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Updated: May 10, 2026
Study of In Vivo Glucose Metabolism in High-fat Diet-fed Mice Using Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT)
Published on: January 7, 2018
Cellular mechanisms by which FGF21 improves insulin sensitivity in male mice
João Paulo G Camporez1, François R Jornayvaz, Max C Petersen
1Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06536-9812, USA.
Abstract:
Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid metabolism and is currently being pursued as a therapeutic agent for insulin resistance and type 2 diabetes. However, the cellular mechanisms by which FGF21 modifies insulin action in vivo are unclear. To address this question, we assessed insulin action in regular chow- and high-fat diet (HFD)-fed wild-type mice chronically infused with FGF21 or vehicle. Here, we show that FGF21 administration results in improvements in both hepatic and peripheral insulin sensitivity in both regular chow- and HFD-fed mice. This improvement in insulin responsiveness in FGF21-treated HFD-fed mice was associated with decreased hepatocellular and myocellular diacylglycerol content and reduced protein kinase Cε activation in liver and protein kinase Cθ in skeletal muscle. In contrast, there were no effects of FGF21 on liver or muscle ceramide content. These effects may be attributed, in part, to increased energy expenditure in the liver and white adipose tissue. Taken together, these data provide a mechanism by which FGF21 protects mice from lipid-induced liver and muscle insulin resistance and support its development as a novel therapy for the treatment of nonalcoholic fatty liver disease, insulin resistance, and type 2 diabetes.
Insights
Fibroblast growth factor 21 (FGF21) improves insulin sensitivity in mice by reducing harmful lipid metabolites in the liver and muscle. This suggests FGF21 as a potential therapy for metabolic disorders like type 2 diabetes and fatty liver disease.
Area of Science:
- Metabolic disease research
- Endocrinology
- Molecular biology
Background:
- Fibroblast growth factor 21 (FGF21) regulates glucose and lipid metabolism.
- FGF21 is a potential therapeutic for insulin resistance and type 2 diabetes.
- The precise cellular mechanisms of FGF21's action on insulin sensitivity remain unclear.
Purpose of the Study:
- To investigate the cellular mechanisms by which FGF21 improves insulin action in vivo.
- To assess the effects of FGF21 on insulin sensitivity in mice fed regular chow and high-fat diets (HFD).
Main Methods:
- Wild-type mice on regular chow or HFD were chronically infused with FGF21 or vehicle.
- Insulin action was assessed in liver and peripheral tissues.
- Hepatocellular and myocellular diacylglycerol and ceramide content were measured.
- Protein kinase C (PKC) epsilon and theta activation were analyzed.
Main Results:
- FGF21 administration improved hepatic and peripheral insulin sensitivity in both diet groups.
- In HFD-fed mice, FGF21 reduced liver and muscle diacylglycerol content and decreased PKCε and PKCθ activation.
- FGF21 did not alter ceramide levels in the liver or muscle.
- Increased energy expenditure in the liver and white adipose tissue may contribute to FGF21's effects.
Conclusions:
- FGF21 administration improves insulin sensitivity by reducing lipid-induced insulin resistance in liver and muscle.
- These findings elucidate a mechanism for FGF21's metabolic benefits.
- FGF21 shows promise as a therapeutic for nonalcoholic fatty liver disease, insulin resistance, and type 2 diabetes.
