<smlcap>L</smlcap>-Carnitine Ameliorates Cancer Cachexia in Mice Partly via the Carnitine Palmitoyltransferase-Associated PPAR-γ Signaling Pathway

Abstract

<b><i>Background:</i></b><smlcap>L</smlcap>-Carnitine has been demonstrated to ameliorate cachectic symptoms. In the present study, we sought to investigate the role of the peroxisome proliferator-activated receptor-γ (PPAR-γ) signaling pathway in the ameliorative effects of <smlcap>L</smlcap>-carnitine on cancer cachexia in a colon-26 tumor-bearing mouse model. <b><i>Methods:</i></b> The cachectic mice received <smlcap>L</smlcap>-carnitine (p.o.) or etomoxir (i.p.), or pioglitazone hydrochloride (p.o.) or GW9662 (i.p.). The physiological cachexia parameters, biochemical parameters, and serum cytokines were measured. The expression levels of representative molecules in the PPAR-γ signaling pathway were measured by using quantitative real-time polymerase chain reaction (qRT-PCR) or Western blot analysis. <b><i>Results:</i></b> Oral administration of <smlcap>L</smlcap>-carnitine at 9 mg/kg/day improved the cachexia parameters and biochemical parameters in cancer cachectic mice. The elevated serum concentrations of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) were decreased by <smlcap>L</smlcap>-carnitine. These ameliorative effects of <smlcap>L</smlcap>-carnitine were lessened by the carnitine palmitoyltransferase I (CPT I) inhibitor, etomoxir. The mRNA and protein expression levels of PPAR-α and PPAR-γ were decreased in the livers of cancer cachectic mice and increased after <smlcap>L</smlcap>-carnitine administration, which attenuated the increased mRNA expression levels of sterol-regulatory element-binding protein-1c (SREBP-1c) and fatty acid synthase (FAS). Similar to pioglitazone, <smlcap>L</smlcap>-carnitine augmented the phosphorylation of PPAR-γ and attenuated the expression levels of phospho-p65 and cyclooxygenase (COX)-2. Additionally, the above-mentioned effects of <smlcap>L</smlcap>-carnitine were reversed by GW9662. <b><i>Conclusion:</i></b><smlcap>L</smlcap>-Carnitine exerts its ameliorative effects in cancer cachexia in association with the PPAR-γ signaling pathway.