(P09-21-26) Long-Term Comparison of Ketogenic Diet and Ketone Esters on Hepatic Lipid Content and Glucose Metabolism

Objectives: Exogenous and endogenous strategies to increase circulating ketone concentrations reduce body weight and adiposity in preclinical rodent and human clinical studies, respectively, but little is known regarding their effects on lipid and glucose metabolism. Therefore, the objective of this investigation was to perform a parallel comparison of a ketogenic diet (KD) and two commercially available ketone precursors on body weight, hepatic lipid content, and markers of whole-body glucose metabolism.

Methods: Five-week-old male C57BL/6J mice were fed a high-fat, high-sugar (HFHS, 40% fat, 40% sucrose) diet for 10 weeks. Mice were then randomized to continue the HFHS (control (CON), n =7) diet, KD (85% fat, 5% dextrose, n = 9) or a HFHS diet supplemented with ketone monoester (KME, 25% by kcals, n = 7) or ketone diester (KDE, 25% by kcals, n = 8) for ~ 26 weeks. Body weight, adiposity, hepatic lipid content, glucose (1.5 g/kg body weight i.p.) and insulin (0.5 U/kg body weight i.p.) tolerance tests were conducted.

Results: Compared to control (47.8 ± 2.8 g), body weight was 38% (29.7 ± 2.7 g) and 21% (37.7 ± 4.6 g) lower in the KME and KDE groups (p < 0.05 for all), whereas KD increased body weight by 15% (p < 0.05). Hepatic lipid content was decreased in KME (76.6%) and KDE (58.9%), but not statistically significant in KD despite a 15.1% decrease compared to CON (p > 0.05). Insulin tolerance was improved in the KME group only compared to CON (p < 0.05). Glucose tolerance was statistically similar among groups (p > 0.05 for all), but an exploratory analysis revealed that incremental AUC was 12.5% lower than CON in the KD group. Circulating glucose concentrations were lower in the KD (24%) and KME (29.3%) groups compared to CON (p < 0.05 for all), while KDE did not show significant changes following a fasting and refeeding period.

Conclusions: HFHS-fed mice administered dietary exogenous ketone esters (KME and KDE) have lower body weight and improved hepatic lipid and insulin tolerance compared to HFHS-fed controls. The KD group showed improved circulating glucose and signs of decreased hepatic lipid content despite having higher body weight, highlighting the role of ketosis on metabolism.

Funding Sources: This study was supported by award number P30DK079626 from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK).