Live lean and CRISPR – Engineering metabolism with FGF21 and FNDC5 Article Swipe

Obesity and its associated comorbidities such as type 2 diabetes and cardiovascular diseases are – despite all the current efforts in research – still difficult to tackle therapeutically. For people struggling with body weight, diet and physical activity can have profound beneficial effects. The main benefit of exercise is rendering a negative energy balance by skeletal muscle usage of carbohydrates and lipids. Muscle tissue also plays an important endocrine role in systemic metabolism, mainly through the secretion of hormones known as myokines. However, for several reasons for most people increasing physical activity remains ineffective for obesity treatment and weight maintenance. In a recent study by Zhu et al., they demonstrated a new approach to increase the expression of the myokines FGF21 and irisin via gene therapy in mice.1 They used an adeno-associated virus (AAV)-mediated delivery of both the activating CRISPR-Cas9 (CRISPRa) and single guide RNA system2 specifically to muscle cells. This cutting-edge strategy seeks to tackle obesity by taking the advantage of the beneficial ability of these myokines to promote the browning of the adipose tissue and enhancing energy metabolism (Figure 1). The idea of leveraging some of the beneficial effects of exercise and physical activity by using one of the many secreted molecules as a therapy is appealing. In recent years, the muscle secretome has become a focal point of investigation, in part due to technological advancements for enhanced discovery. Exercise is a whole-body physiological challenge, and that muscle cells coordinate systemic metabolism by releasing metabolites and peptide hormones should not come as a surprise.3 Of particular interest are those that have been shown to promote the browning of the adipose tissue because thermogenic adipocytes help to burn calories and are associated with metabolic health in humans.4 In this study by Zhu et al., the authors chose to use FGF21 and irisin, which have emerged as prominent players in this area. Although FGF21 is mainly produced and secreted by the liver in response to nutritional and cellular stress signals, other cell types, including skeletal myocytes, also produce FGF21 under certain conditions.5 FGF21 has been in the spotlight for a plethora of reasons, foremost for its beneficial effects on lipid and carbohydrate metabolism.6 Likewise, irisin is a cleaved fragment of the FNDC5 protein, and although there is still a lot of debate about its mechanism of action and physiological significance, it is found in human plasma7 and is regulated by PGC1α in response to exercise,8 which makes it a potential therapeutic agent. Zhu et al. demonstrated in their study that the forced expression of FGF21 or irisin in obese mice led to a marked increase in plasma levels of the two hormones, which was associated with weight loss and increased browning of adipose tissue.1 In mice, adipose tissue browning is frequently observed and quickly develops with stress.4 In humans, however, adipose tissue plasticity is limited, and human adipocytes are resilient to browning. Only in rare and severe circumstances, such as adrenergic stress after burn injury, the browning of subcutaneous adipose tissue is observed in humans.9 In this light, if the gene therapy of browning hormones will be useful for inducing weight loss and metabolic benefit in humans as a therapy can be doubted. In addition, the authors observed a reduction in food intake,1 which is a desired therapeutic outcome, as caloric intake is a major hub for losing weight. In most cases, however, limiting food intake by regulating appetite might have adverse side effects such as nausea and depression. Indeed, rather than inducing adipose browning, FGF21 has also been linked to dietary sweet and alcohol preference.10 In light of the reduced food intake, in order to become a viable therapeutic, nutrient deficiencies or even undesired weight loss have to be ruled out on a long-term scale. Pharmacological use of FGF21 has focused on the administration of long-acting analogues, as wild-type recombinant FGF21 has a short half-life and is subject to degradation, limiting its efficacy as a viable treatment option. However, some of the tested analogues have presented with undesired side effects, such as increased heart rate and blood pressure, or a reduction in bone mass.6 Addressing this concern, Zhu et al. presented an innovative strategy that involves CRISPRa-mediated transcriptional control within muscle cells.1 This approach holds great potential in overcoming the limitations posed by natural instabilities of applied hormones, especially FGF21 or incretin hormones. However, a major limitation of this gene therapy using sustained expression of the CRISPRa system is that it cannot be physiologically regulated or switched off. This might create problems as plasma levels are chronically high and might create long-term complications in the overexpressing muscle. Future developments will have to create a desirable demand-driven and tunable expression system. In conclusion, the work by Zhu et al. provides a promising example of AAV-mediated gene therapy using the CRISPRa technology, which underscores the therapeutic potential of FGF21 and irisin for obesity-linked metabolic disorders. It will be exciting to see this versatile and straightforward technology entering the clinical stage for living a leaner and healthier life. A.B. was supported by the German Center for Cardiovascular Research (DZHK), the DFG SPP2306 on ferroptosis and the ERC Starting Grant PROTEOFIT. We apologize to colleagues whose work we could not cite due to space limitations. The authors declare no conflicts of interest related to this work. Data sharing is not applicable to this article as no new data were created or analysed in this study.