Sarcopenic obesity (SO) refers to the condition in which an individual simultaneously has excess body fat and reduced muscle mass and function [1]. As a disease associated with both obesity and aging, it affects approximately 11% of the elderly population. It is associated with a higher risk of falls, bone fracture, and metabolic diseases, and its prevalence is expected to increase due to the aging demographic [2,3]. Compared to obesity or sarcopenia alone, SO poses a greater risk of frailty and disability, therefore worsening the burden of aging-related diseases, and leading to a poor prognosis [4].

Time-restricted feeding (TRF) has been extensively demonstrated as an effective dietary intervention for reducing obesity and improving metabolic disease [5]. Recent studies indicated that intermittent TRF can increase muscle mass, motor coordination and endurance [6,7], while another study found that TRF combined with a resistance training did not increase muscle mass but significantly improved muscle strength [8]. TRF was discovered to enhance muscle function by increasing glycine production and utilization and activating AMPK signaling pathway in the drosophila model of obesity [9]. Given that the accuracy of diagnosing SO is critical for the implementation of effective treatment strategies, ongoing efforts have been made to refine and optimize its diagnostic criteria and definitions in human populations [10]. Concurrently, progress in establishing animal models of SO has provided valuable references and a solid foundation for the exploration of the therapeutic effects of TRF on SO and better understanding of the underlying mechanisms involved [11,12].

Organokines may act as key mediators that mediate the crosstalk between various tissues via endocrine, paracrine, and autocrine pathways [13]. One specific organokines, fibroblast growth factor 21 (FGF21), is primarily produced by the liver under normal physiological conditions and represents the main source of serum FGF21 [14]. FGF21 lacks the heparin-binding domain that allows it to enter the blood and act as an endocrine hormone, and it activates downstream signaling by collaborating with receptors FGFRs on the cell surface in target organ [15]. FGF21 has been found to play a critical role in regulating bile acid, lipid, and glucose metabolism in both humans and rodents [16]. Previous studies have revealed that FGF21 upregulates the expression of uncoupling protein 1 (UCP1) and PPAR-γ coactivator-1α (PGC-1α), enhancing the browning and thermogenesis of white adipose tissue (WAT) and suppressing adipogenesis [17]. FGF21 also improves insulin sensitivity and has other metabolic benefits by stimulating the secretion of adiponectin from adipocytes [18]. Interestingly, studies have also found a positive correlation between FGF21 levels and muscle mass. FGF21 is believed to promote optimal muscle function by promoting damaged mitochondrial clearance, which are the powerhouses of the cells [19,20]. Therefore, FGF21 may exert significant regulatory influence on age-related SO. One study demonstrated that TRF protects against high-fat diet (HFD)-induced fatty liver by modulating liver FGF21 [21]. It also improves the reproductive capacity of female mice [22] and ameliorating cardiac dysfunction [23]. The comprehensive mechanisms by which TRF-induced FGF21 regulates age-related SO are still not well understood and require further investigation. Consequently, this study hypothesizes that TRF may ameliorate SO by elevating liver FGF21 levels, thereby improving the function of adipose and muscle tissue.

Our study aims to explore the potential of TRF in improving adipose tissue deposition and muscle dysfunction in human obesity subjects and mice with SO. We will specifically focus on age-related SO in mice induced by a HFD, as well as in obese human subjects. We have observed that TRF significantly reduce fat deposition and improve muscle function. Mechanistically, the TRF intervention is linked to increased liver FGF21 protein levels. Furthermore, it enhanced the responsiveness of both adipose and muscle tissues to FGF21, thereby promoting the browning of WAT and improving mitochondrial function and quality control in muscle.