Uncovering The Mechanisms Of Caloric Restriction- Induced Insulin Sensitivity: The Potential Role Of Adipose Tissue-Derived miRNAs

• Grant number: 24/20995-1
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: April 01, 2025
• End date: March 31, 2028
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Marcelo Alves da Silva Mori
• Grantee: Cristiane dos Santos
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 21/08354-2 - The interplay between the immune system and metabolism as a key determinant of the aging process, AP.TEM

Abstract

The global prevalence of obesity and type 2 diabetes mellitus has reached epidemic levels, now recognized as a critical health crisis of the 21st century. Lifestyle interventions are essential and first-line treatment for managing these metabolic disorders. Within this context, caloric restriction (CR) stands out as a longstanding and promising strategy for improving glucose homeostasis, promoting insulin sensitivity, weight loss, and enhancing overall health span. However, the mechanisms through which CR improves insulin sensitivity are not yet fully understood and likely extend beyond hormonal changes, fasting periods, or weight loss. We hypothesize that CR reprograms adipose tissue (AT) to produce a unique profile of miRNAs, which are subsequently released into the bloodstream via extracellular vesicles (EVs) and act to enhance insulin sensitivity in peripheral tissues. To test this hypothesis, we propose using both murine models subjected to a moderate 20% CR protocol and samples from human patients undergoing caloric deficit. We will conduct three main approaches: 1) To evaluate the contribution of AT-derived miRNAs in the insulin-sensitizing effects of CR, we will utilize AdicerKO mice, a model with impaired miRNA biogenesis specifically in adipocytes. Additionally, to identify the profile of AT-specific miRNAs and track their presence in circulation and peripheral tissues, we will employ a transgenic mouse model (UPRT/AdipoqCre mice) that labels miRNAs produced by adipocytes, allowing for precise tracking of these molecules. Identifying key AT-derived miRNAs modulated by CR will enable us to explore potential miRNAs controlling insulin sensitivity. 2) To investigate whether AT-derived, EV-associated miRNAs have a direct effect on insulin sensitivity, we will treat murine cell lines (i.e., hepatocytes and myocytes) with EVs isolated from the plasma of CR or ad libitum (AL) fed wild type or AdicerKO mice. We will also conduct adoptive EV transfers from CR mice to obese mice to assess if CR-derived EVs can improve insulin sensitivity in vivo. Moreover, we will test the role of candidate miRNAs in controlling insulin sensitivity in these cells. These approaches will allow us to determine the association between AT-derived EV-miRNAs from CR mice and insulin sensitivity (in vivo and in vitro). 3) Finally, to examine the impact of CR on EV-miRNA profile in humans and to identify potential translational targets, we will analyze samples from individuals enrolled in a Bariatric Surgery Program, where reduced caloric intake is achieved through both lifestyle adjustments and surgical intervention. Using this approach, we expect to identify some overlap between mice and human EV-miRNAs. Through this project, we aim to demonstrate that CR-induced improvements in insulin sensitivity are at least in part mediated by AT-derived EV-miRNAs and to identify potential targets and miRNA mimics capable of replicating the benefits of CR.