Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice

A phase 2b RCT in people with biopsy-confirmed MASH and fibrosis failed to meet predefined histological endpoints with MSDC-0602 K.

“However, a phase 2b RCT in people with biopsy-confirmed MASH and fibrosis failed to meet the predefined histological endpoints [192].”

In patients with NASH, 52 weeks of MSDC-0602 K reduced steatosis.

“| Harrison et al. | MSDC-0602 K (52 weeks) | NASH | Steatosis/ ballooning/ inflammation | ↑ | ↓ | ↔ | NR |”

Unlike in placebo group, weight gain did not adversely affect insulin levels with MSDC-0602 K.

“Interestingly, unlike in the placebo group, weight gain did not adversely affect insulin levels.”

In the liver, FGF21 downregulates lipogenesis.

“In the liver, FGF21 upregulates β-oxidation [160] and downregulates lipogenesis [167].”

Adiponectin levels rose with higher dosages of MSDC-0602 K.

“Of note, also adiponectin levels rose with the higher dosages.”

In patients with NASH, 52 weeks of MSDC-0602 K did not change fibrosis.

“| (2020) [192] | | F1-F3 | ↓/↔/↔; NAS ↔, fibrosis ↔ | 62,5 mg: +1,4 % | | | |”

In patients with NASH, 52 weeks of MSDC-0602 K did not change NAS.

“| (2020) [192] | | F1-F3 | ↓/↔/↔; NAS ↔, fibrosis ↔ | 62,5 mg: +1,4 % | | | |”

Prolonged administration of FGF21 or FGF21 analogues decreases body weight in rodents and non-human primates, and has more modest effects on body weight in humans.

“prolonged administration of FGF21 or FGF21 analogues has important metabolic effects, including a marked decrease in body weight in rodents and non-human primates, and more modest effects on body weight in humans3,40,58,77,78.”

Pharmacological administration of FGF21 to obese rodents reverses diabetes and obesity through increasing energy expenditure.

“Pharmacological administration of FGF21 to obese rodents reverses diabetes and obesity through increasing energy expenditure77,78.”

Prolonged FGF21 administration to DIO mice significantly decreases body weight, adiposity, hepatic triglycerides and cholesterol; reverses hyperglycaemia and hypertriglyceridaemia; and secondarily increases insulin sensitivity.

“Prolonged FGF21 administration to DIO mice significantly decreases body weight, adiposity, and hepatic triglycerides and cholesterol; reverses plasma hyperglycaemia and hypertriglyceridaemia; and secondarily increases insulin sensitivity78.”

Administration of high doses of FGF21 increases both energy expenditure and physical activity.

“administration of high doses of FGF21 has been shown to increase both energy expenditure and physical activity78.”

Pharmacological administration of FGF21 decreases plasma glucose and lipid levels in mice.

“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”

Pharmacological administration of FGF21 improves insulin and leptin sensitivity in mice.

“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”

Pharmacological administration of FGF21 decreases hepatic steatosis in mice.

“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”

Pharmacological administration of FGF21 increases energy expenditure in mice.

“Pharmacological administration of FGF21 decreases plasma glucose and lipid levels, improves insulin and leptin sensitivity, decreases hepatic steatosis, increases energy expenditure [[131], [132], [133], [134], [135], [136]], and decreases sugar and alcohol intake in mice [[137], [138], [139], [140], [141], [142]].”

Administering FGF21 to obese or diabetic rodents and primates markedly reduced body weight and significantly improved carbohydrate and lipid homeostasis.

“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).”

In diabetic and obese animal models, FGF21 administration decreases blood glucose levels and body weight, improves insulin and leptin sensitivity, improves plasma lipid profiles, and decreases hepatic steatosis.

“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).”

FGF21 treatment elicits significant metabolic changes in many tissues, including the liver and adipose tissues.

“It is clear that FGF21 treatment elicits significant metabolic changes in many tissues, including the liver and adipose tissues (21, 141).”

In animal models, FGF21 treatment not only prevents but also reverses diabetes and obesity.

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

FGF21 administration increases energy expenditure and the browning of adipose tissues in vivo.

“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.”

Repeated daily administration of FGF21 increases metabolic rate, promotes weight loss, and thus secondarily improves insulin sensitivity and glucose homeostasis.

“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).”

In rodents, pharmacological levels of FGF21 increase energy expenditure, which results in increased food intake.

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

Recombinant FGF21 or FGF21 variants have beneficial metabolic effects in mice; only a small trend toward glucose lowering was reported in humans.

“Extensive efforts have also been made with the use of recombinant FGF21 or FGF21 variants as potential therapy, due to beneficial metabolic effects observed in mice 152, 153; however, only a small trend toward glucose lowering was reported in humans 154.”