Lung cancer is the leading cause of cancer-related death and the large majority of patients experience cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting. The nature of tissue wasting in lung CC, however, is poorly described as the majority of patients present with weight loss at diagnosis and mouse models of lung CC evolve too rapidly to discern the timing or mechanisms underlying tissue wasting. We recently described a preclinical model of inducible KrasG12D-driven lung cancer (G12D mice) that develops CC over a longer period (12 weeks) than commonly used models (2-3 weeks), providing the temporal resolution to define CC progression. From this model, we found that adipose tissue loss (>50% of adipose depots) occurs early (3-6 weeks), prior to muscle loss. Adipose wasting was accompanied by transcriptional upregulation of lipolytic machinery and a rise in circulating glycerol levels, indicative of increased lipolysis. Thus, in the present study, we evaluated whether pharmacological inhibition of lipolysis during early adipose loss (3-6 weeks) could prevent CC-induced tissue wasting. At 3 weeks post-induction, G12D and wild-type (WT; Kras+/+) mice were randomized to either a control diet (WT-CON or G12D-CON), or a diet containing the lipolysis inhibitor Atglistatin (WT-Ai or G12D-Ai, 2 mmol/kg of diet) until week 6. Body weight was not preserved in G12D-Ai mice compared to G12D-Con mice over the 3-week feeding period, although there was a trend towards an effect of Ai to preserve adipose weights in G12D-Ai mice compared to G12D-Con mice. Similarly, Ai did not modify skeletal muscle weights in G12D mice. Interestingly, lung cancer (G12D-CON) increased liver triglyceride content and Ai (G12D-Ai) reduced liver triglycerides back to control levels (WT-CON & WT-Ai), suggesting that lung CC is associated with hepatic lipid deposition that can be normalized with Ai. Thus, while adipose triglyceride lipase inhibition with Ai was unable to alter CC-associated tissue wasting, our results suggest that Ai may correct lung cancer-associated impaired liver lipid metabolism. As dysregulated liver substrate metabolism is associated with liver metastasis and survival, Ai may have therapeutic utility in lung cancer outside of CC. Funding Support: R21 CA283492 and the University of Vermont Cancer Center This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
Beal et al. (Fri,) studied this question.