Age-related susceptibility to insulin resistance is due to a combination of CPT1B decline and lipid overload

BACKGROUND Advanced age increases the susceptibility to diet-induced insulin resistance (IR). A key driver of this phenomenon is lipid accumulation in the skeletal muscle. It is debated, however, whether this is due to dietary lipid overload or decline of mitochondrial function. To address the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we put young and aged mice on a low- or high-fat diet (HFD). RESULTS As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals glycolytic protein levels were reduced and less flexible to the diet. CONCLUSION We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their interaction. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR. ### Competing Interest Statement The authors have declared no competing interest.