Unveiling the Molecular Legacy of Transient Insulin Resistance: Implications for Hepatic Metabolic Adaptability [ATAC-Seq]

Metabolic flexibility (MetF) refers to an organism's capacity to adapt to changes in metabolic supplies and energy demands. MetF involves various organs, such as skeletal muscle, white adipose tissues, and the liver, and plays a critical role in altering fuel selection. Insulin acts as a central coordinator of MetF, regulated at the molecular level through various mechanisms, including signaling cascades, transcriptional responses, and circadian regulation. Insulin resistance (IR) can hinder MetF, leading to the development of type 2 diabetes and obesity. These conditions are primarily linked to long-term, chronic exposure to sedentary lifestyles, unbalanced diets, and disruptions in circadian rhythms. However, transient episodes of IR significantly elevate the risk of later-in-life development of type 2 diabetes, as seen in cases like gestational diabetes and stress-induced hyperglycemia. Despite their significance to human health, the molecular processes underlying metabolic dysregulation after these transient episodes remain poorly understood. In our study, we demonstrate that a temporary and fully reversible insulin receptor blockade in young mice results in later-in-life hepatic abnormalities that impair the PPARα-mediated response to a high-fat diet. This impairment is associated with increased histone repressive marks at PPARα-centered loci and decreased hepatic content of PPARα endogenous ligands. Transient insulin receptor blockade temporarily disrupts the liver's circadian rhythm, and this disruption specifically propagates to high-fat diet-fed animals. Our findings reveal that PPARα ligand responsiveness is critically influenced by the circadian clock, adding another layer of (dys)regulation to hepatic homeostasis due to early transient events. In summary, our data suggest that seemingly reversible and unnoticed metabolic challenges in early adulthood may predispose the liver to exacerbated metabolic dysfunctions when confronted with chronic challenges later in life.