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Biology and therapeutic potential of FGF21 signaling pathway

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In recent years, the biology of FGF21 has been in the spotlight owing to its therapeutic potential to treat obesity, diabetes and the associated metabolic abnormalities. FGF21 was first reported as a novel metabolic regulator rather than a classical factor to promote growth in 2005. Significant acceleration ...

In recent years, the biology of FGF21 has been in the spotlight owing to its therapeutic potential to treat obesity, diabetes and the associated metabolic abnormalities. FGF21 was first reported as a novel metabolic regulator rather than a classical factor to promote growth in 2005. Significant acceleration of FGF21 research came with the discovery in 2007 of its co-receptor, the membrane-spanning betaKlotho that is primarily expressed in the metabolically relevant tissues. Studies with pharmacological administration of recombinant FGF21, overexpression and ablation of FGF21 gene in mice under fasting and starvation, and in conditions of dietary or genetically-induced obesity have revealed its modulatory roles in maintaining the homeostasis of systemic lipid, glucose and energy metabolism. This field was further lifted through the identification of its main corresponding receptor, the FGFR1c tyrosine kinase that forms a complex with betaKlotho, in the major FGF21-targeted tissues, the white and brown adipose tissues. The pursuit of FGF21 and its signaling pathway as prototypic pharmacophores for the treatment of metabolic disorders have since been the driving force for the rapid advances in FGF21 biology. Multiple tissues were identified to produce FGF21 in response to diverse stressful pathophysiological challenges, such as the liver, muscle, pancreas, heart and adipose tissues, under the transcriptional control of several nuclear receptors and transcription factors. There are several tissues implicated as the target of FGF21 actions primarily in an endocrine fashion of tissue-tissue crosstalk, which include the white and brown adipose tissues, among others. The pleiotropic metabolic effects of FGF21 have been reported across several important pathophysiological areas. These encompass (1) modulation of lipolysis and fatty acid oxidation in white adipose tissue, and thermogenesis and futile energy expenditure in brown fat; (2) stimulation of ketogenesis and fatty acid oxidation in the liver, and the adaptive response to starvation; (3) increase of insulin sensitivity and lowering of plasma glucose level; (4) lowering of systemic lipids, cholesterol and atherogenic apolipoproteins, (5) reduction of body weight, amelioration of fatty liver and cardiovascular disease, and other conditions associated with obesity and diabetes; (6) neuroendocrine effects; and (7) experimental extension of life span. Although a first clinical trial with a FGF21 analog has unraveled the evidence of FGF21 bioactivity in man, many basic mechanistic questions regarding the therapeutic utility of FGF21 remain to be answered.

In this Research Topic, we attempt to analyze and provide the field with an update of the current state of the art on the FGF21 biology from the dimension of basic science to the dimension of therapeutic utility.


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