of body mass index and IR.

Patients visiting the obesity clinic of the Antwerp University Hospital (a tertiary referral facility) were recruited from 2006 to 2014.

Obese patients with biopsy-proven NASH (n = 32) and healthy livers (n = 26) were matched on body mass index and homeostasis model assessment of IR.

Transcriptomic analyses were performed on liver biopsies. Plasma concentrations of <em>21</em> BA species and 7α-hydroxy-4-cholesten-3-one, a marker of BA synthesis, were determined by liquid chromatography-tandem mass spectrometry. Plasma <em>fibroblast</em> <em>growth</em> <em>factor</em> 19 was measured by enzyme-linked immunosorbent assay.

Plasma BA concentrations did not correlate with any hepatic lesions, whereas, as previously reported, primary BA strongly correlated with IR. Transcriptomic analyses showed unaltered hepatic BA metabolism in NASH patients. In line, plasma 7α-hydroxy-4-cholesten-3-one was unchanged in NASH. Moreover, no sign of hepatic BA accumulation or activation of BA receptors-farnesoid X, pregnane X, and vitamin D receptors-was found. Finally, plasma fibroblast growth factor 19, secondary-to-primary BA, and free-to-conjugated BA ratios were similar, suggesting unaltered intestinal BA metabolism and signaling.

In obese patients, BA alterations are related to the metabolic phenotype associated with NASH, especially IR, but not liver necroinflammation.

The cardioprotective effects of SGLT2 (sodium-glucose cotransporter 2) inhibitors may be related to their ability to induce a fasting-like paradigm, which triggers the activation of nutrient deprivation pathways to promote cellular homeostasis. The most distinctive metabolic manifestations of this fasting mimicry are enhanced gluconeogenesis and ketogenesis, which are not seen with other antihyperglycemic drugs. The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1α (proliferator-activated receptor gamma coactivator 1-alpha) and FGF<em>21</em> (<em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em>). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy-a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1/PGC-1α/FGF<em>21</em> signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1α, and FGF<em>21</em> by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. Therefore, promotion of ketogenic nutrient deprivation signaling by SGLT2 inhibitors may explain their cardioprotective effects, even though SGLT2 is not expressed in the heart.

Keywords: autophagy; fasting; lysosomes; metformin; pharmacology.

OBJECTIVE

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) reduces plasma glucose and triglycerides, and increases free fatty acid oxidation in animal models of diabetes. The aim of the present study was to assess the relationships of serum FGF<em>21</em> with glucose oxidation (GOx) and lipid oxidation (LOx) in the baseline and insulin-stimulated conditions in lean and obese subjects.

METHODS

Cross-sectional study.

METHODS

Eighty-four subjects with normal glucose tolerance, 42 lean (body mass index (BMI) <25 kg m(-2)) and 42 overweight or obese (BMI between 25 and 40 kg m(-2)).

METHODS

Euglycemic hyperinsulinemic clamp and indirect calorimetry in the baseline state and during last 30 min of the clamp. The change in respiratory quotient (ΔRQ) in response to insulin was used as a measure of metabolic flexibility. Serum FGF<em>21</em> was determined in the baseline state and after the clamp.

RESULTS

Obese subjects had higher LOx in the baseline and insulin-stimulated conditions, lower insulin-stimulated GOx and ΔRQ (all P<0.05). Fasting serum FGF<em>21</em> did not differ between the groups. Insulin infusion resulted in an increase in serum FGF<em>21</em> in the obese (P=0.0001), but not in the lean group (P=0.76). Postclamp serum FGF<em>21</em> was higher in the obese subjects (P=0.0007). In this group, postclamp FGF<em>21</em> was related to LOx during the clamp (r=0.32, P=0.044), change in GOx and LOx in response to insulin (r=-0.44, P=0.005; r=0.47, P=0.002; respectively) and ΔRQ (r=-0.50, P=0.001).

CONCLUSIONS

An increase in serum FGF<em>21</em> in response to insulin in obese subjects might represent inappropriate response, possibly associated with metabolic inflexibility in obesity and insulin resistance.

<em>Fibroblast</em> <em>Growth</em> <em>Factor</em> <em>21</em> (FGF<em>21</em>) elicits an array of metabolic effects. However, the physiological role of FGF<em>21</em> during thermal challenges is not clear. In this study, we assessed the tissue source of FGF<em>21</em> and its site of action to regulate core body temperature in response to cold. Using mice lacking FGF<em>21</em> specifically in the liver (FGF<em>21</em> LivKO) or adipose tissues (FGF<em>21</em> AdipoKO), we performed a series of cold exposure studies to examine the tissue specific induction of FGF<em>21</em> in response to cold. We also examined the physiological site of FGF<em>21</em> action during cold exposure by impairing FGF<em>21</em> signaling to adipose tissues or the central nervous system (CNS) using genetic ablation of the FGF<em>21</em> co-receptor β-klotho in adipose tissues (KLB AdipoKO) or pharmacological blockage of FGF<em>21</em> signaling. We found that only liver-derived FGF<em>21</em> enters circulation during acute cold exposure and is critical for thermoregulation. While FGF<em>21</em> signaling directly to adipose tissues during cold is dispensable for thermoregulation, central FGF<em>21</em> signaling is necessary for maximal sympathetic drive to brown adipose tissue to maintain thermoregulation during cold. These data demonstrate a previously unrecognized role for FGF<em>21</em> in the maintenance of body temperature in response to cold.

Backgroud: Myocardial fibrosis results in myocardial remodelling and dysfunction. Celastrol, a traditional oriental medicine, has been suggested to have cardioprotective effects. However, its underlying mechanism is unknown. This study investigated the ability of celastrol to prevent cardiac fibrosis and dysfunction and explored the underlying mechanisms.

METHODS

Animal and cell models of cardiac fibrosis were used in this study. Myocardial fibrosis was induced by transverse aortic constriction (TAC) in mice. Cardiac hypertrophy and fibrosis were evaluated based on histological and biochemical measurements. Cardiac function was evaluated by echocardiography. The levels of transforming <em>growth</em> <em>factor</em> beta 1 (TGF-β1), extracellular signal regulated kinases 1/2 (ERK1/2) signalling were measured using Western blotting, while the expression of miR-<em>21</em>was analyzed by real-time qRT-PCR in vitro and in vivo. In vitro studies, cultured cardiac <em>fibroblasts</em> (CFs) were treated with TGF-β1 and transfected with microRNA-<em>21</em>(miR<em>21</em>).

RESULTS

Celastrol treatment reduced the increased collagen deposition and down-regulated α-smooth muscle actin (α-SMA), atrial natriuretic peptide (ANP), brain natriuretic peptides (BNP), beta-myosin heavy chain (β-MHC), miR-<em>21</em> and p-ERK/ERK. Cardiac dysfunction was significantly attenuated by celastrol treatment in the TAC mice model. Celastrol treatment reduced myocardial fibroblast viability and collagen content and down-regulated α-SMA in cultured CFs in vitro. Celastrol also inhibited the miR-<em>21</em>/ERK signalling pathway. Celastrol attenuated miR-<em>21</em> up-regulation by TGF-β1 and decreased elevated p-ERK/ERK levels in CFs transfected with miR-<em>21</em>.

CONCLUSIONS

MiR-<em>21</em>/ERK signalling could be a potential therapeutic pathway for the prevention of myocardial fibrosis. Celastrol ameliorates myocardial fibrosis and cardiac dysfunction, these probably related to miR-<em>21</em>/ERK signaling pathways in vitro and in vivo.

Soy protein β-conglycinin has serum lipid-lowering and anti-obesity effects. We showed that single ingestion of β-conglycinin after fasting alters gene expression in mouse liver. A sharp increase in <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) gene expression, which is depressed by normal feeding, resulted in increased postprandial circulating FGF<em>21</em> levels along with a significant decrease in adipose tissue weights. Most increases in gene expressions, including FGF<em>21</em>, were targets for the activating transcription <em>factor</em> 4 (ATF4), but not for peroxisome proliferator-activated receptor α. Overexpression of a dominant-negative form of ATF4 significantly reduced β-conglycinin-induced increases in hepatic FGF<em>21</em> gene expression. In FGF<em>21</em>-deficient mice, β-conglycinin effects were partially abolished. Methionine supplementation to the diet or primary hepatocyte culture medium demonstrated its importance for activating liver or hepatocyte ATF4-FGF<em>21</em> signaling. Thus, dietary β-conglycinin intake can impact hepatic and systemic metabolism by increasing the postprandial circulating FGF<em>21</em> levels.

Dietary protein restriction increases adipose tissue uncoupling protein 1 (UCP1), energy expenditure and food intake, and these effects require the metabolic hormone <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>). Here we test whether the induction of energy expenditure during protein restriction requires UCP1, promotes a resistance to cold stress, and is dependent on the concomitant hyperphagia. Wildtype, Ucp1-KO and Fgf<em>21</em>-KO mice were placed on control and low protein (LP) diets to assess changes in energy expenditure, food intake and other metabolic endpoints. Deletion of Ucp1 blocked LP-induced increases in energy expenditure and food intake, and exacerbated LP-induced weight loss. While LP diet increased energy expenditure and Ucp1 expression in an FGF<em>21</em>-dependent manner, neither LP diet nor the deletion of Fgf<em>21</em> influenced sensitivity to acute cold stress. Finally, LP-induced energy expenditure occurred even in the absence of hyperphagia. Increased energy expenditure is a primary metabolic effect of dietary protein restriction, and requires both UCP1 and FGF<em>21</em> but is independent of changes in food intake. However, the FGF<em>21</em>-dependent increase in UCP1 and energy expenditure by LP has no effect on the ability to acutely respond to cold stress, suggesting that LP-induced increases in FGF<em>21</em> impact metabolic but not thermogenic endpoints.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is an endocrine hormone produced by the liver that regulates nutrient and metabolic homeostasis. FGF<em>21</em> production is increased in response to macronutrient imbalance and signals to the brain to suppress sugar intake and sweet-taste preference. However, the central targets mediating these effects have been unclear. Here, we identify FGF<em>21</em> target cells in the hypothalamus and reveal that FGF<em>21</em> signaling to glutamatergic neurons is both necessary and sufficient to mediate FGF<em>21</em>-induced sugar suppression and sweet-taste preference. Moreover, we show that FGF<em>21</em> acts directly in the ventromedial hypothalamus (VMH) to specifically regulate sucrose intake, but not non-nutritive sweet-taste preference, body weight, or energy expenditure. Finally, our data demonstrate that FGF<em>21</em> affects neuronal activity by increasing activation and excitability of neurons in the VMH. Thus, FGF<em>21</em> signaling to glutamatergic neurons in the VMH is an important component of the neurocircuitry that functions to regulate sucrose intake.

<strong class="sub-title"> Keywords: </strong> FGF<em>21</em>; PVN; VMH; brain; glucose sensing; hepatokine; hypothalamus; liver; macronutrient; sugar intake; sweet-taste preference.

BACKGROUND

As periodontal tissues are constantly exposed to mechanical stress during mastication, the relationship between mechanical stimulation and biochemical phenomena has been extensively investigated.

OBJECTIVE

The aim of the present study was to assess the change in the production of angiogenic regulators produced by human gingival fibroblasts (HGF) and periodontal ligament fibroblasts (HPLF), cultured on a flexible substrate, before and after application of cyclic tensile stretching.

METHODS

Both cell types were stretched in a Flexercell Strain Unit to 7, 14 and 21% elongation, at a frequency of 12 cycles/min. Medium cultured with HGF or HPLF was examined by enzyme-linked immunosorbent assay (ELISA) for vascular endothelial growth factor (VEGF), Western blotting of pigment epithelium-derived factor (PEDF) and in vitro angiogenesis assay. The residual cells were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) for both VEGF and PEDF mRNA expression.

RESULTS

Stretching increased the VEGF mRNA level and VEGF secretion in both HGF and HPLF. The concentration of VEGF in the conditioned medium of the stretched HPLF was almost the same as that of stretched HGF. In the in vitro angiogenesis assay, the conditioned medium of HPLF after stretching showed a dramatic increase in tube formation. In contrast, stretched HGF did not show enhanced tube formation, despite the increase in VEGF secretion by stretched HGF. The mRNA levels of PEDF, an inhibitor of angiogenesis, were higher in HGF than HPLF. The protein level of PEDF in HGF was also higher than that in HPLF.

CONCLUSIONS

These findings suggest that under mechanical stress HPLF promotes angiogenesis via expression of VEGF, whereas under the same conditions angiogenesis is not promoted in HGF, due to the expression of PEDF.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>21</em> is a distinctive member of the FGF family that functions as an endocrine <em>factor</em>. It is expressed predominantly in the liver, but is also found in adipose tissue and the pancreas. Pharmacological studies have shown that FGF<em>21</em> normalizes glucose and lipid homeostasis, thereby preventing the development of metabolic disorders, such as obesity and diabetes. Despite <em>growing</em> evidence for the therapeutic potential of FGF<em>21</em>, paradoxical increases of FGF<em>21</em> in different disease conditions point to the existence of FGF<em>21</em> resistance. In this review, we give a critical appraisal of recent advances in the understanding of the regulation of FGF<em>21</em> production under various physiological conditions, its antidiabetic actions, and the clinical implications. We also discuss recent preclinical and clinical trials using engineered FGF<em>21</em> analogs in the management of diabetes, as well as the potential side effects of FGF<em>21</em> therapy.

During the periparturient phase, cows are typically in an inflammation-like condition, and it has been suggested that inflammation associated with the development of stress of the endoplasmic reticulum (ER) in the liver contributes to the development of fatty liver syndrome and ketosis. In the present study, we investigated the hypothesis that feeding grape seed and grape marc meal extract (GSGME) as a plant extract rich in flavonoids attenuates inflammation and ER stress in the liver of dairy cows. Two groups of cows received either a total mixed ration as a control diet or the same total mixed ration supplemented with 1% of GSGME over the period from wk 3 prepartum to wk 9 postpartum. Dry matter intake during wk 3 to 9 postpartum was not different between the 2 groups. However, the cows fed the diet supplemented with GSGME had an increased milk yield and an increased daily milk protein yield. Cows supplemented with GSGME moreover had a significantly reduced mRNA abundancy of <em>fibroblast</em> <em>growth</em> <em>factor</em> (FGF) <em>21</em>, a stress hormone induced by various stress conditions, in the liver in wk 1 and 3 postpartum. In contrast, mRNA abundances of a total of 3 genes involved in inflammation and 14 genes involved in ER stress response, as well as concentrations of triacylglycerols and cholesterol, in liver samples of wk 1 and 3 postpartum did not differ between the 2 groups. Overall, this study shows that supplementation of GSGME did not influence inflammation or ER stress in the liver but increased milk yield, an effect that could be due to effects on ruminal metabolism.

Tumor-induced osteomalacia (TIO) is a rare acquired form of hypophosphatemic osteomalacia, which is usually attributed to the overproduction of <em>fibroblast</em> <em>growth</em> <em>factor</em> 23 (FGF-23) by benign mesenchymal neoplasms. Localization and thereafter surgical resection of tumors lead to a cure. The present study aimed to investigate the clinical data, diagnostic methods, and follow-up after tumor resection at one medical center in Shanghai to characterize the profile of this rare disorder and to share our successful experience in diagnosis and treatment. Twenty-three patients with adult-onset hypophosphatemia osteomalacia seen in Shanghai Sixth People's Hospital from 2009 to 2014 and 95 normal individuals were enrolled. After taking a medical history and performing a physical examination, we analyzed the laboratory results (including the serum FGF-23 levels) and localized the tumors by 18F-fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET/CT), 99mTc-octreotide (99mTc-OCT) scintigraphy, and magnetic resonance imaging (MRI). On the basis of the results of laboratory tests and imaging findings, tumor resection was conducted in 17 patients with a certain diagnosis of TIO. The results demonstrated that the 17 patients (nine men and eight women, average age 46.6 ± 12.9 years) had TIO. FGF-23 level was elevated in 94.1 % of patients (16 of 17 patients) . Serum phosphorus level decreased in 100 % of patients. 18F-FDG PET/CT revealed five tumors, 99mTc-OCT scintigraphy revealed two tumors, physical examination revealed nine tumors, and MRI revealed one tumor, among which 58.8 % of the causative tumors (10 of 17 tumors) were located in the lower extremities. After tumor resection, serum phosphorus levels normalized in 100 % of patients (all 17 patients) in 4-<em>21</em> days and FGF-23 levels decreased in 90 % of patients (nine of ten patients). We found 64.7 % of the tumors (11 of 17 tumors) were phosphaturic mesenchymal tumors or a phosphaturic mesenchymal tumor mixed connective tissue variant. Measurement of serum phosphorus and FGF-23 levels in patients with suspected TIO is of paramount importance for diagnosing of TIO. 18F-FDG PET/CT, 99mTc-OCT scintigraphy, and physical examination play a considerable role in revealing TIO-associated tumors. TIO-associated tumors were more frequently located in the lower extremities than in other places; thus, the lower extremities need to be carefully checked. Complete surgical resection results in normalization of parameters in laboratory tests and relief of symptoms of TIO patients.

Gonadotropin-releasing hormone analogue (GnRHa) therapy is an established method of androgen withdrawal in the treatment of prostate cancer. The present study investigated if the expression of prostate GnRH receptors (GnRHRs) might influence the response to GnRHa. GnRHR protein expression was first studied in a panel of prostate cancer cell lines. In androgen-dependent cells, GnRHR expression was unchanged following acute or chronic androgen withdrawal. In these cells, GnRHa significantly inhibited androgen-induced cell proliferation (p = 0.01). In contrast, GnRHa was unable to further suppress basal levels of cell proliferation induced by androgen withdrawal. In androgen-independent prostate cancer cells, variable levels of GnRHR expression were observed. In these cells, GnRHa treatment blocked cell proliferation (p = 0.001) and invasion (up to 70%) induced by <em>fibroblast</em> <em>growth</em> <em>factor</em> stimulation. Crucially, this effect was only evident in cells that expressed high levels of the GnRHR. GnRHa treatment also significantly inhibited the ability of these cells to recover from a cytotoxic insult (50% inhibition). The clinical significance of prostate GnRHR was tested by immunohistochemistry in a preliminary cohort of patients treated with GnRHa or surgical castration. There was no association between GnRHR expression and pathological grade, clinical stage, time to PSA nadir (p = 0.82) (n = 35) or progression to hormone refractory disease (p = 0.22) (n = <em>21</em>), irrespective of the treatment method. GnRHa therapy in the presence of high GnRHR expression however, was found to be associated with longer disease-specific survival (mean survival 85 months, p = 0.002). In contrast, high GnRHR expression was not associated with survival among surgically castrated patients (mean survival 50 months, p = 0.7). Taken together, these data support the notion of a functional interaction between GnRHa and the GnRHR, which results in an anti-tumourigenic effect on prostate cancer cells. Findings from this report have direct implications for the use of GnRHR as a novel therapeutic target in hormone refractory prostate cancer.

<em>Fibroblast</em> <em>growth</em> <em>factors</em> (FGFs) are responsible for the regulation of a wide range of biological functions, among which cellular proliferation, survival, migration, and differentiation could be pointed out. FGF19 controls the enterohepatic bile acid/cholesterol system, and FGF<em>21</em> modulates fatty acid/glucose metabolism. Obesity, type 2 diabetes, coronary artery disease, and cancer, all can alter FGF<em>21</em> circulating concentrations. In contrast to FGF<em>21</em>, metabolic diseases exhibit reduced serum FGF19 levels. Accordingly, FGF19 and FGF<em>21</em> play important roles in regulating glucose and lipid metabolism. Hence, we present here a timely review on the relationship between FGF19/<em>21</em> and metabolic diseases, especially obesity, and their probable role in development and treatment of obesity seems necessary.

Many articles have discussed the relationship between fructose consumption and the incidence of obesity and related diseases. Fructose is absorbed in the intestine and metabolized in the liver to glucose, lactate, glycogen, and, to a lesser extent, lipids. Unabsorbed fructose causes bacterial fermentation, resulting in irritable bowl syndrome. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important for the treatment of metabolic syndrome and fructose malabsorption. Carbohydrate response element binding protein (ChREBP) is a glucose-activated transcription <em>factor</em> that controls approximately 50% of de novo lipogenesis in the liver. ChREBP target genes are involved in glycolysis (Glut2, liver pyruvate kinase), fructolysis (Glut5, ketohexokinase), and lipogenesis (acetyl CoA carboxylase, fatty acid synthase). ChREBP gene deletion protects against high sucrose diet-induced and leptin-deficient obesity, because Chrebp-/- mice cannot consume fructose or sucrose. Moreover, ChREBP contributes to some of the physiological effects of fructose on sweet taste preference and glucose production through regulation of ChREBP target genes, such as <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>21</em> and glucose-6-phosphatase catalytic subunits. Thus, ChREBP might play roles in fructose metabolism. Restriction of excess fructose intake will be beneficial for preventing not only metabolic syndrome but also irritable bowl syndrome.

OBJECTIVE

This study was designed to measure serum <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) levels in patients with polycystic ovary syndrome (PCOS) and healthy subjects.

METHODS

A total of 37 women were evaluated. Serum levels FGF<em>21</em>, glucose, lipid profile, hormones (follicle-stimulating hormone, luteinising hormone, oestradiol, testosterone, thyroid stimulating hormone, prolactin and insulin) were determined in 24 PCOS (15 subjects of PCOS BMI < 25 kg/m2, 9 subjects of PCOS BMI ≥ kg/m2) and 13 control group (BMI < 25 kg/m2).

RESULTS

Serum FGF<em>21</em> levels were higher in the PCOS group [99.5 (173.7) pg/ml] than in the control group [52.0 (88.0) pg/ml]. LH and T are significantly higher in PCOS cases (respectively; p < 0.05, p < 0.01). A positive correlation was found between FGF<em>21</em> and luteinising hormone and testosterone (respectively; r = 0.43 p = 0.007, r = 0.38, p = 0.02). Multivariate discriminant analysis showed that BMI, triglyceride, HOMA-IR, fasting glucose with rise of FGF<em>21</em> were found significant in PCOS.

CONCLUSIONS

Our study indicates that FGF<em>21</em> in cases with PCOS exhibit an increase along with the increase of BMI and also has a positive correlation with LH and T. Further studies are required to clarify the aetiology and effects of FGF<em>21</em> in women with PCOS.

Polycystic kidney disease (PKD) is a commonly inherited disorder characterized by cyst formation and fibrosis (Wilson, N Engl J Med 350:151-164, 2004) and is caused by mutations in cilia or cilia-related proteins, such as polycystin 1 or 2 (Oh and Katsanis, Development 139:443-448, 2012; Kotsis et al., Nephrol Dial Transplant 28:518-526, 2013). A major pathological feature of PKD is the development of interstitial inflammation and fibrosis with an associated accumulation of inflammatory cells (Grantham, N Engl J Med 359:1477-1485, 2008; Zeier et al., Kidney Int 42:1259-1265, 1992; Ibrahim, Sci World J 7:1757-1767, 2007). It is unclear whether inflammation is a driving force for cyst formation or a consequence of the pathology (Ta et al., Nephrology 18:317-330, 2013) as in some murine models cysts are present prior to the increase in inflammatory cells (Phillips et al., Kidney Blood Press Res 30:129-144, 2007; Takahashi et al., J Am Soc Nephrol JASN 1:980-989, 1991), while in other models the increase in inflammatory cells is present prior to or coincident with cyst initiation (Cowley et al., Kidney Int 43:522-534, 1993, Kidney Int 60:2087-2096, 2001). Additional support for inflammation as an important contributor to cystic kidney disease is the increased expression of many pro-inflammatory cytokines in murine models and human patients with cystic kidney disease (Karihaloo et al., J Am Soc Nephrol JASN 22:1809-1814, 2011; Swenson-Fields et al., Kidney Int, 2013; Li et al., Nat Med 14:863-868, 2008a). Based on these data, an emerging model in the field is that disruption of primary cilia on tubule epithelial cells leads to abnormal cytokine cross talk between the epithelium and the inflammatory cells contributing to cyst <em>growth</em> and fibrosis (Ta et al., Nephrology 18:317-330, 2013). These cytokines are produced by interstitial <em>fibroblasts</em>, inflammatory cells, and tubule epithelial cells and activate multiple pathways including the JAK-STAT and NF-κB signaling (Qin et al., J Am Soc Nephrol JASN 23:1309-1318, 2012; Park et al., Am J Nephrol 32:169-178, 2010; Bhunia et al., Cell 109:157-168, 2002). Indeed, inflammatory cells are responsible for producing several of the pro-fibrotic <em>growth</em> <em>factors</em> observed in PKD patients with fibrosis (Nakamura et al., Am J Nephrol 20:32-36, 2000; Wilson et al., J Cell Physiol 150:360-369, 1992; Song et al., Hum Mol Genet 18:2328-2343, 2009; Schieren et al., Nephrol Dial Transplant <em>21</em>:1816-1824, 2006). These <em>growth</em> <em>factors</em> trigger epithelial cell proliferation and myofibroblast activation that stimulate the production of extracellular matrix (ECM) genes including collagen types 1 and 3 and fibronectin, leading to reduced glomerular function with approximately 50% of ADPKD patients progressing to end-stage renal disease (ESRD). Therefore, treatments designed to reduce inflammation and slow the rate of fibrosis are becoming important targets that hold promise to improve patient life span and quality of life. In fact, recent studies in several PKD mouse models indicate that depletion of macrophages reduces cyst severity. In this chapter, we review the potential mechanisms of interstitial inflammation in PKD with a focus on ADPKD and discuss the role of interstitial inflammation in progression to fibrosis and ESRD.

The treatment of diabetic wounds is a considerable clinical challenge. In this study, mouse dermal <em>fibroblasts</em> retrovirally transduced with the human platelet-derived <em>growth</em> <em>factor</em> B (PDGF-B) gene were used to treat diabetic mouse wounds. The PDGF-B gene was obtained from human umbilical vein endothelial cells, cloned into retroviral vectors, and introduced into diabetic mouse C57B1/ks-db/db dermal <em>fibroblasts</em>. In vitro results demonstrated production of PDGF-B protein by these transduced cells at steady-state levels of 1000 ng PDGF-B/10(6) cells/24 hours, and expression of PDGF-B mRNA. These cells were seeded onto polyglycolic acid scaffold matrices and used to treat diabetic mouse 20-mm x 20-mm full-thickness excisional dorsal skin wounds. Measurement of the residual epithelial gap at <em>21</em> days showed significantly accelerated healing (P < 0.05) of wounds treated with PDGF-transduced cells (epithelial gap 10.46 +/- 1.20 mm) compared with untreated wounds (14.66 +/- 0.591 mm), wounds treated with polyglycolic acid alone (14.80 +/- 0.575 mm), or wounds treated with negative control LNCX-transduced cells (13.76 +/- 0.831 mm). Immunohistochemical staining showed intense staining for PDGF in wounds treated with PDGF-B-transduced cells. This study demonstrates the promising potential for gene therapy in diabetic wound healing.

<em>Fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em> (FGF<em>21</em>) is a metabolic hormone primarily secreted from the liver and functions in multiple tissues. Various transcription <em>factors</em> induce FGF<em>21</em> expression in the liver, which indicates that FGF<em>21</em> is a mediator of multiple environmental cues. FGF<em>21</em> alters metabolism under starvation conditions, protects the body from energy depletion, and extends life span. Pharmacological administration of FGF<em>21</em> alleviates dyslipidemia and induces weight loss in obese animals. In addition to the well-studied functions of FG<em>21</em>, several lines of recent evidence indicate a possible link between FGF<em>21</em> and non-alcoholic fatty liver disease (NAFLD). High serum levels of FGF<em>21</em> are associated with NAFLD and its risk <em>factors</em>, such as endoplasmic reticulum stress and chronic inflammation. In addition, FGF<em>21</em> alleviates the major risk <em>factors</em> of NAFLD, including obesity, dyslipidemia, and insulin insensitivity. Thus, FGF<em>21</em> is a potential drug candidate for diseases, such as NAFLD, dyslipidemia, and type 2 diabetes. In this review, the research perspectives of FGF<em>21</em> and therapeutic potencies of FGF<em>21</em> as a modulator of NAFLD are summarized.

Previously, we reported sexually dimorphic bone mass and body composition phenotypes in Igfbp2(-/-) mice (-/-), where male mice exhibited decreased bone and increased fat mass, whereas female mice displayed increased bone but no changes in fat mass. To investigate the interaction between IGF-binding protein (IGFBP)-2 and estrogen, we subjected Igfbp2 -/- and +/+ female mice to ovariectomy (OVX) or sham surgery at 8 weeks of age. At 20 weeks of age, mice underwent metabolic cage analysis and insulin tolerance tests before killing. At harvest, femurs were collected for microcomputed tomography, serum for protein levels, brown adipose tissue (BAT) and inguinal white adipose tissue (IWAT) adipose depots for histology, gene expression, and mitochondrial respiration analysis of whole tissue. In +/+ mice, serum IGFBP-2 dropped 30% with OVX. In the absence of IGFBP-2, OVX had no effect on preformed BAT; however, there was significant "browning" of the IWAT depot coinciding with less weight gain, increased insulin sensitivity, lower intraabdominal fat, and increased bone loss due to higher resorption and lower formation. Likewise, after OVX, energy expenditure, physical activity and BAT mitochondrial respiration were decreased less in the OVX-/- compared with OVX+/+. Mitochondrial respiration of IWAT was reduced in OVX+/+ yet remained unchanged in OVX-/- mice. These changes were associated with significant increases in Fgf<em>21</em> and Foxc2 expression, 2 proteins known for their insulin sensitizing and browning of WAT effects. We conclude that estrogen deficiency has a profound effect on body and bone composition in the absence of IGFBP-2 and may be related to changes in <em>fibroblast</em> <em>growth</em> <em>factor</em> <em>21</em>.

Obesity is a serious and costly issue to the medical welfare worldwide. Probiotics have been suggested as one of the candidates to resolve the obesity-associated problems, but how they combat obesity is not fully understood. Herein, we investigated the effects of Lactobacillus reuteri 263 (L. reuteri 263) on antiobesity using four groups of Sprague-Dawley rats (n=10/group), namely, C (normal diet with vehicle treatment), HE [high-energy diet (HED) with vehicle treatment], 1X (HED with 2.1×109 CFU/kg/day of L. reuteri 263) and 5X (HED with 1.05×1010 CFU/kg/day of L. reuteri 263), for 8 weeks. L. reuteri 263 improved the phenomenon of obesity, serum levels of proinflammatory <em>factors</em> and antioxidant enzymes. More importantly, L. reuteri 263 increased oxygen consumption in white adipose tissue (WAT). The mRNA expressions of thermogenesis genes uncoupling protein-1, uncoupling protein-3, carnitine palmitoyltransferase-1 and cell death-inducing DFFA-like effector-a were up-regulated in WAT of the 5X group. Moreover, L. reuteri 263 might induce browning of WAT due to the higher mRNA levels of browning-related genes peroxisome proliferator-activated receptor-γ, PR domain containing-16, Pparγ coactivator-1α, bone morphogenetic protein-7 and <em>fibroblast</em> <em>growth</em> <em>factor</em>-<em>21</em> in the 1X and 5X groups compared to the HE group. Finally, L. reuteri 263 altered the expressions of genes involved in glucose and lipid metabolisms in WAT, including increasing the levels of glucose transporter type 4 and carbohydrate-responsive element-binding protein and decreasing the expression of Acetyl-CoA carboxylase-1. The results suggest that L. reuteri 263 may treat obesity through energy metabolism remodeling of WAT in the high-energy-diet-induced obese rats.