Plasma Fibroblast Growth Factor 21 Research Articles

The effect of hydration status on plasma FGF21 concentrations in humans:A subanalysis of a randomised crossover trial.

Fibroblast growth factor 21 (FGF21) has recently been implicated in thirst in rodent models. The mechanisms for this are currently uncertain, and it is unclear whether hydration status can alter FGF21 concentrations, potentially providing an additional mechanism by which hypohydration induces thirst. The aim of this study is therefore to understand whether hydration status can alter circulating FGF21 in humans. Using a heat tent and fluid restriction, we induced hypohydration (1.9% body mass loss) in 16 healthy participants (n = 8 men), and compared their glycaemic regulation to a rehydration protocol (heat tent and fluid replacement) in a randomised crossover design. After the hypohydration procedure, urine specific gravity, urine and serum osmolality, and plasma copeptin (as a marker for arginine vasopressin) increased as expected, with no change after the rehydration protocol. In the fasted state, the median paired difference in plasma FGF21 concentrations from the rehydrated to hypohydrated trial arm was -37 (interquartile range -125, 10) pg∙mL-1(P = 0.278), with average concentrations being 458 ± 462 pg∙mL-1 after hypohydration and 467 ± 438 pg∙mL-1 after rehydration; mean difference -9 ± 173 pg∙mL-1. To our knowledge, these are the first causal data in humans investigating hydration and FGF21, demonstrating that an acute bout of hypohydration does not impact fasted plasma FGF21 concentrations. These data may suggest that whilst previous research has found FGF21 administration can induce thirst and drinking behaviours, a physiological state implicated in increased thirst (hypohydration) does not appear to impact plasma FGF21 concentrations in humans.

Fibroblast growth factor 21 (FGF21) in children and adolescents with chronic kidney disease.

Fibroblast growth factor 21 (FGF21) is one of the members of endocrine arm of FGF family. Its actions as a glucose and lipids metabolism regulator are widely known. Although the mechanism of FGF21 action in kidneys is still under investigation, FGF21 was considered as a marker of early kidney function decline. While many researchers focused on adult subjects in this matter, there are no data regarding children. Therefore, we have investigated the relationship between plasma or urine FGF21 levels and kidney function in a group of 42 pediatric patients with chronic kidney disease (CKD). Anthropometrical parameters and blood pressure were taken, routine biochemical tests were performed. The concentration of FGF21 in serum and urine was determined by enzyme immunoassay. The results revealed significantly higher serum FGF21 concentration among children from CKD group. However, serum FGF21 level was not related to gender, proteinuria, eGFR or renal replacement therapy. Urine FGF21 concentration correlated negatively with albuminuria and positively with eGFR. Documented negative correlation of FGF21 fractional excretion and eGFR is not enough to support the role of FGF21 as a biomarker for predicting kidney disease progression in children and adolescents. Other mechanisms including local kidney FGF21 production or enhanced excretion due to higher extrarenal production may result in higher urine FGF21 concentrations.

222-LB: Diabetes Induces Liver Inflammation and FGF21 through C-Jun NH2-Terminal Kinase Pathways

Fibroblast growth factor 21 (FGF-21) is a hormone that regulates important metabolic pathways. Serum fibroblast FGF-21 levels were significantly higher in obesity and type 2 diabetes mellitus (T2DM). Previously, we have found that the JNK pathway played a critical role in diabetes-induced Kupffer cell activation, and pJNK1 inhibition decreases Kupffer cell activation induced by diabetes. We aim to study the involvement c-Jun NH2-terminal kinase pathways in the regulatory mechanisms of liver inflammation and FGF-21 in diabetes. Type 1 diabetic Akita mice (C57BL/6J-Ins2Akita) and type 2 diabetic Leprdb/db mice (C57BL/6J- Leprdb/db) were used. Leprdb/db-JNK1-/- and Ins2Akita-JNK1-/- mice were produced and used to study the role of pJNK in the regulatory mechanisms of diabetes on liver inflammation and FGF-21. Diabetic mice demonstrated increased ICAM, iNOS, interleukin 1 beta (IL-1β), FGF-21, and FMO3 expression of liver; and tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells; and plasma FGF-21 levels. Ins2Akita-JNK1-/- and Leprdb/db-JNK1-/- mice demonstrated decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver; and ICAM, iNOS, and FMO3 expression in aorta, tumor necrosis factor alpha (TNF-α), and iNOS expression in Kupffer cells, plasma IL-6 and TNF-α levels; dipeptidyl peptidase (DPP-4) activity. JNK inhibitor, SP600125, injection into adipose tissue of Leprdb/db mice significantly decreased ICAM, iNOS, IL-1β, and FMO3 expression of liver and serum FGF-21 levels. Altogether, our data suggest that diabetes induces liver inflammation, FGF-21, and insulin resistance through c-Jun NH2-terminal kinase. Disclosure L. Chen: None. Funding National Science Council (MOST 107-2314-B-010-043-MY3)

The Consequences of LP Diet on Food Intake, Energy Expenditure and Hepatic and Hypothalamic FGF21 Are Reproduced by lLsine or Threonine Deficiency in Rats

Abstract Objectives In mice, low protein (LP) diets increase food intake (FI) thereby energy intake, to compensate for protein deficiency, but mice do not gain fat because total energy expenditure (TEE) is also increased. Fibroblast Growth Factor 21 (FGF21), which is expressed in the liver and in the brain, appears as a key player in these effects. The present study hypothesized that both LP diet but also only lysine or threonine deficiency can modulate FGF21 in the liver and in the hypothalamus that in turn is involved in the control of FI and energy expenditure. Methods Growing rats were fed for 3 weeks: i) LP diets containing 3-5-8-12-15 or 20% of milk protein, or ii) the same diets but supplemented with free amino acids at the level of the 20% protein diet except for lysine or threonine leading to lysine or threonine deficient diets. Body weight and FI were measured daily and energy expenditure were measured by indirect calorimetry. At the end of the experiment, rats were euthanized, tissues and biological fluids were removed and frozen, and body composition as well as gene expression and plasma FGF21 were analyzed. Results Diets with 3 and 5% protein, and diets highly deficient in lysine or threonine (85% and 75%) result in significant growth retardation. LP 3% and 5% induced an increase in relative FI. Surprisingly, an increase in TEE was observed under LP 5% protein, due to an increase in motor activity. Hepatic FGF21 expression is increased at 3 and 5% and strongly decreased at 12, 15 and 20% protein. In contrast, in the hypothalamus, FGF21 expression was significantly lower in LP 3% compared to a 20% protein diet, and for the other LP diets, the values are intermediate. Plasma FGF21 was higher in 3, 5, 8 and 12% protein than in 15 and 20% protein diets. Lysine or threonine deficiency were able to reproduce the effect of LP diet at 3 and 5% whereas at 8%, only the deficiency of threonine was able to reproduce the LP effect. Conclusions These results showed that hepatic and hypothalamic expression FGF21 are inversely affected by protein deficiency. Such situations of deficiency induced an up-regulation of hepatic expression of FGF21 that increased TEE and a down-regulation of hypothalamic expression of FGF21 that could led to hyperphagia. Interestingly, the levels of FGF21 observed for the 3, 5, 8% protein diets could be due at least to lysine and threonine deficiency. Funding Sources ABIES, AlimH department of INRAe.

Possible associations between plasma fibroblast growth factor 21 levels and cognition in bipolar disorder.

Bipolar disorder (BD) is a mental disorder characterized by extreme changes in mood polarity. It is also characterized by cognitive and metabolic dysfunctions. Fibroblast growth factor 21 (FGF21) is an endocrine protein that has a multifaceted function such as glucose and lipid regulation in the periphery, and neuroprotection and induction of synaptic plasticity in the central nervous system. Previous studies reported inconsistent results concerning peripheral FGF21 levels in patients with BD. In this study, we compared plasma FGF21 levels between 26 patients with BD and 51 healthy controls using a human FGF21 ELISA Kit. There was no significant difference in plasma FGF21 levels between the patients and controls. We found significant positive correlations between plasma FGF21 levels and some cognitive parameters (word association and motor speed). If our results are replicated that higher peripheral FGF21 may be associated with better cognitive performance in patients with BD.

Fibroblast Growth Factor-21, Leptin, and Adiponectin Responses to Acute Cold-Induced Brown Adipose Tissue Activation.

BackgroundAdipocyte-derived hormones play a role in insulin sensitivity and energy homeostasis. However, the relationship between circulating fibroblast growth factor 21 (FGF21), adipocytokines and cold-induced supraclavicular brown adipose tissue (sBAT) activation is underexplored.ObjectiveOur study aimed to investigate the relationships between cold-induced sBAT activity and plasma FGF21 and adipocytokines levels in healthy adults.DesignNineteen healthy participants underwent energy expenditure (EE) and supraclavicular infrared thermography (IRT) within a whole-body calorimeter at baseline and at 2 hours post-cold exposure. 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scans were performed post-cold exposure. PET sBAT mean standardized uptake value (SUV mean), MR supraclavicular fat fraction (sFF), anterior supraclavicular maximum temperature (Tscv max) and EE change (%) after cold exposure were used to quantify sBAT activity.Main Outcome MeasuresPlasma FGF21, leptin, adiponectin, and tumor necrosis factor alpha (TNFα) at baseline and 2 hours post-cold exposure. Body composition at baseline by dual-energy x-ray absorptiometry (DXA).ResultsPlasma FGF21 and adiponectin levels were significantly reduced after cold exposure in BAT-positive subjects but not in BAT-negative subjects. Leptin concentration was significantly reduced in both BAT-positive and BAT-negative participants after cold exposure. Adiponectin concentration at baseline was positively strongly associated with sBAT PET SUV mean (coefficient, 3269; P = 0.01) and IRT Tscv max (coefficient, 6801; P = 0.03), and inversely correlated with MR sFF (coefficient, −404; P = 0.02) after cold exposure in BAT-positive subjects but not in BAT-negative subjects.ConclusionHigher adiponectin concentrations at baseline indicate a greater cold-induced sBAT activity, which may be a novel predictor for sBAT activity in healthy BAT-positive adults.HighlightsA higher adiponectin concentration at baseline was associated with higher cold-induced supraclavicular BAT PET SUV mean and IRT Tscv max, and lower MR supraclavicular FF. Adiponectin levels maybe a novel predictor for cold-induced sBAT activity.

Hepatic Fat Content Is Associated with Fasting-Induced Fibroblast Growth Factor 21 Secretion in Mice Fed Soy Proteins.

Previous studies suggest that circulating fibroblast growth factor 21 (FGF21) levels are elevated in patients with fatty liver, while fasting-induced secretion of FGF21 is lower in obese patients. It has been reported that soy protein prevents hepatic fat accumulation and induces FGF21 secretion. The present study was designed to evaluate the response of circulating FGF21 levels to feeding and fasting in mice fed soy protein-rich diets. For this, C57BL/6J mice were distributed into control, high-fat high-sucrose (HFHS)-casein protein, HFHS-soy protein, and HFHS-β-conglycinin diet groups. Plasma samples were collected after 10 and 11 wk either in dark periods with feeding conditions or light periods under fasting conditions using a crossover design. After a 12-wk period of feeding, HFHS-induced hepatic fat accumulation was significantly reduced in the groups fed HFHS-soy protein and HFHS-β-conglycinin as compared to that in the HFHS-casein-fed group (p<0.05). Plasma FGF21 concentration was significantly higher in the dark/feeding periods in the HFHS-casein group (p<0.05), while in the HFHS-β-conglycinin group it was higher in the light/fasting periods (p<0.05). The amount of mesenteric fat was significantly lower in the HFHS-β-conglycinin group than in the HFHS-casein and HFHS-soy protein groups (p<0.01). The fasting-induced FGF21 secretion was significantly and negatively correlated with hepatic fat content (p<0.05). The present study revealed that hepatic fat accumulation was associated with lower fasting-induced FGF21 secretion, which was regulated better by dietary intake of soy protein. These results support the preventive effects of soy protein on central obesity.

FGF21, not GCN2, influences bone morphology due to dietary protein restrictions

BackgroundDietary protein restriction is emerging as an alternative approach to treat obesity and glucose intolerance because it markedly increases plasma fibroblast growth factor 21 (FGF21) concentrations. Similarly, dietary restriction of methionine is known to mimic metabolic effects of energy and protein restriction with FGF21 as a required mechanism. However, dietary protein has been shown to be required for normal bone growth, though there is conflicting evidence as to the influence of dietary protein restriction on bone remodeling. The purpose of the current study was to evaluate the effect of dietary protein and methionine restriction on bone in lean and obese mice, and clarify whether FGF21 and general control nonderepressible 2 (GCN2) kinase, that are part of a novel endocrine pathway implicated in the detection of protein restriction, influence the effect of dietary protein restriction on bone. MethodsAdult wild-type (WT) or Fgf21 KO mice were fed a normal protein (18 kcal%; CON) or low protein (4 kcal%; LP) diet for 2 or 27 weeks. In addition, adult WT or Gcn2 KO mice were fed a CON or LP diet for 27 weeks. Young New Zealand obese (NZO) mice were placed on high-fat diets that provided protein at control (16 kcal%; CON), low levels (4 kcal%) in a high-carbohydrate (LP/HC) or high-fat (LP/HF) regimen, or on high-fat diets (protein, 16 kcal%) that provided methionine at control (0.86%; CON-MR) or low levels (0.17%; MR) for up to 9 weeks. Long bones from the hind limbs of these mice were collected and evaluated with micro-computed tomography (μCT) for changes in trabecular and cortical architecture and mass. ResultsIn WT mice the 27-week LP diet significantly reduced cortical bone, and this effect was enhanced by deletion of Fgf21 but not Gcn2. This decrease in bone did not appear after 2 weeks on the LP diet. In addition, Fgf21 KO mice had significantly less bone than their WT counterparts. In obese NZO mice dietary protein and methionine restriction altered bone architecture. The changes were mediated by FGF21 due to methionine restriction in the presence of cystine, which did not increase plasma FGF21 levels and did not affect bone architecture. ConclusionsThis study provides direct evidence of a reduction in bone following long-term dietary protein restriction in a mouse model, effects that appear to be mediated by FGF21.

Hepatic stearoyl CoA desaturase 1 deficiency increases glucose uptake in adipose tissue partially through the PGC-1α–FGF21 axis in mice

Increased carbohydrate consumption increases hepatic de novo lipogenesis, which has been linked to the development of chronic metabolic diseases, including obesity, hepatic steatosis, and insulin resistance. Stearoyl CoA desaturase 1 (SCD1) is a critical lipogenic enzyme that catalyzes the synthesis of two monounsaturated fatty acids, oleate and palmitoleate, from the saturated fatty acids stearate and palmitate, respectively. SCD1-deficient mouse models are protected against diet-induced adiposity, hepatic steatosis, and hyperglycemia. However, the mechanism of this protection by SCD1 deficiency is unclear. Using liver-specific SCD1 knockout (LKO) mice fed a high-carbohydrate, low-fat diet, we show that hepatic SCD1 deficiency increases systemic glucose uptake. Hepatic SCD1 deficiency enhanced glucose transporter type 1 (GLUT1) expression in the liver and also up-regulated GLUT4 and adiponectin expression in adipose tissue. The enhanced glucose uptake correlated with increased liver expression and elevated plasma levels of fibroblast growth factor 21 (FGF21), a hepatokine known to increase systemic insulin sensitivity and regulate whole-body lipid metabolism. Feeding LKO mice a triolein-supplemented but not tristearin-supplemented high-carbohydrate, low-fat diet reduced FGF21 expression and plasma levels. Consistently, SCD1 inhibition in primary hepatocytes induced FGF21 expression, which was repressed by treatment with oleate but not palmitoleate. Moreover, deletion of the transcriptional coactivator PPARγ coactivator 1α (PGC-1α) reduced hepatic and plasma FGF21 and white adipocyte tissue-specific GLUT4 expression and raised plasma glucose levels in LKO mice. These results suggest that hepatic oleate regulates glucose uptake in adipose tissue either directly or partially by modulating the hepatic PGC-1α-FGF21 axis.

Factor-Associated Risk Factors of Mild Cognitive Impairment in Thalassemia Patients : Probable Role of FGF21

Background Iron overload is the most common complication in thalassemia patients resulted from multiple blood transfusions and increased intestinal iron absorption. Heart and liver abnormalities remain major organs involved in patients with iron overload. There is limited data regarding the association between the iron overload and the risk of cognitive impairment in patients with thalassemia. Fibroblast growth factor 21 (FGF21) is a protein with wide ranging functions, including cell development, cell proliferation, and wound healing. Our previous study reported the FGF21 level was independently associated with cognitive impairment in non-elderly patients with metabolic syndrome. Therefore, the aim of this study is to determine the prevalence and associated risk factors of cognitive impairment in thalassemia patients. Methods This study was a cross-sectional and single-center study. All thalassemia patients, age 18 years or older, who attended the adult hematology clinic, Faculty of Medicine, Chiang Mai University, between November 2018 and July 2019 were enrolled in the study. The diagnosis of thalassemia was based on a hemoglobin analysis using a high-performance liquid column chromatography (HPLC) method. Patients who had pre-existing neurological disorders, psychiatric problems, history of brain surgery or history of traumatic brain injury were excluded from the study. Cognitive function was assessed using the Montreal cognitive assessment (MoCA) test. Data regarding age, sex, type and severity of thalassemia, level of education, transfusion status, maximum ferritin in the past 5 years and current medications were collected. The laboratory investigations included complete blood count, reticulocyte count, serum creatinine, electrolyte, liver function test and serum ferritin were performed at the time of enrollment. Blood samples for FGF21 level were collected from all participants. Results A total of 76 thalassemia patients were enrolled in this study. Seventy percent of patients were female with a median age of 31 years old (18-59). More than half of patients were graduated with a bachelor's degree. Beta-thalassemia/hemoglobin E disease was the most common type of thalassemia. Splenectomy was done in 48.7% of patients. Majority of patients (76.3%) developed iron overload and were treated with iron-chelating agents. Median serum ferritin and maximum serum ferritin in past 5 years were 1,418.5 ng/ml and 1,945.0 ng/ml, respectively. Mild cognitive impairment (MoCA score &lt;26) was observed in 76.3% of patients. Median serum ferritin and plasma FGF21 levels were 1,463.0 ng/ml, and 390.10 pg/ml, respectively. Plasma FGF21 level was positively associated with serum ferritin and maximum serum ferritin in past 5 years, but showed a negative correlation with hemoglobin level. Interestingly, MoCA score was negative associated with plasma FGF21 level and was not different among type of thalassemia, splenectomy, gender, transfusion status, and hemoglobin level (Figure 1). Conclusions A high prevalence of mild cognitive impairment was occurred in thalassemia patients (76%). FGF21 level was independently associated with cognitive impairment in thalassemia patients. Therefore, the possible role of FGF21 level in cognitive impairment in thalassemia patients should be further investigated. Disclosures No relevant conflicts of interest to declare.

The relationship of circulating fibroblast growth factor 21 levels with pericardial fat: The Multi-Ethnic Study of Atherosclerosis

Previous small studies have reported an association between circulating fibroblast growth factor 21 (FGF21) levels and pericardial fat volume in post-menopausal women and high cardiovascular disease (CVD) risk patients. In this study, we investigated the relationship of FGF21 levels with pericardial fat volume in participants free of clinical CVD at baseline. We analysed data from 5765 men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) with both pericardial fat volume and plasma FGF21 levels measured at baseline. 4746 participants had pericardial fat volume measured in at least one follow-up exam. After adjusting for confounding factors, ln-transformed FGF21 levels were positively associated with pericardial fat volume at baseline (β = 0.055, p < 0.001). When assessing change in pericardial fat volume over a mean duration of 3.0 years using a linear mixed-effects model, higher baseline FGF21 levels were associated with higher pericardial fat volume at baseline (2.381 cm3 larger in pericardial fat volume per one SD increase in ln-transformed FGF21 levels), but less pericardial fat accumulation over time (0.191 cm3/year lower per one SD increase in ln-transformed FGF21 levels). Cross-sectionally, higher plasma FGF21 levels were significantly associated with higher pericardial fat volume, independent of traditional CVD risk factors and inflammatory markers. However, higher FGF21 levels tended to be associated with less pericardial fat accumulation over time. Nevertheless, such change in pericardial fat volume is very modest and could be due to measurement error. Further studies are needed to elucidate the longitudinal relationship of baseline FGF21 levels with pericardial fat accumulation.

GPR120 controls neonatal brown adipose tissue thermogenic induction.

Adaptive induction of thermogenesis in brown adipose tissue (BAT) is essential for the survival of mammals after birth. We show here that G protein-coupled receptor protein 120 (GPR120) expression is dramatically induced after birth in mouse BAT. GPR120 expression in neonatal BAT is the highest among GPR120-expressing tissues in the mouse at any developmental stage tested. The induction of GPR120 in neonatal BAT is caused by postnatal thermal stress rather than by the initiation of suckling. GPR120-null neonates were found to be relatively intolerant to cold: close to one-third did not survive at 21°C, but all such pups survived at 25°C. Heat production in BAT was significantly impaired in GPR120-null pups. Deficiency in GPR120 did not modify brown adipocyte morphology or the anatomical architecture of BAT, as assessed by electron microscopy, but instead impaired the expression of uncoupling protein-1 and the fatty acid oxidation capacity of neonatal BAT. Moreover, GPR120 deficiency impaired fibroblast growth factor 21 (FGF21) gene expression in BAT and reduced plasma FGF21 levels. These results indicate that GPR120 is essential for neonatal adaptive thermogenesis.

301-LB: Effects of Amino Acid Restriction on Development of Type 2 Diabetes in NZO Mice by FGF21 Secretion

Dietary protein restriction (PR) is emerging as an alternative approach to treat obesity and glucose intolerance since it increases plasma fibroblast growth factor 21 (FGF-21) levels. Also, dietary methionine restriction (MR) is known to mimic the metabolic effects of PR by increasing FGF-21 and inducing beneficial effects. Therefore, we tested in New Zealand Obese (NZO) mice, a model of polygenic obesity and type 2 diabetes, whether a moderate PR or a MR protects against diabetes. Moreover, we investigated whether a decreased methionine intake caused by vegetarian and vegan diets modulates plasma FGF-21 in humans. NZO mice were placed on high-fat diets that provided protein at control (18 gm%), low levels (4 gm%), or on high-fat diets (protein, 18 gm%) that provided methionine at control (0.86 gm%) or low levels (0.17 gm%) for up to 9 weeks. Changes in glucose homeostasis and energy expenditure were assessed. Among humans, plasma FGF-21 levels were investigated by comparing vegetarians and vegans to omnivores, and the effect of short-term vegetarian diet on FGF-21 induction was evaluated. PR prevented the onset of hyperglycemia only when protein was substituted by fat. When protein was substituted by carbohydrates, mice developed hyperglycemia two weeks later than the control, despite elevated plasma FGF-21 levels and increased energy expenditure. MR elevated plasma FGF-21 levels and prevented the onset of hyperglycemia. Human plasma FGF-21 levels were higher in vegans and vegetarians compared to omnivores. Interestingly, already a short-term switch to a vegetarian diet increased plasma FGF-21 in omnivores. Thus, restriction of dietary protein and methionine elevates plasma FGF-21 levels, which protect from hyperglycemia, an effect compromised by high dietary carbohydrates in NZO mice. Patients at high risk of developing type 2 diabetes may benefit from dietary changes in favor of methionine restriction, via increased circulating levels of FGF-21, without protein and calorie restriction. Disclosure T. Castaño-Martinez: None. W. Jonas: None. D. Weber: None. C. Weikert: None. T. Laeger: None. Funding Deutsche Forschungsgemeinschaft

Intestinal serine protease inhibition increases FGF21 and improves metabolism in obese mice.

Trypsin is the major serine protease responsible for intestinal protein digestion. An inhibitor, camostat (CS), reduced weight gain, hyperglycemia, and dyslipidemia in obese rats; however, the mechanisms for these are largely unknown. We reasoned that CS creates an apparent dietary protein restriction, which is known to increase hepatic fibroblast growth factor 21 (FGF21). Therefore, metabolic responses to CS and a gut-restricted CS metabolite, FOY-251, were measured in mice. Food intake, body weight, blood glucose, branched-chain amino acids (LC/MS), hormone levels (ELISA), liver pathology (histology), and transcriptional changes (qRT-PCR) were measured in ob/ob, lean and diet-induced obese (DIO) C57BL/6 mice. In ob/ob mice, CS in chow (9-69 mg/kg) or FOY-251 (46 mg/kg) reduced food intake and body weight gain to a similar extent as pair-fed mice. CS decreased blood glucose, liver weight, and lipidosis and increased FGF21 gene transcription and plasma levels. In lean mice, CS increased liver FGF21 mRNA and plasma levels. Relative to pair feeding, FOY-251 also increased plasma FGF21 and induced liver FGF21 and integrated stress response (ISR) transcription. In DIO mice, FOY-251 (100 mg/kg po) did not alter peak glucose levels but reduced the AUC of the glucose excursion in response to an oral glucose challenge. FOY-251 increased plasma FGF21 levels. In addition to previously reported satiety-dependent (cholecystokinin-mediated) actions, intestinal trypsin inhibition engages non-satiety-related pathways in both leptin-deficient and DIO mice. This novel mechanism improves metabolism by a liver-integrated stress response and increased FGF21 expression levels in mice. NEW & NOTEWORTHY Trypsin inhibitors, including plant-based consumer products, have long been associated with metabolic improvements. Studies in the 1980s and 1990s suggested this was due to satiety hormones and caloric wasting by loss of protein and fatty acids in feces. This work suggests an entirely new mechanism based on the lower amounts of digested protein available in the gut. This apparent protein reduction may cause beneficial metabolic adaptation by the intestinal-liver axis to perceived nutrient stress.

Plasma Fibroblast Growth Factor 21 Is Associated With Severity of Nonalcoholic Steatohepatitis in Patients With Obesity and Type 2 Diabetes.

The relationship between plasma fibroblast growth factor 21 (FGF21), insulin resistance, and steatohepatitis has not been systematically assessed. To determine if higher plasma FGF21 is associated with worse steatohepatitis on liver biopsy in patients with nonalcoholic fatty liver disease (NAFLD). Cross-sectional study in a university hospital. Patients with a body mass index >25 (n = 187) underwent: (i) euglycemic hyperinsulinemic clamp to assess tissue-specific insulin resistance (IR); (ii) liver magnetic resonance spectroscopy for intrahepatic triglyceride quantification, (iii) liver biopsy (if NAFLD present; n = 146); and (iv) fasting plasma FGF21 levels. Patients were divided into three groups: (i) No NAFLD (n = 41); (ii) No nonalcoholic steatohepatitis (NASH) (patients with isolated steatosis or borderline NASH; n = 52); and (iii) NASH (patients with definite NASH; n = 94). Groups were well-matched for age/sex, prevalence of type 2 diabetes mellitus, and hemoglobin A1c. During euglycemic hyperinsulinemic insulin clamp, insulin sensitivity in skeletal muscle and adipose tissue worsened from No NAFLD to NASH (both P < 0.001). Plasma FGF21 levels correlated inversely with insulin sensitivity in adipose tissue (r = -0.17, P = 0.006) and skeletal muscle (r = -0.23, P = 0.007), but not with liver insulin sensitivity. Plasma FGF21 was higher in patients with NASH (453 ± 262 pg/mL) when compared with the No NASH (341 ± 198 pg/mL, P = 0.03) or No NAFLD (325 ± 289 pg/mL, P = 0.02) groups. Plasma FGF21 increased with the severity of necroinflammation (P = 0.02), and most significantly with worse fibrosis (P < 0.001), but not with worsening steatosis (P = 0.60). Plasma FGF21 correlates with severity of steatohepatitis, in particular of fibrosis, in patients with NASH. Measurement of FGF21 may help identify patients at the highest risk of disease progression.

Methionine restriction prevents onset of type 2 diabetes in NZO mice

Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet–induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.—Castaño-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schürmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.

High plasma FGF21 levels predicts major cardiovascular events in patients treated with atorvastatin (from the Treating to New Targets [TNT] Study)

BackgroundHigher plasma fibroblast growth factor 21 (FGF21) levels predict incident cardiovascular events in type 2 diabetes patients. However, whether FGF21 levels predict cardiovascular events in statin-treated patients in the general population is unknown. We investigated whether FGF21 levels predict major cardiovascular event (MCVE) in the Treating to New Targets (TNT) trial participants. MethodsAfter 8-week run-in on atorvastatin 10 mg/day, 10,001 patients with stable coronary disease in the TNT trial were randomized to 10 mg or 80 mg/day of atorvastatin for a median of 4.9 years. We analyzed data from 1996 patients with plasma FGF21 levels measured at randomization. Among them, 1835 patients had FGF21 measured one-year post-randomization. ResultsHigher ln-transformed FGF21 levels at randomization were associated with higher risk of incident MCVE (adjusted hazards ratio per SD increase = 1.18, P = 0.019). At 1-year post-randomization, FGF21 levels were lower in patients randomized to receive 80 mg versus 10 mg atorvastatin (186.9 versus 207.5 pg/mL respectively, P = 0.006). Higher ln-transformed FGF21 levels at 1-year post-randomization were also associated with higher subsequent risk of MCVEs (adjusted hazards ratio per SD increase = 1.24, P = 0.009). However, changes in FGF21 levels over 1-year were not related to subsequent MCVE risk. FGF21 levels had significant incremental value in net reclassification improvement in MCVE risk prediction. ConclusionsHigher plasma FGF21 levels are associated with higher CVD risk in statin-treated high-risk patients. Higher dose atorvastatin is associated with a reduction in FGF21 levels. FGF21 provides incremental value in CVD risk prediction in statin-treated patients.

Fasting decreases plasma FGF21 in obese subjects and the expression of FGF21 receptors in adipose tissue in both lean and obese subjects

Fibroblast growth factor 21 (FGF21) is a metabolic regulator of energy and lipid metabolism. FGF21 is highly expressed in liver while FGF21 receptors (beta-klotho (KLB) and FGFR1c) are highly expressed in white adipose tissues (WATs). Plasma FGF21 has been shown to be increased after 7–10 days of fasting but oppositely plasma FGF21 is also increased in obesity. The aim of this study was to measure the effect of 60 h of fasting on plasma FGF21 levels in obese and lean subjects and to determine the gene expression of KLB and FGFR1c in the subcutaneous WAT before, during and after 60 h of fasting. Eight obese (BMI >30 kg/m2) and seven lean subjects (BMI <25 kg/m2) were fasted for 60 h and blood samples were taken at time 0 and after 12, 36 and 60 h of fasting. A biopsy from the subcutaneous WAT was taken at time 0, 12 and 60 h of fasting. FGF21 was measured in plasma by an ELISA and mRNA expression of KLB and FGFR1c was measured in WAT by quantitative PCR (qPCR). The fast significantly decreased plasma FGF21 in obese subjects while no change in plasma FGF21 was observed in lean subjects. Interestingly, KLB was significantly decreased in WAT in response to fasting in both lean and obese subjects indicating a potential important adaptive regulation of KLB in response to fasting.

FGF21 Is a Hormonal Mediator of the Human "Thrifty" Metabolic Phenotype.

Fibroblast growth factor 21 (FGF21) regulates energy expenditure (EE) and influences weight change during low-protein overfeeding in rodent models. The change in EE after a low-protein overfeeding diet is a predictor of weight change in humans and a feature of the "thrifty" metabolic phenotype. However, there are no studies showing an association between circulating FGF21 and diet-related EE in humans. We assessed the changes in plasma FGF21 concentrations after 24 h of seven dietary interventions with different macronutrient content while in a whole-room indirect calorimeter in 64 healthy subjects with normal glucose regulation. Plasma FGF21 concentration consistently increased by threefold only after the two low-protein (3%) overfeeding diets, one high in carbohydrate (75%) and the other high in fat (46%), with larger increases in FGF21 being associated with greater increases in 24-h EE. Subjects with smaller increases in FGF21 after the low-protein high-fat diet gained more weight after 6 months in free-living conditions. Therefore, the individual predisposition to weight gain over time can be assessed by 24-h overfeeding a low-protein diet and measurements of plasma FGF21 concentrations. Individuals with a blunted FGF21 response to a low-protein diet have a thrifty metabolism and are at risk for future weight gain.

Fibroblast growth factor 21 as a biomarker for long-term complications in organic acidemias

BackgroundThere is increasing evidence that long-term complications in organic acidemias are caused by impaired mitochondrial metabolism. Currently, there is no specific biomarker to monitor mitochondrial dysfunction in organic acidemias. Serum fibroblast growth factor 21 (FGF-21) is a biomarker for mitochondrial disease and could be a candidate to monitor mitochondrial function in the deleterious course of disease.MethodsData of 17 patients with classical organic acidemias (11 propionic acidemia (PA), four methylmalonic acidemia (MMA) and two isovaleric acidemia (IVA) patients) were included. The clinical course was evaluated; metabolic decompensations and long-term complications were correlated with plasma FGF-21 levels. Cardiomyopathy, prolonged QT interval, renal failure, and optic neuropathy were defined as long-term complications.ResultsPatients ages ranged from 16 months up to 32 years. Serious long-term complications occurred in eight patients (five PA and three MMA patients). In MMA and PA patients plasma FGF-21 levels during stable metabolic periods were significantly higher in patients with long-term complications (Mdn = 2556.0 pg/ml) compared to patients without (Mdn = 287.0 pg/ml). A median plasma FGF-21 level above 1500 pg/ml during a stable metabolic period, measured before the occurrence of long-term complications, had a positive predictive value of 0.83 and a negative predictive value of 1.00 on long-term complications in MMA and PA patients.ConclusionThis study demonstrates the potential role of FGF-21 as a biomarker for long-term complications in classical organic acidemias, attributed to mitochondrial dysfunction.