Ketone Ester Administration Improves Glycemia in Obese Mice

Am J Physiol Cell Physiol. 2023 Aug 14. doi: 10.1152/ajpcell.00300.2023. Online ahead of print.ABSTRACTDuring periods of prolonged fasting/starvation, the liver generates ketones (i.e., β-hydroxybutyrate [βOHB]) that primarily serve as alternative substrates for ATP production. Previous studies have demonstrated that elevations in skeletal muscle ketone oxidation contribute to obesity-related hyperglycemia, whereas inhibition of succinyl CoA:3-ketoacid CoA transferase (SCOT), the rate-limiting enzyme of ketone oxidation, can alleviate obesity-related hyperglycemia. As circulating ketone levels are a key determinant of ketone oxidation rates, we tested the hypothesis that increases in circulating ketone levels would worsen glucose homeostasis secondary to increases in muscle ketone oxidation. Accordingly, male C57BL/6J mice were subjected to high-fat diet-induced obesity, whereas their lean counterparts received a standard chow diet. Lean and obese mice were orally administered either a ketone ester (KE) or placebo, followed by a glucose tolerance test. In tandem, we conducted isolated islet perifusion experiments to quantify insulin secretion in response to ketones. We observed that exogenous KE administration robustly increases circulating βOHB levels, which was associated with an improvement in glucose tolerance only in obese mice. These observations were independent of muscle ketone oxidation, as they were replicated in mice with a skeletal muscle-specific SCOT deficien...

Source: Am J Physiol Cell Ph... - August 14, 2023 Category: Cytology Authors: Sayed Amirhossein Tabatabaei Dakhili Kunyan Yang Cassandra A A Locatelli Christina T Saed Amanda A Greenwell Jordan S F Chan Jadin J Chahade Jared Scharff Shahad Al Imarah Farah Eaton Peter A Crawford Keshav Gopal Erin E Mulvihill John R Ussher Source Type: research