Obesity Is a Fibroblast Growth Factor 21 (FGF21)-Resistant State

By F. Fisher, Patricia C. Chui, P. Antonellis, Holly A. Bina, A. Kharitonenkov, J. Flier, E. Maratos-Flier. Diabetes, 2010

816 citations recorded by the source corpus.

OBJECTIVE Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity. RESEARCH DESIGN AND METHODS To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21. RESULTS When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice. CONCLUSIONS These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.

Subfields: Epidemiology, Molecular Biology, Nephrology

View Paper: https://www.semanticscholar.org/paper/db8af70e713cca0e3199dbb6ca27944963e29882

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

In Molecular Biology

Citations in the corpus

Adipose Tissue Distribution, Inflammation and Its Metabolic Consequences, Including Diabetes and Cardiovascular Disease (2020, background): “This conclusion was reached based on some observations that circulating FGF21 levels are increased in obesity, with lower FGF21 receptor expression levels on target tissues such as adipose tissue (146, 384).”
Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. (2013, background): “Second, FGF21 resistance in adipose tissues has been reported in obese animals (Fisher et al., 2010; Ge et al., 2011) and may be further aggravated by chronic inflammation with the progression of obesity (Dı́az-Delfı́n et al., 2012).”