Recent Research into the Effects of Increased FGF21 Levels
The protein FGF21 came to be an area of interest because its production is increased as a result of calorie restriction, an intervention that extends healthy life span in near all species tested to date. Further investigation found that genetic engineering to artificially boost FGF21 production extends life in mice, probably through effects on the well-known insulin signaling systems that appear involved in the way in which the operation of metabolism determines natural variations in life span. Like many such approaches to slowing aging in mice, it isn't expected to have as significant an effect in long-lived humans as it does in short-lived mice. Researchers are also interested in the positive impact of FGF21 on regeneration, however: it has been shown to slow thymus degeneration and enhance liver regeneration, for example. Here, researchers further investigate the impact of altered levels of FGF21 on metabolism:
Mildly stressing muscle metabolism boosts levels of a beneficial hormone that prevents obesity and diabetes in mice, according to a new study. The new findings show that triggering a certain type of metabolic stress in mouse muscle cells causes them to produce and secrete significant amounts of fibroblast growth factor-21 (FGF21), which then has widespread beneficial effects on whole-body metabolism. The mice in the experiments were completely protected from obesity and diabetes that normally develop due to aging or eating a high-fat diet. Moreover, triggering the FGF21 production after the mice had become obese and diabetic reversed these conditions and returned the mice to normal weight and blood sugar levels.
"There is a biological phenomenon known as hormesis where a little bit of stress a can be a good thing." Researchers used genetic engineering to reduce levels of a mitochondrial protein called OPA1 in the muscles of mice. Mitochondria are tiny organelles that produce a cell's energy. This OPA1 deficiency disrupted muscle metabolism and caused a small amount of muscle loss in the mice. Despite the mild muscle atrophy, which did decrease grip strength, the older mice with OPA1 deficiency had greater endurance on the treadmill than older control mice. In addition, activity levels and energy expenditure that normally decline in mice as they age were preserved in OPA1 deficient mice.
Interestingly, the altered mice also were completely protected from the weight gain and glucose intolerance that normally develop in mice as they age or when they eat a high-fat diet. Moreover, the research team showed that reducing OPA1 levels in muscle, after mice had become obese and diabetic, reversed these problems - normalizing body weight and reversing glucose intolerance even though the high fat diet continued. These metabolic improvements correlated with increased levels of circulating FGF21. The researchers were able to prove that muscle was the source of the FGF21 by creating a mouse that had the OPA1 deficiency and also was missing the FGF21 gene in muscle. These mice were no longer able to produce FGF21 in muscle in response to OPA1 deficiency, and, just like control mice, they became obese and developed diabetes. "These experiments prove that muscle is the source of circulating FGF21 in the OPA1 deficient mice, and that muscle-derived FGF21 prevents diet-induced obesity and insulin resistance in these mice."
Further investigation demonstrated that the small degree of mitochondrial stress induced in muscle by the reduction of OPA1 is sufficient to activate another cellular stress response pathway called endoplasmic reticulum (ER) stress, which then dramatically increases FGF21 levels. "The follow up work on this will be understanding how a little bit of mitochondrial stress can actually increase the ER stress response and if we can mimic that safely. There are agents that have been used to activate ER stress pathways. So, I think the opportunity here would be to find ways to turn on this pathway in a very controlled way to get enough of this subsequent FGF21 response in muscle to be of benefit."