RESUMEN
Objective: The ketone diester, R,S-1,3-butanediol diacetoacetate (BD-AcAc2), attenuates the accretion of adiposity and reduces hepatic steatosis in high-fat diet-induced obese mice when carbohydrate energy is removed from the diet to accommodate energy from the ester. Reducing carbohydrate energy is a potential confounder due to the well-known effects of carbohydrate restriction on components of energy balance and metabolism. Therefore, the current investigation was designed to determine whether the addition of BD-AcAc2 to a high-fat, high-sugar diet (with no reduction in carbohydrate energy) would attenuate the accretion of adiposity and markers of hepatic steatosis and inflammation. Methods: Sixteen 11-week-old male C57BL/6J mice were randomized to one of two groups for 9 weeks (n = 8 per group): 1) Control (CON, HFHS diet) or 2) Ketone ester (KE, HFHS diet + BD-AcAc2, 25% by kcals). Results: Body weight increased by 56% in CON (27.8 ± 2.5 to 43.4 ± 3.7 g, p < 0.001) and by 13% in KE (28.0 ± 0.8 to 31.7 ± 3.1 g, p = 0.001). Non-alcoholic fatty liver disease activity scores (NAS) for hepatic steatosis, inflammation, and ballooning were lower in the KE group compared to CON (p < 0.001 for all). Markers of hepatic inflammation [Tnfα (p = 0.036); Mcp1 (p < 0.001)], macrophage content [(Cd68 (p = 0.012)], and collagen deposition and hepatic stellate cell activation [(αSma (p = 0.004); Col1A1 (p < 0.001)] were significantly lower in the KE group compared to CON. Conclusion: These findings extend those of our previous work and show that BD-AcAc2 attenuates the accretion of adiposity and reduces markers of liver steatosis, inflammation, ballooning, and fibrosis in lean mice placed on a HFHS diet where carbohydrate energy was not removed to accommodate energy from addition of the diester.
RESUMEN
Cachexia is a debilitating comorbidity affecting many lung cancer patients. We have previously found that cachectic mice with lung cancer have reduced serum ketone body levels due to low PPARα activity in the liver. Restoring hepatic PPARα activity with fenofibrate increased circulating ketones and delayed muscle and white adipose tissue wasting. We hypothesized that the loss of circulating ketones plays a pathophysiologic role in cachexia and performed two dietary intervention studies to test this hypothesis. In the first study, male and female mice were randomized to consume either a very low carbohydrate, ketogenic diet (KD) or normal chow (NC) after undergoing tumor induction. The KD successfully restored serum ketone levels and decreased blood glucose in cachectic mice but did not improve body weight maintenance or survival. In fact, there was a trend for the KD to worsen survival in male but not in female mice. In the second study, we compounded a ketone ester supplement into the NC diet (KE) and randomized tumor-bearing mice to KE or NC after tumor induction. We confirmed that KE was able to acutely and chronically increase ketone body abundance in the serum compared to NC. However, the restoration of ketones in the circulation was not able to improve body weight maintenance or survival in male or female mice with lung cancer. Finally, we investigated PPARα activity in the liver of mice fed KE and NC and found that animals fed a ketone ester supplement showed a significant increase in mRNA expression of several PPARα targets. These data negate our initial hypothesis and suggest that restoring ketone body availability in the circulation of mice with lung cancer does not alter cachexia development or improve survival, despite increasing hepatic PPARα activity.
RESUMEN
Traumatic brain injury (TBI) is a leading cause of human death and disability with no effective therapy to fully prevent long-term neurological deficits in surviving patients. Ketone ester supplementation is protective in animal models of neurodegeneration, but its efficacy against TBI pathophysiology is unknown. Here, we assessed the neuroprotective effect of the ketone monoester, 3-hydroxybutyl-3-hydroxybutyrate, (KE) in male Sprague Dawley rats (n=32). TBI was induced using the controlled cortical impact (CCI) with Sham animals not receiving the brain impact. KE was administered daily by oral gavage (0.5 ml/kg/day) and provided ad libitum at 0.3% (v/v) in the drinking water. KE supplementation started immediately after TBI and lasted for the duration of the study. Motor and sensory deficits were assessed using the Neurobehavioral Severity Scale-Revised (NSS-R) at four weeks post-injury. The NSS-R total score in CCI + KE (1.2 ± 0.4) was significantly lower than in CCI + water (4.4 ± 0.5). Similarly, the NSS-R motor scores in CCI + KE (0.6 ± 0.7) were significantly lower than CCI + water (2.9 ± 1.5). Although the NSS-R sensory score in the CCI + KE group (0.5 ± 0.2) was significantly lower compared to CCI + water (1.8 ± 0.4), no difference was observed between CCI + water and Sham + water (1.0 ± 0.2) groups. The lesion volume was smaller in the CCI + KE (10 ± 3 mm3) compared to CCI + water (47 ± 11 mm3; p < 0.001). KE significantly decreased Iba1+ stained areas in the cortex and hippocampus, and GFAP+ stained areas in all brain regions analyzed - prefrontal cortex, hippocampus, cortex, amygdala (p < 0.01). In summary, our results indicate that KE can protect against TBI-induced morphological and functional deficits when administered immediately after an insult.