β-Hydroxy-β-Methylbutyrate Supplementation Inhibits Pancreatic Tumor Growth and Preserves Muscle Mass in Obese Mice

Cachexia, a complex catabolic state, frequently accompanies pancreatic ductal adenocarcinoma (PDAC), the fourth leading cause of cancer-related death in the US. We previously showed in a murine PDAC model that leucine supplementation improves muscle protein synthesis, but unfortunately also enhances PDAC cell growth, through activation of the mechanistic target of rapamycin (mTOR) signaling pathway. Utilizing the same murine PDAC model, herein we test the hypothesis that the leucine metabolite β-hydroxy-β-methylbutyrate (HMB) enhances muscle protein synthesis but (unlike leucine) suppresses PDAC cell growth. Male C57BL/6 mice received either control diet (n=60) or a diet-induced obesity (DIO) regimen (n=60) for 10 weeks, then were subcutaneously injected (right flank) with Panc02 PDAC cells and further randomized to continue their diets ± HMB supplementation and ± gemcitabine chemotherapy. We determined that: a) DIO, relative to control diet, significantly increased Panc02 tumor growth (nearly 4-fold) and impaired chemotherapeutic response to gemcitabine; b) HMB significantly increased muscle fiber size and muscle mTOR activity in both DIO- and control-fed mice; c) HMB decreased tumor growth and partially rescued gemcitabine responsiveness in DIO-fed mice, but had no antitumor effect in control mice; d) gene expression profiling and additional qPCR, immunohistochemistry and in vitro studies indicate DIO promotes an immunosuppressive tumor microenvironment that is normalized by treatment with HMB. These preclinical findings suggest that HMB has muscle-sparing and anti-tumor activities against PDAC in the context of obesity. 13 samples were analyzed each representing a tumor sample from a different mouse. 3 control diet un-supplemented, 3 control diet HMB supplemented, 3 diet induced obesity (high fat diet) un-supplemented, and 4 diet induced obesity HMB supplemented.