Acyl-CoA Binding Protein for the Experimental Treatment of Anorexia
Introduction
This report aims to reveal the recent research findings published by Hui Chen et al. in “Science Translational Medicine”, which explores the application of exogenous Acyl-Coenzyme A Binding Protein (ACBP) in Anorexia Nervosa.
Anorexia Nervosa is a prevalent and difficult-to-treat eating disorder that primarily affects adolescents and young adults. Symptoms include decreased appetite, weight loss, and increased energy consumption. Although it is known to be associated with reduced levels of the appetite-suppressing hormone leptin and increased levels of the appetite-stimulating hormone ghrelin, these regulatory factors are not widely recognized as causes. Additionally, patients with anorexia nervosa typically have lower plasma concentrations of ACBP, an ancient appetite-stimulating factor encoded by the Diazepam Binding Inhibitor (DBI) that is secreted through a non-traditional autophagy pathway. Based on this, the study aims to explore the treatment of experimental anorexia by supplementing ACBP.
The research was conducted collaboratively by scientists from multiple research institutions, including Centre de Recherche des Cordeliers, Université Paris Cité, Sorbonne Université, and others. The paper was published in the journal “Science Translational Medicine”.
Research Process and Methods
Research Model and Experimental Design
The study primarily used a mouse model of anorexia induced by Chronic Restraint Stress (CRS) to investigate the effects of ACBP in alleviating experimental anorexia. Specifically, mice were restrained for 2 hours daily for 14 days to induce weight loss and decreased appetite.
Development of Chemogenetic System
The research team developed a chemogenetic system based on Streptavidin-Binding Peptide (SBP) and autophagy-independent Retention Using Selective Hooks (RUSH) to control ACBP secretion. The ACBP gene with a signal peptide was introduced into mouse liver cells, and its secretion was induced by biotin. The effectiveness of this system was verified by the rapid increase in plasma ACBP concentration under biotin stimulation, and it was proven to be autophagy-independent after the addition of autophagy inhibitors.
ACBP Enhancement in Experimental Anorexic Mouse Models
Subsequently, the research team compared mouse models under different stressors (CRS or chemotherapy drugs such as cisplatin, doxorubicin, paclitaxel, etc.) by intravenous injection of biotin. They found that enhancing ACBP could effectively reverse weight loss and improve appetite. Through a combination of immunoblotting, enzyme-linked immunosorbent assay (ELISA), and metabolic analysis, the study further confirmed the role of ACBP in the liver and peripheral tissues, as well as its effects on intrahepatic glucose metabolism.
Research Results
Impact of Low ACBP Concentration on Prognosis of Anorexia Nervosa Patients
The study found that Body Mass Index (BMI) was positively correlated with ACBP concentration in healthy volunteers, but this correlation was lacking or even reversed in anorexia nervosa patients. Particularly in hyperphagic-purgative AN patients, low plasma ACBP concentration predicted a poorer prognosis. After hospitalization, as BMI normalized, ACBP concentration increased but still could not significantly affect weight recovery.
Effectiveness of ACBP Secretion System Confirmed in Experimental Models
In mouse models induced by chronic restraint stress, plasma ACBP concentration significantly decreased, but could be effectively increased through biotin induction of the RUSH system, preventing weight loss. Compared to the control group, mice with biotin-induced ACBP release showed significant weight gain and appetite relief. Additionally, Dual-Energy X-ray Absorptiometry (DEXA) revealed that ACBP enhancement also improved fat mass, lean body mass, and bone mineral content.
Peripheral ACBP’s Effect on Central Appetite Regulation
Further experiments showed that injected recombinant ACBP cannot cross the blood-brain barrier but mainly accumulates in the liver, kidneys, adipose tissue, and muscles. Therefore, ACBP’s appetite-stimulating effect is likely achieved through peripheral metabolic pathways and related hormones such as Growth Differentiation Factor 15 (GDF15), Lipocalin-2 (LCN2), and the regulation of norepinephrine and cortisol.
Long-term ACBP Enhancement’s Impact on Behavioral and Physiological Indicators
Mouse models with elevated ACBP concentrations at homeostasis showed increased appetite and weight gain, while continuous supplementation of exogenous ACBP (e.g., through subcutaneous osmotic pump implantation) could prevent weight loss induced by CRS or cisplatin. Additionally, ACBP had a significant effect on depressive-like behavior, manifested as increased immobility time in forced swim tests and partial recovery of liver transcriptome.
Conclusion and Significance
The research results show that ACBP can significantly alleviate anorexia symptoms caused by stress or chemotherapy by regulating metabolic and hormonal signaling pathways in the periphery. This method of supplementing ACBP through chemogenetic systems or recombinant proteins provides a new strategy for treating anorexia, especially in cases of anorexia nervosa and chemotherapy-induced appetite loss.
Research Highlights
- Innovative Experimental Method: Developed a chemogenetic system that achieved controlled secretion of ACBP.
- Broad Application Potential: ACBP not only alleviates stress and chemotherapy-induced anorexia but also has significant effects on weight and appetite, potentially applicable to the treatment of anorexia nervosa in the future.
- In-depth Mechanism Research: Through various experimental methods, the study further revealed the mechanism of ACBP action, summarizing its different effects in peripheral metabolism and the central nervous system.
This study provides new insights into understanding and treating anorexia nervosa, with potential for future clinical application and verification.