High-fat diet and obesity each increase tumor cell proliferation and muscle wasting in experimental cancer cachexia

High-fat diet (HFD) and associated obesity are suggested to predispose to cancer development, complicate cancer treatment, and accelerate mortality. Paradoxically, obese patients with lung cancer are reported to live longer, suggesting that high body mass is protective. Given that cachexia-tumor-induced weight loss with adipose and muscle wasting-is prevalent in lung cancer, we speculated that patients with obesity might survive longer due to the protective effect of larger tissue reservoirs, slowing time to fatal wasting. Thus, we modeled this condition using lean and high-fat diet (HFD)-induced obese mice with Lewis lung carcinoma (LLC) tumors versus nontumor-bearing controls. We also assessed the effects of feeding HFD to lean mice with and without LLC tumors. HFD and obese-HFD mice without tumors gained weight over the study, with obese-HFD mice exhibiting low muscle mass with obesity at endpoint. Low-fat diet (LFD)-fed lean mice with LLC tumors (LFD-LLC) showed no change in total body weight, but exhibited reduced skeletal muscle, heart, and fat pad mass along with hepatosplenomegaly at endpoint. HFD and pre-existing obesity both modified the response to Lewis lung carcinoma (LLC) tumors. HFD did not affect tumor-induced weight loss, fat loss, or tumor burden, but worsened loss of gastrocnemius, tibialis anterior, and heart muscle, prevented hepatosplenomegaly, and enhanced tumor cell proliferation and expression of the cachexia-inducing cytokine, interleukin-6 (IL-6). Obese-HFD mice showed greater tumor burden versus LFD and the worst cachexia phenotypes, including greater weight loss and muscle loss than HFD or LFD. This worsened cachexia was associated with increased blood-borne inflammatory cytokines, increased phosphorylated STAT3 in muscle, and increased IL-6 expression in muscle, spleen, and tumor. Obese-HFD was associated with the highest rate of tumor cell proliferation in vivo, and serum from obese HFD mice increased LLC cell proliferation in vitro. Thus, HFD and pre-existing obesity each separately enhance inflammation, cachexia, and tumor growth. These distinct contributions of HFD and chronic adiposity are potential therapeutic targets to slow cachexia and tumor growth in cancer.<b>NEW & NOTEWORTHY</b> High-fat diet and obesity are linked to increased cancer risk, but the impact on cachexia development remains unclear. Using mouse models, this study demonstrates high-fat diet and obesity each exacerbate muscle wasting, tumor growth, and tumor and muscle IL-6 expression. Our study reveals distinct, overlapping effects with implications for cancer and cachexia interception.