Exercise promotes fat loss, improves insulin resistance, and enhances mitochondrial function, serving as a core strategy against obesity and diabetes. However, not everyone can sustain regular exercise, particularly those with excess weight, muscle degeneration, or chronic disease risks, where exercise barriers hinder metabolic disease treatment. Could a “drug” replicate exercise effects? In April 2025, a study led by Professors Weida Li, Shaorong Gao, and Rongrong Le, published in Cell Reports Medicine, reported that CD47-blocking antibodies mimic exercise effects—activating skeletal muscle energy regulation pathway AMPK without physical activity, achieving significant fat loss, improved glucose tolerance, and preserved muscle mass, introducing the concept of an “exercise mimetic target.”
Figure 1. Journal, Title, Author Information, and Abstract
The study analyzed human transcriptomic and proteomic data, revealing elevated CD47 expression in skeletal muscle of obese individuals, while regular exercise significantly downregulates CD47. In animal experiments, high-fat diet-fed mice injected with CD47-blocking antibodies showed marked metabolic improvements, including reduced body weight gain and fat mass, increased lean mass, enhanced glucose tolerance and lipid profiles, and improved mitochondrial function and exercise endurance.
Figure 2. Body Weight Changes and NMR Body Composition Comparison Between CD47 Antibody and Control Groups
Notably, treated mice exhibited higher basal metabolic rates without significant changes in food intake or daily activity, suggesting the effect stems from metabolic regulation rather than behavioral changes.
Figure 3. Spontaneous Food Intake, Physical Activity, and Treadmill-Measured Running Distance and Duration
Previously, CD47 was primarily linked to tumor immunotherapy. As a widely expressed transmembrane protein, CD47 is traditionally known as a “self-recognition” molecule, interacting with SIRPα to signal “do not phagocytose” to macrophages, maintaining immune homeostasis. This study highlights CD47’s negative regulatory role in skeletal muscle metabolism, where its blockade significantly activates the AMPK pathway.
Key findings include: CD47-blocking antibodies specifically activate AMPK in skeletal muscle, with minimal effects on liver, adipose tissue, or the CNS; AMPK activation is accompanied by ACC phosphorylation and PGC-1α upregulation, indicating enhanced fatty acid oxidation and mitochondrial biogenesis; mechanistically, CD47 promotes HSP90α phosphorylation to inhibit AMPK, while antibody intervention reduces this phosphorylation, relieving AMPK suppression; various mouse models (global knockout, skeletal muscle-specific knockout, and induced overexpression) confirmed CD47’s direct and tissue-specific regulation of AMPK activity.
Compared to existing metabolic drugs like GLP-1 receptor agonists or SGLT2 inhibitors, CD47-blocking antibodies offer potential advantages: selective action on skeletal muscle, avoiding side effects from AMPK overactivation in non-target organs like the heart; significant preservation or enhancement of muscle mass, addressing the common “fat and muscle loss” issue in weight loss therapies; and no impact on feeding behavior or activity patterns, suggesting broader applicability.
The study also suggests CD47 blockade may influence skeletal muscle stem cell proliferation, offering potential applications in muscle degenerative diseases. Could a future arrive where weight loss and fitness are achieved without exhaustive exercise?
