The impact of lipid-rich nutrition on ketogenesis and muscle weakness in sepsis

TL;DR

This study explores how lipid-rich nutrition affects ketogenesis and muscle weakness in sepsis, finding that glucose suppresses ketosis and that neither LCT nor MCT with glucose improved muscle function.

Contribution

The study reveals that glucose suppresses ketosis and that lipid mixtures with glucose fail to mitigate sepsis-induced muscle weakness.

Findings

Pure LCT induced ketosis but worsened muscle weakness, which was reduced with glucose supplementation.

gLCT and gMCT failed to induce adequate ketosis or improve muscle function in septic mice.

Hmgcs2 protein expression was suppressed in gMCT compared to gLCT mice.

Abstract

Administration of ketone bodies attenuated the severity of sepsis-induced muscle weakness in preclinical studies. Whether lipid-rich emulsions may likewise mitigate such muscle weakness by stimulating the endogenous ketogenic capacity remains uncertain, especially in relation to glucose, a critical suppressor of ketogenesis. This study investigated the ketogenic potential of parenteral nutrition rich in long- and/or medium-chain triglycerides with differing glucose content on sepsis-induced muscle weakness.

We used a parenterally fed murine model of prolonged sepsis-induced muscle weakness to investigate specific lipid mixtures in two consecutive studies. Septic mice receiving standard total parenteral nutrition (TPN) and healthy control (HC) animals were included as references in both studies. In a first study, septic mice received pure long-chain triglycerides (LCT) or long-chain triglycerides supplemented with glucose (gLCT). The second study compared a gLCT mixture to a mixed medium- and long-chain triglyceride emulsion supplemented with glucose (gMCT). After 5 days of sepsis, markers of ketone body metabolism, muscle function, and muscle and liver metabolomics were measured.

In study one, ketosis was undetectable with TPN-treatment, but substantially increased with pure LCT (median 1.39 mmol/L, p < 0.001). Supplemental glucose suppressed ketosis sixfold (median 0.24 mmol/L, p < 0.001). The sepsis-induced muscle weakness was exacerbated in LCT mice, while muscle force was comparable between TPN-treated and gLCT mice (TPN 60.9%; gLCT 60.9%; LCT 33.1% of HC 128.7 mN/mm2, p < 0.001). The decrease in muscle glycolytic metabolites in LCT mice relative to TPN-treated mice was attenuated by supplemental glucose. In study 2, unexpectedly, ketosis was similarly low in gLCT and gMCT mice (p = 0.1), and muscle force was equally reduced in all septic groups (TPN 68.1%; gLCT 74.0%; gMCT 65.9% of HC 105.9 mN/mm2, p = 0.5) as compared to HC mice. Protein expression of the rate-limiting enzyme of ketogenesis, Hmgcs2, was suppressed in gMCT as compared to gLCT mice (p = 0.04).

Pure LCT infusion induced ketosis, but aggravated muscle weakness, which was attenuated by providing supplemental glucose. Combined with glucose, neither long-chain triglycerides nor mixed medium- and long-chain triglycerides were able to induce adequate ketosis or attenuate sepsis-induced muscle weakness.

The online version contains supplementary material available at 10.1186/s40635-026-00867-8.

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