ABSTRACT
Patients diagnosed with obesity are prescribed opioid medications at a higher rate than the general population; however, it is not known if eating a high fat diet might impact individual sensitivity to these medications. To explore the hypothesis that eating a high fat diet increases sensitivity of rats to the effects of morphine, 24 female Sprague-Dawley rats (n=8/diet) ate either a standard laboratory chow (17% kcal from fat), a high fat/low carbohydrate (ketogenic) chow (90.5% kcal from fat), or a traditional high fat/high carbohydrate chow (60% kcal from fat). Morphine-induced antinociception was assessed using a warm water tail withdrawal procedure, during which latency (in seconds) for rats to remove their tail from warm water baths was recorded following saline or morphine (0.32-56 mg/kg, IP) injections. Morphine was administered acutely and chronically, which involved 19 days of twice daily injections (increasing in 1/4 log dose increments every 3 days: 3.2-56 mg/kg, IP) to induce dependence and assess tolerance. The adverse effects of morphine (i.e., tolerance, withdrawal, changes in body temperature) were assessed throughout the study. Morphine induced comparable antinociception in rats eating different diets, and all rats developed tolerance following chronic morphine exposure. Additional adverse effects of morphine were also comparable among rats eating different diets; however, withdrawal-induced weight loss was less severe for rats eating ketogenic chow. These results suggest that dietary manipulation might modulate the severity of withdrawal-related weight loss, in ways that could be relevant for patients. Significance Statement The present study in female rats suggests that eating a high fat/low carbohydrate (ketogenic) or a traditional high fat/high carbohydrate diet does not impact the pain-relieving or adverse effects of opioids (i.e., tolerance or withdrawal). However, eating a ketogenic diet may have beneficial effects on opioid withdrawal-related weight loss. Individuals diagnosed with obesity taking opioids for pain-related conditions might therefore consider adopting a ketogenic diet when opioid administration is discontinued to potentially mitigate withdrawal-related weight loss.
ABSTRACT
Lipids are essential for tumours because of their structural, energetic, and signaling roles. While many cancer cells upregulate lipid synthesis, growing evidence suggests that tumours simultaneously intensify the uptake of circulating lipids carried by lipoproteins. Which mechanisms promote the uptake of extracellular lipids, and how this pool of lipids contributes to cancer progression, are poorly understood. Here, using functional genetic screens, we find that lipoprotein uptake confers resistance to lipid peroxidation and ferroptotic cell death. Lipoprotein supplementation robustly inhibits ferroptosis across numerous cancer types. Mechanistically, cancer cells take up lipoproteins through a pathway dependent on sulfated glycosaminoglycans (GAGs) linked to cell-surface proteoglycans. Tumour GAGs are a major determinant of the uptake of both low and high density lipoproteins. Impairment of glycosaminoglycan synthesis or acute degradation of surface GAGs decreases the uptake of lipoproteins, sensitizes cells to ferroptosis and reduces tumour growth in mice. We also find that human clear cell renal cell carcinomas, a distinctively lipid-rich tumour type, display elevated levels of lipoprotein-derived antioxidants and the GAG chondroitin sulfate than non-malignant human kidney. Altogether, our work identifies lipoprotein uptake as an essential anti-ferroptotic mechanism for cancer cells to overcome lipid oxidative stress in vivo, and reveals GAG biosynthesis as an unexpected mediator of this process.