Endocrine Abstracts

Identifying effective strategies and underneath molecular signatures is crucial to combat certain metabolic diseases with increasing incidence such as obesity and MASLD (metabolic dysfunction-associated steatotic liver disease). The hepatic secretome plays a crucial role at controlling global energy metabolism and inflammation in MASLD. However, the interplay between diet composition and the eating architecture on the dynamic response of secretome as a tool to improve disease outcomes remains unknown. Under these conditions, we aim to elucidate the influence of the hepatic secretome on the energetic homeostasis as a potential therapeutic mechanism in metabolic diseases. To this end, male C57BL/6 mice (1 year old) were subjected to 5 months of 4:10 feeding cycles [4 days of very low-calorie intake (VLCI) followed by 10 days of ad libitum feeding] under Standard (SD) and high-fat diet (HFD) feeding regime. Liver RNAseq was performed, and the modulation of secretome genes was studied by associating their expression with physiological data, mouse parameters, and biological energy homeostasis. VLCI effectively reduces body weight and fat mass, improving physical performance and glucose regulation. Hepatic RNAseq identified a total of 1607 secretome genes. A Heatmap and PCA analysis significantly distinguished the secretome profile between VLCI and ad libitum (AL) mice, under SD and HFD feeding regime. Subsequently, a Volcano Plot analysis between VLCI and AL mice, identified a molecular signature of 269 and 135 differentially expressed secretome genes [FC>1.2, P<0.05] induced by VLCI under Standard and high-fat diets, respectively, of which, a VLCI-specific signature of 46 genes were over-expressed and down-expressed identically in both SD and HFD. Moreover, a Gene Ontology analysis revealed specific metabolic pathways (cholesterol metabolism, regulation of kinase activity, etc.) related with VLCI intervention, independently of diet composition (SD or HFD). Finally, the VLCI-imprinted signature correlated with energy balance signals in the liver and plasma, including insulin, mTOR pathway, or beta-hydroxybutyrate. In summary, this study not only upholds the effectiveness of fasting-based strategies to enhance physiological health but also identifies a strong and dynamic modulation of the secretome, identifying VLCI-specific signature independent of diet composition. Therefore, our data smggest that secretome modulation could have a therapeutic impact on metabolic diseases involving energy balance dysregulation.

Fundings: AEI (AEI/10.13039/501100011033); Ramon y Cajal-MCIN (RYC2021-033751-I); RETOS-MCIN (PID2019-106893RA-I00), European Union NextGenerationEU/PRTR; Ramón Areces Foundation (CIVP21S13338).