Effects of Ketogenic Diet in Young Adult and Old Rats

Abstract

Ketogenic diets (KD) have been promoted extensively for weight loss and health. However, their effects in aged skeletal muscle are not well‐defined. In this study, we tested the effect of a ketogenic diet in young adult (YA; 5 month old) and old (O; 28 month old) male Fisher 344 rats (n = 4–6/group). Rats were assigned to either standard chow (STD; Evigo Teklad Rodent Diet, 8604; 32% protein, 14% fat, 54% carbohydrate) or ketogenic diet (KETO; Envigo Teklad Custom Diet, TD.10911; 22.4% protein, 77.1% fat, 0.5% carbohydrate) for 4 weeks, and weighed weekly. KETO rats were pair fed isocalorically with STD chow rats within each age group with the YA rats eating 0.132 kcal/g body weigh/day, and O rats eating 0.109 kcal/g body weight/day. After 24 or 25 days glucose tolerance testing was performed by fasting the rats for 6 hours followed by an injection of 1 mg glucose/g BW. Blood glucose concentration was measured from tail blood immediately before and 15, 30, 60 and 120 minutes after the glucose injection. Ketones were also measured from tail blood immediately before the glucose injection. After the 4‐week treatment period, rats were euthanized and gastrocnemius muscle was collected for determination of mitochondrial respiration and AMP‐activated protein kinase (AMPK; an important stimulator of glucose and fatty acid metabolism) phosphorylation. We found that KETO feeding increased blood ketone levels, albeit non‐significantly (p=0.065), in YA but not O rats. KETO resulted in significant weight loss within 2 weeks in both YA and O rats. Glucose tolerance was impaired in O‐STD vs. YA‐STD rats, while KETO impaired glucose tolerance in YA, but not O rats. KETO increased mitochondrial respiration in YA, but not O rats. AMPK phosphorylation was decreased by KETO vs. STD diet in YA, but not O rats. We conclude that a KETO diet induces a significant drop in body weight and enhanced mitochondrial respiration, but impaired glucose tolerance in YA rats, suggesting a shift from glycolytic to oxidative metabolism. Somewhat surprisingly, these KETO‐induced changes in YA rats are associated with decreased AMPK activation. O rats are resistant to all of these effects of KETO diet except for weight loss, suggesting impaired metabolic plasticity with old age. Further study will be required to elucidate the exact molecular pathways underlying these shifts.Support or Funding InformationThis research was supported by Brigham Young University Mentoring Environment Grants (MEG) and Gerontology Research Grants.