FGF21 Gene Editing    

Fibroblast growth factor 21 (FGF21) is an endocrine hormone that regulates energy homeostasis and insulin sensitivity. FGF21 is produced by the liver in response to various nutritional, physiological and pathological stimuli, and signals to multiple tissues including the adipose tissues and central nervous system (CNS) to mediate metabolic effects on carbohydrate and lipid metabolism. Extended pharmacological administration of FGF21 to diabetic or obese rodents increases energy expenditure and browning of adipose tissues, and markedly reduces body weight without significantly affecting food intake. Although FGF21 was identified in a screen for factors that induce glucose uptake in white adipocytes in vitro by insulin-independent mechanisms, FGF21 was subsequently found to significantly enhance insulin sensitivity in vivo. Remarkably, despite being identified as a factor that regulates glucose metabolism, the most striking and consistent metabolic effects of FGF21 across species are on lipid metabolism in animal models of obesity and diabetes mellitus.

FGF21 and Hepatic Function

As a physiologic regulator, FGF21 was initially described, in mice, as a hepatic factor that, as a target of PPARα, increased in expression in the fasted state. FGF21 in mice also is markedly induced by the consumption of a ketogenic diet; this effect is attenuated in the absence of PPARα. Moreover, ketogenic diets require robust hepatic fatty acid oxidation which is dependent on increased expression of FGF21. When FGF21 expression is reduced in mice that eat this diet, significant fatty liver, associated with severe triglyceridemia is observed. Generally circulating FGF21 derives largely from the liver, and circulating levels correlate well with hepatic expression. In the liver, apart from induction of expression with fasting and KD, increased expression is also seen in the context of obesity in mice and humans, an effect likely downstream of PPARα. This increase in the obese state likely reflects the deposition of fat in the liver and indeed in humans, serum FGF21 levels appear to correlate well with Nonalcoholic fatty liver disease (NAFLD), suggesting that FGF21 action is impaired. Treatment of mice consuming a lipotoxic diet with FGF21 normalizes liver function, reducing fibrosis and inflammation. Similarly, pharmacologic treatment reduces fatty liver. This suggests that analogue or modified FGF21 may have a role in the treatment of human liver disease. Although the wide incidence and prevalence of NAFLD, almost nothing is available in terms of pharmacotherapy and at present dietary therapy is the most common approach to treatment. Development of a novel pharmacologic intervention would have a significant impact on the progress of a disease which is now the most common cause of liver dysfunction world-wide.

FGF21 in Cardiac and Skeletal Muscle

Recent studies have shown that FGF21 plays a critical role in cardiac remodeling. Indeed, the heart expresses FGFR1, fibroblast growth factor receptor 1, β-klotho, as well as FGF21. Besides, in rodents, it has been reported that FGF21 expression protects against pathologic cardiac hypertrophy, oxidative stress, and myocardial infarction. In the heart, FGF21 acts in the manner of an autocrine and controls autophagy in obesity-induced cardiomyopathy. In skeletal muscle, FGF21 expression was found undetectable or to be limitedly expressed in basal conditions. However, several physiological and/or pathological conditions triggered FGF21 expression in muscle as well as showing a secretion into the blood. It was found that autophagy inhibition, specifically in skeletal muscle, was protected from obesity and HFD because FGF21 was dramatically induced in muscles.

FGF21 and Pharmacotherapy

Pharmacological dosing of FGF21 improves the metabolic profile of mice and nonhuman primates, making FGF21 an extremely attractive candidate for the treatment of obesity and diabetes. Several approaches have been undertaken to target FGF21 signaling in humans. Some companies have generated FGF21 variants or analogs that have increased stability and efficacy over native FGF21 protein. Of these, LY2405319 has been tested in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. After 28 days of treatment, subjects receiving LY2405319 lost weight and exhibited improved serum lipid profiles, indicating the value of targeting FGF21 signaling. Other companies are stabilizing FGF21 through conjugation to other moieties such as PEG or immunoglobulins, which have proven efficacy in animal models by improving glucose tolerance and reducing body weight, but no data have been published from clinical studies.

FGF21 Gene Editing Service

CRISPR/Cas9 Platform^CB at Creative Biogene is dedicated to offering comprehensive CRISPR/Cas9 gene editing services and products for academic research, biotech research and pharmaceutical drug discovery. With deep gene editing knowledge and extensive experience in experimental operation and data processing, we help you effectively control FGF21 genes knockout/knockin/point mutation in cells or animals via CRISPR/Cas9 technology.

Service	Details	Alternative cell lines or animal species
FGF21 Gene Editing Cell Line Generation	gRNA design and synthesis Transfect the cell lines you're interested Select the high expression cells and sort monoclonal cell Validate the knockout/knockin/point mutation of FGF21 by PCR and sequencing Provide cryogenic preserved vials of stable cells and final reports	HEK239T, Hela, HepG2, U87, Ba/F3, CHO, MDA-MB-453, MDA-MB-231NIH3T3, T47D, Neuro2a, MCF7, RKO, K562, RAW264.7, etc.
FGF21 Gene Editing Animal Model Generation	FGF21 gene conventional knockout animals FGF21 gene conditional knockout animals FGF21 point mutation animals FGF21 knockin animals	Mouse, rat, rabbit, zebrafish, C. elegans, etc.

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