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Very long-chain ceramides in skeletal muscle associate with systemic insulin resistance independent of obesity

ABSTRACT: Lipids are bioactive signaling molecules implicated in tissue-specific and whole-body insulin resistance, with ceramides and diacylglycerols (DAGs) as prominent species. Their precise roles remain unclear. Here, we leverage natural genetic variation in 399 male Diversity Outbred Australia (DOz) mice fed chow or a high-fat diet to examine the relationship between muscle lipids and insulin sensitivity. Fat mass was significantly associated with 55% of muscle lipid features and whole-body insulin sensitivity, with DAGs enriched in this association. To disentangle adiposity and muscle lipid contributions, we used: (1) linear models correcting lipid features for fat mass, and (2) insulin sensitivity quartiles within adiposity bins. Both approaches identified very long-chain ceramides, not DAGs, as linked to insulin resistance. RNA sequencing and proteomics from the same muscles associated these ceramides with cellular stress, mitochondrial dysfunction, and protein synthesis regulation. Meanwhile, DAGs correlated with leptin gene expression, suggesting an adipocyte, rather than myocyte, origin. These findings highlight very long-chain ceramides as key muscle lipids associated with insulin resistance, independent of adiposity.

ORGANISM(S): Mus musculus

PROVIDER: GSE290031 | GEO | 2025/08/06

REPOSITORIES: GEO

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Project description:Aims/hypothesis: While lipid deposition in skeletal muscle is considered to be involved in obesity-associated insulin resistance, neutral intramyocellular lipid (IMCL) accumulation per se does not necessarily induce insulin resistance. We previously demonstrated that overexpression of the lipid droplet coat protein perilipin 2 augments intramyocellular lipid content while improving insulin sensitivity. Another member of the perilipin family, perilipin 5 (PLIN5), is predominantly expressed in oxidative tissues like skeletal muscle. Here we investigated the effects of PLIN5 overexpression M-bM-^@M-^S in comparison with effects of PLIN2 M-bM-^@M-^S on skeletal muscle lipid levels, gene expression profiles and insulin sensitivity. Methods: Gene electroporation was used to overexpress PLIN5 in tibialis anterior muscle of rats fed a high fat diet. Eight days after electroporation, insulin-mediated glucose uptake in skeletal muscle was measured by means of a hyperinsulinemic euglycemic clamp. Electron microscopy, fluorescence microscopy and lipid extractions were performed to investigate IMCL accumulation. Gene expression profiles were obtained using microarrays. Results: TAG storage and lipid droplet size increased upon PLIN5 overexpression. Despite the higher IMCL content, insulin sensitivity was not impaired and DAG and acylcarnitine levels were unaffected. In contrast to the effects of PLIN2 overexpression, microarray data analysis revealed a gene expression profile favoring FA oxidation and improved mitochondrial function. Conclusions/interpretation: Both PLIN2 and PLIN5 increase neutral IMCL content without impeding insulin-mediated glucose uptake. As opposed to the effects of PLIN2 overexpression, overexpression of PLIN5 in skeletal muscle promoted expression of a cluster of genes under control of PPARM-NM-1 and PGC1M-NM-1 involved in FA catabolism and mitochondrial oxidation. Rats received a high fat diet for 3 weeks; 2 weeks after start of the diet intervention Plin5 (OXPAT) or Plin2 (ADRP) were overexpressed in either the right or left tibialis anterior muscle. One week later pooled tibialis anterior muscle samples were analysed on microarrays.

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Very long-chain ceramides in skeletal muscle associate with systemic insulin resistance independent of obesity

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