18 | Double-edge sword of ketogenic diet: hepatic improvement at the expense of musculoskeletal health

Alessandro Antonioli¹, T. Raiteri², A. Provera¹, S. Reano³, S. Tini¹, S. Sutti¹, N. Filigheddu³, F. Prodam¹ | ¹Department of Health Sciences, University of Piemonte Orientale, Novara, Italy; ²Department of Medicine and Surgery, University of Perugia, Perugia, Italy; ³Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

The Western diet (WD), marked by elevated levels of sugars and saturated fats, significantly contributes to obesity and its related health complications. Ketogenic diets (KDs) represent dietary approaches characterized by minimal carbohydrate intake, high fat, and adequate protein levels. Energy is sourced from ketone bodies (KBs), derived primarily from fat oxidation. Given the increasing evidence supporting the effectiveness of KDs in reducing inflammation, oxidative stress, and improving mitochondrial function, we hypothesized that KDs could hold promise in addressing obesity-related conditions. To test this hypothesis, we subjected mice to a Western diet (WD) for 16 weeks, followed by a transition to an ad libitum KD, or continued adherence to WD for an additional 2, 4 or 8 weeks. Our finding demonstrated that the switch from WD to KD elicited opposite effects on liver, muscle, and bone. On one hand, it markedly improved hepatic outcomes, on the other hand, KD did not produce positive effects within muscle and bone. Indeed, KD further exacerbated muscle wasting and myofiber size reduction. In vitro we examined various doses of palmitate (PA) and butyrate (BU) on C2C12-derived myotubes to further investigate the impact of fatty acids and KBs on muscle cells. PA significantly reduced myotube diameter in a dosedependent manner but also induced ROS production, and mitochondrial membrane depolarization. In contrast, low doses of BU protected against PA-induced atrophy in myotubes, while high dose appear to be ineffective or may even contribute to atrophy. Our findings suggest that KD could exert different actions on several tissues, suggesting that if it favors a rapid weight loss, eliciting an improvement in glucose metabolism and liver function, some detrimental effects could be present on other organs. Optimization of dietary timing, duration, and nutrient composition tailored doses of KBs should be taken into account in future studies.