Research
Hormonal
High-fat diets (HFD) induce insulin resistance in rodents primarily through the accumulation of diacylglycerol (DAG) and ceramides, which inhibit insulin signaling via PKC and PP2A activation respectively.
This explains why high-fat diets can lead to metabolic issues at a cellular level: excess fat storage in organs like the liver and muscle triggers specific molecules (DAG and ceramides) that block insulin's ability to signal for glucose uptake.
GoodSupportsHIGH confidence
Studies have shown that lipid deposition in tissues such as muscle and liver inhibit insulin signaling via the toxic molecules DAG and ceramide. DAGs activate protein kinase C that inhibit insulin-PI3K-Akt signaling by phosphorylating serine residues on insulin receptor substrate (IRS). Ceramides are sphingolipids with variable acyl group chain length and activate protein phosphatase 2A that dephosphorylates Akt to block insulin signaling.
Why this rating
Based on extensive rodent studies and molecular biology research cited in the review.
Source
Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms—A Narrative Review
Jibran A. Wali et al. · Nutrients · 2020
DOI 10.3390/nu12051505
narrative_reviewCited 222×
Read the paper DOI resolved against Crossref · corpus check 2026-06-10
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