Fibroblast Growth Factor 21 Overexpression Research Articles

Retinoic Acid Receptor β Stimulates Hepatic Induction of Fibroblast Growth Factor 21 to Promote Fatty Acid Oxidation and Control Whole-body Energy Homeostasis in Mice

Activation of retinoic acid receptor (RAR) with all-trans-retinoic acid (RA) ameliorates glucose intolerance and insulin resistance in obese mice. The recently discovered fibroblast growth factor 21 (FGF21) is a hepatocyte-derived hormone that restores glucose and lipid homeostasis in obesity-induced diabetes. However, whether hepatic RAR is linked to FGF21 in the control of lipid metabolism and energy homeostasis remains elusive. Here we identify FGF21 as a direct target gene of RARβ. The gene transcription of Fgf21 is increased by the RAR agonist RA and by overexpression of RARα and RARβ, but it is unaffected by RARγ in HepG2 cells. Promoter deletion analysis characterizes a putative RA-responsive element (RARE) primarily located in the 5'-flanking region of the Fgf21 gene. Disruption of the RARE sequence abolishes RA responsiveness. In vivo adenoviral overexpression of RARβ in the liver enhances production and secretion of FGF21, which in turn promotes hepatic fatty acid oxidation and ketogenesis and ultimately leads to increased energy expenditure in mice. The metabolic effects of RA or RARβ are mimicked by FGF21 overexpression and largely abolished by FGF21 knockdown. Moreover, hepatic RARβ is bound to the putative RAREs of the Fgf21 promoter in a fasting-inducible manner in vivo, which contributes to FGF21 induction and the metabolic adaptation to prolonged fasting. In addition to other nuclear receptors, such as peroxisome proliferator-activated receptor α and retinoic acid receptor-related receptor α, RAR may act as a novel component to induce hepatic FGF21 in the regulation of lipid metabolism. The hepatic RAR-FGF21 pathway may represent a potential drug target for treating metabolic disorders.

Metabolic Hormone FGF21 Is Induced in Ground Squirrels during Hibernation but Its Overexpression Is Not Sufficient to Cause Torpor

Hibernation is a natural adaptation that allows certain mammals to survive physiological extremes that are lethal to humans. Near freezing body temperatures, heart rates of 3–10 beats per minute, absence of food consumption, and depressed metabolism are characteristic of hibernation torpor bouts that are periodically interrupted by brief interbout arousals (IBAs). The molecular basis of torpor induction is unknown, however starved mice overexpressing the metabolic hormone fibroblast growth factor 21 (FGF21) promote fat utilization, reduce body temperature, and readily enter torpor–all hallmarks of mammalian hibernation. In this study we cloned FGF21 from the naturally hibernating thirteen-lined ground squirrel (Ictidomys tridecemlineatus) and found that levels of FGF21 mRNA in liver and FGF21 protein in serum are elevated during hibernation torpor bouts and significantly elevated during IBAs compared to summer active animals. The effects of artificially elevating circulating FGF21 concentrations 50 to 100-fold via adenoviral-mediated overexpression were examined at three different times of the year. This is the first time that a transgenic approach has been used in a natural hibernator to examine mechanistic aspects of hibernation. Surgically implanted transmitters measured various metrics of the hibernation phenotype over a 7-day period including changes in motor activity, heart rate and core body temperature. In April fed-state animals, FGF21 overexpression decreased blood insulin and free fatty acid concentrations, effects similar to those seen in obese mice. However, elevated FGF21 concentrations did not cause torpor in these fed-state animals nor did they cause torpor or affect metabolic parameters in fasted-state animals in March/April, August or October. We conclude that FGF21 is strongly regulated during torpor and IBA but that its overexpression is not sufficient to cause torpor in naturally hibernating ground squirrels.

Fibroblast Growth Factor-21 Is a Promising Dietary Restriction Mimetic

Dietary or caloric restriction (DR or CR), typically a 30%-40% reduction in ad libitum or "normal" nutritional energy levels, has been reported to extend life span and health span in diverse organisms, including mammals. Although the life span benefit of DR in primates and humans is unproven, preliminary evidence suggests that DR confers health span benefits. A serious effort is underway to discover or engineer DR mimetics. The most straightforward path to a DR mimetic requires a detailed understanding of the molecular mechanisms that underlie DR and related life span-enhancing protocols. Increased expression of fibroblast growth factor-21 (FGF21), a putative mammalian starvation master regulator, promotes many of the same beneficial physiological changes seen in DR animals, including decreased glucose levels, increased insulin sensitivity, and improved fatty acid/lipid profiles. Ectopic over-expression of FGF21 in transgenic mice (FGF21-Tg) extends life span to a similar extent as DR in a recent study. FGF21 may achieve these effects by attenuating growth hormone (GH)/insulin-like growth factor-1 (IGF1) signaling. Although FGF21 expression does not increase during DR, and therefore is unlikely to mediate DR, it does increase during short-term starvation in rodents, which is a critical component of alternate day fasting, a DR-like protocol that also increases life span and health span in mammals. Various drugs have been reported to induce FGF21, including peroxisome proliferator-activated receptor-α (PPARα) agonists such as fenofibrate, the histone deacetylase inhibitor sodium butyrate, and adenosine monophosphate (AMP) kinase activators metformin and 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR). Of these, only metformin has been reported to extend life span in mammals, and the extent of benefit is less than that seen with ectopic FGF21 expression. Perhaps the most parsimonious explanation is that high, possibly un-physiological, levels of FGF21 are needed to achieve maximum life span and health span benefits and that sufficiently high levels are not achieved by the identified FGF21 inducers. More in-depth studies of the effects of FGF21 and its inducers on longevity and health span are warranted.

The starvation hormone, fibroblast growth factor-21, extends lifespan in mice.

Fibroblast growth factor-21 (FGF21) is a hormone secreted by the liver during fasting that elicits diverse aspects of the adaptive starvation response. Among its effects, FGF21 induces hepatic fatty acid oxidation and ketogenesis, increases insulin sensitivity, blocks somatic growth and causes bone loss. Here we show that transgenic overexpression of FGF21 markedly extends lifespan in mice without reducing food intake or affecting markers of NAD+ metabolism or AMP kinase and mTOR signaling. Transcriptomic analysis suggests that FGF21 acts primarily by blunting the growth hormone/insulin-like growth factor-1 signaling pathway in liver. These findings raise the possibility that FGF21 can be used to extend lifespan in other species.DOI: http://dx.doi.org/10.7554/eLife.00065.001

The link between fibroblast growth factor 21 and sterol regulatory element binding protein 1c during lipogenesis in hepatocytes

Recently fibroblast growth factor 21 (FGF21) has been identified as a potent regulator in glucose and lipid homeostasis. Here, we firstly investigated the metabolic role of FGF21 in human liver-derived HepG2 cells, and suggested that overexpression of FGF21 suppressed triglyceride accumulation by inhibiting the transcription of the gene necessary for de novo lipogenesis. The potential mechanism of FGF21 regulating lipogenesis was also explored, which revealed that FGF21 repressed the transcription of sterol regulatory element binding protein 1c (SREBP1c), an essential transcription factor promoting expression of lipogenesis-related genes. Overexpression of FGF21 ameliorated the up-regulation of SREBP1c and fatty acid synthase (FAS) in HepG2 cells elicited by FFAs treatment. Moreover, FGF21 could inhibit the transcriptional levels of the key genes involved in processing and nuclear translocation of SREBP1c, and decrease the protein amount of mature SREBP1c. Unexpectedly, overexpression of SREBP1c in HepG2 cells could also inhibit the endogenous FGF21 transcription. Further experiments demonstrated that SREBP1c could significantly attenuate the promoter activity of FGF21. In conclusion, our data identifies a clear link between FGF21 and SREBP1c during lipogenesis in hepatocyte in culture.