Fibroblast Growth Factor 21 Corrects Obesity in Mice

Coşkun, Tamer; Bina, Holly A.; Schneider, M.; Dunbar, James D.; Hu, Charlie C.; Chen, Yanyun; Moller, David E.; Kharitonenkov, Alexei

doi:10.1210/en.2008-0816

Cited by 905 publications

(985 citation statements)

References 26 publications

Supporting

Mentioning

870

Contrasting

Unclassified

Order By: Relevance

“…Irrespective of the diet, TG mice showed increased plasma FGF21 levels ( Figure 1D) while physical activity levels ( Figure 1E) and body temperature ( Figure S1E) were not affected. These results are in accordance with the pharmacological effects of FGF21 treatment or with FGF21-overexpression promoting distinct metabolic responses [5,41,42]. Unexpectedly, despite the loss of circulating FGF21 (Figure 1D), the phenotype of TG/FGF21 À/À mice was almost identical to TG mice.…”

Section: Resultssupporting

confidence: 84%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

View full text Add to dashboard Cite

Objective: Fibroblast growth factor 21 (FGF21) was recently discovered as stress-induced myokine during mitochondrial disease and proposed as key metabolic mediator of the integrated stress response (ISR) presumably causing systemic metabolic improvements. Curiously, the precise cell-non-autonomous and cell-autonomous relevance of endogenous FGF21 action remained poorly understood. Methods: We made use of the established UCP1 transgenic (TG) mouse, a model of metabolic perturbations made by a specific decrease in muscle mitochondrial efficiency through increased respiratory uncoupling and robust metabolic adaptation and muscle ISR-driven FGF21 induction. In a cross of TG with Fgf21-knockout (FGF21 À/À ) mice, we determined the functional role of FGF21 as a muscle stress-induced myokine under low and high fat feeding conditions. Results: Here we uncovered that FGF21 signaling is dispensable for metabolic improvements evoked by compromised mitochondrial function in skeletal muscle. Strikingly, genetic ablation of FGF21 fully counteracted the cell-non-autonomous metabolic remodeling and browning of subcutaneous white adipose tissue (WAT), together with the reduction of circulating triglycerides and cholesterol. Brown adipose tissue activity was similar in all groups. Remarkably, we found that FGF21 played a negligible role in muscle mitochondrial stress-related improved obesity resistance, glycemic control and hepatic lipid homeostasis. Furthermore, the protective cell-autonomous muscle mitohormesis and metabolic stress adaptation, including an increased muscle proteostasis via mitochondrial unfolded protein response (UPR mt ) and amino acid biosynthetic pathways did not require the presence of FGF21.Conclusions: Here we demonstrate that although FGF21 drives WAT remodeling, the adaptive pseudo-starvation response under elevated muscle mitochondrial stress conditions operates independently of both WAT browning and FGF21 action. Thus, our findings challenge FGF21 as key metabolic mediator of the mitochondrial stress adaptation and powerful therapeutic target during muscle mitochondrial disease.

show abstract

Section: Resultssupporting

confidence: 84%

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Consistent with this hypothesis, administration of Fgf21 to fasted neonates augments the thermogenic gene program in BAT. In WAT, Fgf21 increases the amounts of Pgc-1α to drive beige adipocyte recruitment in response to cold 134,135 .…”

Section: Sympathetic Nerve Control Of Brown and Beige Fatmentioning

confidence: 99%

Brown and beige fat: development, function and therapeutic potential

Harms

Seale

2013

Nat Med

1,897

2,027

View full text Add to dashboard Cite

Adipose tissue, best known for its role in fat storage, can also suppress weight gain and metabolic disease through the action of specialized, heat-producing adipocytes. Brown adipocytes are located in dedicated depots and express constitutively high levels of thermogenic genes, whereas inducible 'brown-like' adipocytes, also known as beige cells, develop in white fat in response to various activators. The activities of brown and beige fat cells reduce metabolic disease, including obesity, in mice and correlate with leanness in humans. Many genes and pathways that regulate brown and beige adipocyte biology have now been identified, providing a variety of promising therapeutic targets for metabolic disease.npg

show abstract

“…FGF21 administration improves metabolic phenotypes such as increased fasting glucose, insulin and triacylglycerol levels in different obese mice models and diabetic rhesus monkeys [123][124][125][126]. Additionally, experiments on FGF21-treated mice indicated that this protein regulates whole body insulin responsiveness by enhanced glucose uptake in skeletal muscle, WAT and BAT and improved suppression of WAT lipolysis [99].…”

Section: Key Facts: Myokines As Therapeutic Targetsmentioning

confidence: 99%

Myokines in insulin resistance and type 2 diabetes

et al. 2014

View full text Add to dashboard Cite

Skeletal muscle represents the largest organ of the body in non-obese individuals and is now considered to be an active endocrine organ releasing a host of so-called myokines. These myokines are part of a complex network that mediates communication between muscle, the liver, adipose tissue, the brain and other organs. Recent data suggest that myokines regulated by muscle contraction may play a key role in mediating the health-promoting effects of regular physical activity. Although hundreds of myokines have recently been described in proteomic studies, we currently have a rather limited knowledge of the specific role these myokines play in the prevention of insulin resistance, inflammation and associated metabolic dysfunction. Several myokines are known to have both local and endocrine functions, but in many cases the contribution of physical activity to the systemic level of these molecules remains as yet unexplored. Very recently, novel myokines such as irisin, which is thought to induce a white to brown shift in adipocytes, have gained considerable interest as potential therapeutic targets. In this review, we summarise the most recent findings on the role of myokines in the regulation of substrate metabolism and insulin sensitivity. We further explore the role of myokines in the regulation of inflammation and provide a critical assessment of irisin and other myokines regarding their potential as therapeutic targets.

show abstract

Fibroblast Growth Factor 21 Corrects Obesity in Mice

Cited by 905 publications

References 26 publications

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action

Brown and beige fat: development, function and therapeutic potential

Myokines in insulin resistance and type 2 diabetes

Contact Info

Product

Resources

About