Unveiling the molecular legacy of transient insulin resistance: Implications for hepatic metabolic adaptability

Abstract

Background & aims: Insulin plays a central role in coordinating metabolic flexibility (MetF). Insulin resistance (IR) can impair MetF, contributing to type 2 diabetes and obesity. Transient IR episodes, like gestational diabetes or stress-induced hyperglycemia, also heighten the risk of later diabetes development. While the health significance of transient IR is well established, we aimed to better understand the heretofore poorly understood molecular processes that occur after such episodes.

Methods: To do this, we characterized the hepatic response to a high-fat diet challenge in mice previously exposed to a transient IR episode. We integrated transcriptomic, epigenomic, lipidomic, and molecular clock assessments to provide a molecular basis for the observed dysregulations.

Results: Our study shows that temporarily blocking the insulin receptor in young mice leads to later-life liver issues by hindering PPARα-mediated adaptation to a high-fat diet. This is linked to decreased histone active marks at PPARα sites and reduced endogenous PPARα ligands. Transient insulin receptor blockade also altered the liver's molecular clock, particularly affecting PPARα transcriptional responsiveness.

Conclusions: Seemingly reversible metabolic challenges in early adulthood may predispose the liver to exacerbated metabolic dysfunctions when confronted with chronic challenges later in life.

Impact and implications: While the health significance of transient insulin resistance is well established, the molecular processes that occur after such episodes are poorly understood. This study thus provides a circadian molecular paradigm for a later-in-life alteration of liver metabolic flexibility following a previous episode of insulin resistance and calls for particular attention to be paid to detecting transient episodes of insulin resistance as they occur in patients with gestational diabetes or stress-induced hyperglycemia. By extension, any transient exposure to compounds altering circadian rhythmicity, such as anti-depressants, might predispose to a compromised metabolic response to an unbalanced diet later in life.

Keywords: Liver; PPARα; REV-ERBα; circadian clock; insulin resistance; metabolic flexibility.