Live lean and CRISPR – Engineering metabolism with FGF21 and FNDC5

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