An isoproteic cocoa butter-based ketogenic diet fails to improve glucose homeostasis and promote weight loss in obese mice

Am J Physiol Endocrinol Metab. 2022 Jul 1;323(1):E8-E20. doi: 10.1152/ajpendo.00435.2021. Epub 2022 May 16.


High-fat and very low-carbohydrate based ketogenic diets have gained considerable popularity as a nonpharmacological strategy for obesity, due to their potential to enhance weight loss and improve glucose homeostasis. However, the effectiveness of a ketogenic diet toward metabolic health is equivocal. To better understand the impact of ketogenic diets in obesity, male and female mice were fed a 60% cocoa butter-based high-fat diet for 16-wk to induce obesity, following which mice were transitioned to either an 85% cocoa butter fat-based ketogenic diet, a 10% cocoa butter fat-based low-fat diet, or maintained on a high-fat diet for an additional 8-wk. All experimental diets were matched for sucrose and protein content and contained an identical micronutrient profile, with complex carbohydrates being the primary carbohydrate source in the low-fat diet. The transition to a ketogenic diet was ineffective at promoting significant body fat loss and improving glucose homeostasis in obese male and female mice. Alternatively, obese male and female mice transitioned to a low-fat and high-complex carbohydrate diet exhibited beneficial body composition changes and improved glucose tolerance that may, in part, be attributed to a mild decrease in food intake and a mild increase in energy expenditure. Our findings support the consumption of a diet low in saturated fat and rich in complex carbohydrates as a potential dietary intervention for the treatment of obesity and obesity-induced impairments in glycemia. Furthermore, our results suggest that careful consideration should be taken when considering a ketogenic diet as a nonpharmacological strategy for obesity.NEW & NOTEWORTHY It has been demonstrated that ketogenic diets may be a nutritional strategy for alleviating hyperglycemia and promoting weight loss in obesity. However, there are a number of inconsistencies with many of these studies, especially with regard to the macronutrient and micronutrient compositions of the diets being compared. Our work demonstrates that a ketogenic diet that is both micronutrient-matched and isoproteic with its comparator diets fails to improve glycemia or promote weight loss in obese mice.

Keywords: glucose homeostasis; insulin resistance; insulin sensitivity; ketogenic diet; obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, Fat-Restricted
  • Diet, Ketogenic*
  • Dietary Carbohydrates / metabolism
  • Dietary Carbohydrates / pharmacology
  • Dietary Fats / metabolism
  • Female
  • Homeostasis
  • Male
  • Mice
  • Mice, Obese
  • Micronutrients
  • Obesity / metabolism
  • Weight Loss


  • Blood Glucose
  • Dietary Carbohydrates
  • Dietary Fats
  • Micronutrients
  • cocoa butter

Grant support