Atorvastatin Reduces Adipose Tissue Browning And Prolong Survival In Cancer Cachexia Mice

Background and aims Cancer cachexia (CC) is a wasting syndrome characterized by systemic inflammation, body weight loss, atrophy of white adipose tissue (WAT) and skeletal muscle. Epidemiological data show that 60–80% of advanced cancer patients are affected by the syndrome, in which 22–40% of deaths are due to CC. During the development of cancer cachexia, a well‐characterized loss of both WAT and skeletal muscle occurs. White‐to‐brown adipose tissue remodeling (browning) in response to CC was demonstrated to take place early during CC stages, before skeletal muscle atrophy. WAT browning is associated with an increased expression of uncoupling protein 1 (UCP1), which leads to increased lipid mobilization and energy expenditure in CC mice. Recently, atorvastatin (ATOR) was proposed to exhibit anti‐cancer properties, including a reduction in adipose tissue loss; nevertheless, few studies have evaluated its effect on survival and WAT browning. Methods Male C57BL/6 mice (6–8 week‐old) were subcutaneously inoculated with 300μl (3,5×10 5 ) of Lewis Lung Carcinoma (TB) and vehicle‐saline (control). Daily oral treatment with Atorvastatin (Citolar®, Pfizer) (100mg/kg per day) or vehicle was started 1 week before tumor cell injection. Samples of different AT depots were collected at day 27 stored at −80° C (5 to 8 animals per each group). Morphological and immunohistochemistry analyses were obtained by light microscopy, while the gene expression analysis was performed by qPCR. For survival studies, rats received daily oral ATOR or vehicle for up to 27 days. Tumor induction was successful in 100% of the animals. Results ATOR treatment reduced WAT browning cachexia‐induced in TB, showing down‐regulation of both gene and protein expression of UCP1 in SCAT (p< 0,01). Subcutaneous adipose tissue mass loss was attenuated in ATOR when compared with TB (25%, p<0.05). In addition, life span increased (29%, P<0.05) as well as treated animals survived for a significantly longer time than TB group. WAT demonstrated a decrease in TNFa, CD68 and CD3 positive cells in the ATOR when compared to with TB. Conclusion In the present study we demonstrated that ATOR treatment seems to be efficient in to attenuate classical cachexia marker such as adipose tissue loss followed by an attenuated browning effect induced by cachexia. In addition, ATOR treatment was efficient into increase both life span and survival end point. Support or Funding Information Financial Support: 15/19259–0