Age-related susceptibility to insulin resistance arises from a combination of CPT1B decline and lipid overload

Abstract

Background The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate 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 combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.

The crucial role and mechanism of insulin resistance in metabolic disease

“…To explore the reasons for this, the investigators found increased fat accumulation in muscle and liver tissue as assessed by 1H NMR spectroscopy and an approximately 40% reduction in mitochondrial oxidative and phosphorylation activity as assessed by in vivo 13C/31P NMR spectroscopy ( 118 ). According to the result of an animal experiment, compared with young mice, aged mice are more susceptible to IR, due to reduced levels of glycolytic proteins and reduced flexible to diet, caused by reduced mitochondrial β-oxidation capacity ( 119 ). However, these hypotheses still need to be further tested and further understanding of the metabolic changes associated with aging.…”

Age and diet modulate the insulin-sensitizing effects of exercise: a tracer-based oral glucose tolerance test

“…Fractional distributions of [6,6-2 H 2 ]-glucose and [U- 13 C]-glucose in bloodspots were measured according to van Dijk et al (38). Glucose was converted into its pentaacetate derivative by adding pyridine/acetic anhydride mixture.…”

“…The copyright holder for this preprint this version posted March 21, 2023. ; https://doi.org/10.1101/2023.03.18.533083 doi: bioRxiv preprint insulin resistance was aggravated by age (13). The studies differ, however, in terms of (i) diet duration, timing and composition, and (ii) mouse strain.…”

“…Aging exacerbates the susceptibility to lipid-induced insulin resistance (11; 12), which amongst other factors involves changes in lipid handling, both in the skeletal muscle (11; 13) and the liver (14). The main route for lipid oxidation is the mitochondrial fatty-acid β-oxidation, with its flux being mostly controlled at the level of carnitine palmitoyltransferase 1 (CPT1) (13; 15).…”

AMPK as a Potential Therapeutic Target for Intervertebral Disc Degeneration

“…Therefore, decreased activity of AMPK may in turn accelerate the process of ageing. Of note, ageing is also a susceptible factor of insulin resistance ( Vieira-Lara et al, 2021 ). Thus, it is speculated that the decline of AMPK activity during ageing may also participate in the occurrence and development of insulin resistance and DM.…”