Fibroblast Growth Factor 21: A Versatile Regulator of Metabolic Homeostasis

In the paper

“Knockdown of hepatic Fgf21 using adenovirus-mediated expression of short hairpin RNAs directed against Fgf21 mRNA resulted in significantly elevated hepatic triglyceride and plasma lipid levels, and impaired ketosis (7).”

What the sources say

• Supported

  The Results report that adenovirus-mediated shRNA knockdown of FGF21 in mice on a ketogenic diet increased hepatic triglycerides and circulating lipids. They also report a significant, though relatively modest, reduction in serum ketones. (LLM, conf=0.94)

  cites [7] source

In the paper

“The Fgf21 promoter has multiple ATF4 binding sites, and GCN2-mediated activation of ATF4 leads to the induction of hepatic and circulating levels of FGF21 (24, 68, 72).”

What the sources say

• Not checked yetcites [24] source
• Not checked yetcites [68] source
• Supported

  The Experimental Procedures identify distal and proximal ATF4 binding sites in the mouse FGF21 promoter. The Discussion links GCN2-dependent ATF4 activation to the acute induction of hepatic Fgf21 and circulating FGF21 during dietary protein restriction. It also notes that GCN2 is not required for the longer-term increase, so the claim should not be read as saying this pathway is always necessary. (LLM, conf=0.90)

  cites [72] source

In the paper

“Mice that lack FGF21 develop marked liver steatosis and injury in response to chronic alcohol consumption despite being able to clear ethanol as effectively as wild-type controls (26).”

What the sources say

• Supported

  The Results section on chronic ethanol consumption in drinking water reports steatosis and liver injury in FGF21-KO mice compared with wild-type mice (Figure 6). The Discussion states that, in this 16-week drinking-water and chow model, the groups had the same serum ethanol levels and capacity to metabolize ethanol. The clearance finding is specific to this model; the paper reports impaired ethanol metabolism in a separate high-fat-diet model. (LLM, conf=0.91)

  cites [26] source

In the paper

“Neither the inducible expression of a constitutively active FGFR1 protein specifically in adipose tissue (11) nor antibody-mediated activation of a chimeric human FGFR1 receptor in brown adipocytes (17) is sufficient to increase energy expenditure or affect body weight in vivo.”

What the sources say

• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [11] sourceExperimental — accuracy not yet measured
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [17] sourceExperimental — accuracy not yet measured

In the paper

“In contrast to the studies supporting a role for adipose-derived FGF21 in regulating thermogenesis, recent work from our lab has found that liver-derived, but not adipose-derived, FGF21 regulates core body temperature during cold exposure.”

In the paper

“Plasma FGF21 levels are induced acutely from the liver in response to cold exposure and liver-derived FGF21 signals to the CNS to increase sympathetic nerve activity to BAT and regulate core body temperature (Figure 3b) (M. Ameka, K.M. Markan & M.J. Potthoff, unpublished data).”

In the paper

“Fibroblast growth factor 21 (FGF21) is an endocrine hormone derived from the liver that exerts pleiotropic effects on the body to maintain overall metabolic homeostasis.”

In the paper

“Unlike traditional FGFs, however, the FGF19 subfamily of FGFs, consisting of FGF19, FGF21, and FGF23, has reduced affinity for HSGAGs and diffuses into circulation to act on distal tissues (9, 106). Thus, these FGFs function as endocrine hormones.”

What the sources say

• Not checked yetcites [9] source
• Not checked yetcites [106] source

In the paper

“A myriad of studies ensued demonstrating that administering FGF21 to obese or diabetic rodents and primates markedly reduced body weight and significantly improved carbohydrate and lipid homeostasis (21, 64, 65, 141).”

What the sources say

• Not checked yetcites [21] source
• Not checked yetcites [64] source
• Not checked yetcites [65] source
• Not checked yetcites [141] source

In the paper

“However, these conclusions have been controversial because other groups have reported that FGF21 is not required for regulating glucose homeostasis and ketosis induced by ketogenic diets (97, 123).”

What the sources say

• Not checked yetcites [97] source
• Not checked yetcites [123] source

In the paper

“However, when nutrients become available following a prolonged fast, FGF21 functions as a metabolic switch to facilitate the transition to the refed state by enhancing insulin-stimulated glucose uptake while acutely maintaining the actions of the fasting response (86).”

What the sources say

• Not checked yetcites [86] source

In the paper

“The overexpression of FGF21 was sufficient to increase hepatic gluconeogenesis, β-oxidation, and ketogenesis, whereas the loss of FGF21 prevented fasting-induced hepatic gluconeogenesis, β-oxidation, and ketogenesis in mice (105).”

What the sources say

• Not checked yetcites [105] source

In the paper

“Low-protein diets (73, 85), amino acid starvation (25, 121), and the amino acid–depleting drug asparaginase (138) also induce plasma FGF21 levels.”

What the sources say

• Not checked yetcites [73] source
• Not checked yetcites [85] source
• Not checked yetcites [25] source
• Not checked yetcites [121] source
• Not checked yetcites [138] source

In the paper

“Consistent with these data, Fgf21 total knockout mice fed a ketogenic diet developed hepatosteatosis and exhibited impaired ketogenesis and glucose control (6).”

What the sources say

• Not checked yetcites [6] source

In the paper

“FGF21 is markedly induced in response to protein restriction (25, 73, 85) but not caloric restriction (73, 148).”

What the sources say

• Not checked yetcites [25] source
• Not checked yetcites [73] source
• Not checked yetcites [85] source
• Not checked yetcites [148] source

In the paper

“FGF21 is markedly induced by ketogenic diets in rodents and has been proposed to be a key mediator of hepatic lipid metabolism during ketotic states (6, 7).”

What the sources say

• Not checked yetcites [6] source
• Not checked yetcites [7] source

In the paper

“While FGFR1c is ubiquitously expressed, β-klotho expression is limited to metabolic tissues and confers specificity for FGF21 signaling.”

In the paper

“These circulating levels of FGF21 are derived from the liver, as the genetic loss of Fgf21 specifically from the liver ablates plasma FGF21 levels during fasting (86).”

What the sources say

• Not checked yetcites [86] source

In the paper

“Administration of FGF21 to the PVN of the hypothalamus restored corticosterone production and reversed the impaired hepatic gluconeogenesis observed in Fgf21 knockout mice (81).”

What the sources say

• Not checked yetcites [81] source

In the paper

“Ad libitum feeding of sucrose for 6–24 hours gradually increases hepatic and plasma FGF21 levels in wild-type mice, and this effect is lost in liver-specific Fgf21 knockout mice (133).”

What the sources say

• Not checked yetcites [133] source

In the paper

“While fructose markedly and acutely increased plasma FGF21 levels in humans, glucose caused a delayed and gradual increase in plasma FGF21 levels (31).”

What the sources say

• Not checked yetcites [31] source

In the paper

“Fgf21 knockout mice exhibit increased hepatic lipogenesis and decreased β-oxidation following alcohol exposure (83).”

What the sources say

• Not checked yetcites [83] source

In the paper

“Consistent with these data in humans, Fgf21 total knockout mice exhibit an increased preference for simple sugars, but not lipids or protein (133).”

What the sources say

• Not checked yetcites [133] source

In the paper

“Specifically, these studies reported that variants rs838133 and rs838145 were associated with higher carbohydrate intake and that FGF21 was a candidate gene in the region (20, 127).”

What the sources say

• Not checked yetcites [20] source
• Not checked yetcites [127] source

In the paper

“Finally, as would be predicted from the human SNP data, Klbfl/fl;CamK2a-Cre mice consume more alcohol and prefer alcohol more than wild-type control mice (116).”

What the sources say

• Not checked yetcites [116] source

In the paper

“In rodents, pharmacological levels of FGF21 increase energy expenditure (64, 141), which results in increased food intake (54, 64).”

What the sources say

• Not checked yetcites [64] source
• Not checked yetcites [141] source
• Not checked yetcites [54] source

In the paper

“Interestingly, administering recombinant FGF21 (116) or the overexpression of FGF21 (125) significantly reduced alcohol preference but not plasma ethanol concentrations.”

What the sources say

• Not checked yetcites [116] source
• Not checked yetcites [125] source

In the paper

“Indeed, the administration of recombinant FGF21 to mice markedly reduces carbohydrate preference without affecting the preferences for lipid and protein (133).”

What the sources say

• Not checked yetcites [133] source

In the paper

“Although variants around the FGF21 locus are associated with changes in macronutrient intake, they are not associated with obesity or type 2 diabetes (120).”

What the sources say

• Not checked yetcites [120] source

In the paper

“An intermediate in this pathway, xylulose-5-phosphate, activates ChREBP (1) and promotes its binding to the carbohydrate response element sites in the promoters of target genes, including FGF21 (53, 130).”

What the sources say

• Not checked yetcites [1] source
• Not checked yetcites [53] source
• Not checked yetcites [130] source

In the paper

“This study found that FGF21 was elevated robustly by low protein and that this induction was maximized when low-protein intake was coupled with high-carbohydrate intake (121).”

What the sources say

• Not checked yetcites [121] source

In the paper

“Notably, without affecting protein levels, excess carbohydrate led to an approximately eightfold increase in circulating FGF21 levels, an effect not observed with increased fat intake (84).”

What the sources say

• Not checked yetcites [84] source

In the paper

“Together, these data reveal that FGF21 is induced in response to excess levels of carbohydrate and that the loss of FGF21 signaling increases carbohydrate preference.”

In the paper

“Since FGF21 administration increases energy expenditure and the browning of adipose tissues in vivo (21, 64, 141), it was hypothesized that FGF21 regulates adaptive thermogenesis in response to cold.”

What the sources say

• Not checked yetcites [21] source
• Not checked yetcites [64] source
• Not checked yetcites [141] source

In the paper

“In addition, treating human primary neck adipocytes with FGF21 increases both thermogenic gene expression and cellular respiration (76).”

What the sources say

• Not checked yetcites [76] source

In the paper

“Consistent with the earlier studies, while FGF21 significantly increased insulin sensitivity in both lean and diet-induced obese wild-type mice, this effect was completely lost in Klbfl/fl;Adiponectin-Cre mice (11).”

What the sources say

• Not checked yetcites [11] source

In the paper

“Importantly, in animal models FGF21 treatment not only prevents (64) but also reverses diabetes and obesity (21, 141).”

What the sources say

• Not checked yetcites [64] source
• Not checked yetcites [21] source
• Not checked yetcites [141] source

In the paper

“For example, while chronic feeding of a high-fat diet clearly represents a state of cellular and mitochondrial stress for skeletal muscle, skeletal muscle does not contribute to circulating levels of FGF21 during feeding of a high-fat diet; instead, circulating levels of FGF21 are derived exclusively from the liver under these conditions (86).”

What the sources say

• Not checked yetcites [86] source

In the paper

“In contrast to the acute metabolic effects, repeated daily administration of FGF21 increases metabolic rate, promotes weight loss, and thus secondarily improves insulin sensitivity and glucose homeostasis (141).”

What the sources say

• Not checked yetcites [141] source

In the paper

“When administered to diabetic and obese animal models, FGF21 provides multiple metabolic benefits and has been shown to decrease blood glucose levels and body weight, improve insulin and leptin sensitivity, improve plasma lipid profiles, and decrease hepatic steatosis (21, 64, 141, 142).”

What the sources say

• Not checked yetcites [21] source
• Not checked yetcites [64] source
• Not checked yetcites [141] source

In the paper

“The acute pharmacological administration of FGF21 increases insulin sensitivity and lowers plasma glucose levels, primarily by stimulating peripheral glucose disposal, while also slightly reducing hepatic glucose production (27, 142).”

What the sources say

• Not checked yetcites [27] source
• Not checked yetcites [142] source

In the paper

“Consistent with a functional role for FGF21 during cold, both Fgf21 total knockout mice (36) and adipose-specific Fgf21 knockout mice (52) exhibit reduced body temperature in response to acute cold exposure.”

What the sources say

• Not checked yetcites [36] source
• Not checked yetcites [52] source

In the paper

“Although FGF21 is induced under conditions of metabolic stress (e.g., fasting, cold), it is also induced under many conditions of cellular stress, leading FGF21 to be referred to in some contexts as a stress hormone (69).”

What the sources say

• Not checked yetcites [69] source

In the paper

“Moreover, in contrast to previous studies, both FGF21 (11) and a bispecific activating antibody for the FGFR1–β-klotho receptor complex (70) were found to efficiently retain their acute insulin-sensitizing effects in adiponectin knockout mice (Figure 4).”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [70] source

In the paper

“Extended FGF21 administration increases energy expenditure, promotes lipid and glucose uptake in BAT, and increases adipose tissue metabolism (88).”

What the sources say

• Not checked yetcites [88] source

In the paper

“FGF21 crosses the blood–brain barrier and acts centrally to regulate multiple processes (50).”

What the sources say

• Not checked yetcites [50] source

In the paper

“Increased insulin sensitization in adipose tissues results in increased glucose uptake in BAT (11) and attenuation of lipolysis in WAT (5).”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [5] source

In the paper

“In addition, FGF21 enhances insulin sensitivity in primary brown adipocytes (86) but not in primary white adipocytes (64, 86).”

What the sources say

• Not checked yetcites [86] source
• Not checked yetcites [64] source

In the paper

“Consistent with recombinant FGF21 administration, the administration of a bispecific FGFR1–β-klotho agonist to diet-induced obese wild-type mice promotes weight loss and improves glucose homeostasis, effects that are lost when β-klotho is removed from the CNS (74).”

What the sources say

• Not checked yetcites [74] source

In the paper

“FGF21 administration increases sympathetic nerve activity to BAT (101) and WAT (28), and browning of WAT depots (28, 101).”

What the sources say

• Not checked yetcites [101] source
• Not checked yetcites [28] source

In the paper

“Positron emission tomography and computed tomography imaging revealed that acute administration of FGF21 with insulin markedly induced glucose uptake in interscapular BAT compared to insulin alone, and this effect is impaired in mice lacking β-klotho in BAT (11).”

What the sources say

• Not checked yetcites [11] source

In the paper

“While lipodystrophic mice do not respond to FGF21 administration, the transplantation of WAT from wild-type mice increases leptin levels and restores FGF21 responsiveness (131).”

What the sources say

• Not checked yetcites [131] source

In the paper

“However, a separate study suggests that this phenotype is due to caloric insufficiency from chronic energy expenditure (119).”

What the sources say

• Not checked yetcites [119] source

In the paper

“When PF-05231023 was administered to obese cynomolgus monkeys, it decreased body weight and mean abdominal fat content but did not affect bone mineral content (126).”

What the sources say

• Not checked yetcites [126] source

In the paper

“Although circulating levels of FGF21 are derived from the liver, adipose-derived circulating microRNAs are packaged into exosomes and regulate plasma FGF21 levels (129).”

What the sources say

• Not checked yetcites [129] source

In the paper

“In mice, FGF21 has been reported to promote bone loss (134, 135); however, this finding could not be replicated (80).”

What the sources say

• Not checked yetcites [134] source
• Not checked yetcites [135] source
• Not checked yetcites [80] source

In the paper

“Similar to the previous study (126), once-weekly administration of PF-05231023 markedly improved plasma lipid profiles without significantly affecting fasting plasma glucose levels (66).”

What the sources say

• Not checked yetcites [126] source
• Not checked yetcites [66] source

In the paper

“While Fgf21 transgenic mice are infertile on a chow diet, this infertility is reversed by high-fat diet feeding (119).”

What the sources say

• Not checked yetcites [119] source

In the paper

“One study found that FGF21 signals to the brain to suppress vasopressin–kisspeptin signaling, which impairs the proestrus surge in luteinizing hormone (100).”

What the sources say

• Not checked yetcites [100] source

In the paper

“However, the concept of FGF21 resistance is controversial, with another group failing to observe FGF21 resistance in mouse models of obesity and insulin resistance (45).”

What the sources say

• Not checked yetcites [45] source

In the paper

“Notably, this FGF21 analog also significantly reduced body weight and metabolic profiles in nonhuman primates, but did so by reducing their food intake rather than by increasing the browning of subcutaneous WAT (126).”

What the sources say

• Not checked yetcites [126] source

In the paper

“The majority of adverse effects were gastrointestinal, but unlike the previous study, systolic and diastolic blood pressure, and pulse rate, increased in a dose-dependent manner (66).”

What the sources say

• Not checked yetcites [66] source

In the paper

“In addition, FGF21 regulates macronutrient preference, sweet taste preference, and alcohol intake through central mechanisms.”

In the paper

“Administering this analog for 28 days resulted in decreased body weight, improved lipid profiles, lowered fasting insulin levels, and a trend toward reduced plasma glucose levels (41).”

What the sources say

• Not checked yetcites [41] source

In the paper

“Circulating human FGF21 is composed of 181 amino acids and is proteolytically cleaved, and inactivated, between Pro-171 and Ser-172 by the endopeptidase fibroblast activation protein (FAP) (29, 150).”

What the sources say

• Not checked yetcites [29] source
• Not checked yetcites [150] source

In the paper

“In the same study, PF-05231023 did not affect systolic or diastolic blood pressure, pulse rate, or electrocardiogram readings.”

What the sources say

• Not checked yetcites [126] source

In the paper

“PF-05231023 significantly decreased body weight and markedly reduced plasma cholesterol and lipid levels.”

What the sources say

• Not checked yetcites [126] source