From Obesity to Muscle Insulin Resistance: The Mediating Roles of Intramyocellular Lipids, Inflammation, and Oxidative Stress

ABSTRACT Obesity is highly correlated to muscle insulin resistance (IR), which significantly impacts metabolic health. One of the primary mechanisms connecting obesity to muscle IR is the accumulation of intramyocellular lipids (IMCL). Excessive lipid accumulation in muscle cells, that is, muscle lipotoxicity, leads to the formation of lipid metabolites, such as diacylglycerol (DAG) and ceramides, which disrupt insulin signalling pathways. These metabolites activate protein kinase C (PKC) and other kinases that inhibit insulin receptor substrate (IRS) proteins, subsequently impairing the insulin signalling cascade and reducing glucose uptake in skeletal muscle cells. This lipid‐induced IR is a critical factor in the development of metabolic disorders associated with obesity. Furthermore, inflammation and oxidative stress may play significant roles in linking obesity with muscle IR. Obesity‐induced inflammation is characterised by increased levels of pro‐inflammatory cytokines, which activate signalling pathways, such as NF‐κB and JNK. This transcription factor and stress protein further impair insulin signalling by promoting serine phosphorylation of IRS proteins. Concurrently, oxidative stress, resulting from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, exacerbates insulin resistance. Elevated ROS levels associated with damaging cellular components, including proteins, lipids, and DNA, may activate stress‐sensitive signalling pathways, inhibiting insulin action. The current review analyses evidence on the interplay between IMCL accumulation, inflammation, and oxidative stress, establishing this interconnected triad as a vicious cycle: lipid metabolites activate inflammatory kinases, while inflammation and ROS further promote lipid deposition and mitochondrial inefficiency. This triad of mechanisms explains why muscle IR in obesity is both a cause and consequence of metabolic disease progression. Understanding these pathways is clinically urgent, as they represent actionable targets for therapies (e.g., peroxisome proliferator‐activated receptor gamma PPARγ agonists to reduce ceramides, anti‐inflammatory strategies to preserve insulin signalling). This synthesis of current evidence highlights how obesity‐induced muscle IR propagates systemic metabolic risk, offering a framework for future translational research.