Macronutrient Composition and Genetic Background Determine the Response to a Ketogenic Diet

Area of Science:

• Metabolic research
• Nutritional science
• Genetics

Background:

• High-fat diets typically cause obesity, but ketogenic diets (KDs) reduce food intake and body weight.
• The underlying mechanisms for KD-induced weight loss and strain-dependent variations remain unclear.

Purpose of the Study:

• To investigate how macronutrient composition and genetic background influence responses to ketogenic diets.
• To elucidate the molecular mechanisms behind diet-induced hypophagia and weight loss in mice.

Main Methods:

• Systematic alteration of macronutrient content in KDs fed to C57BL/6J (B6J) and C57BL/6NJ (B6NJ) mice.
• Analysis of anorexigenic factors (GDF15, LCN2), stress responses (oxidative, integrated stress response), hepatic inflammation, and gene expression (RNA-seq).
• Genetic manipulation including loss-of-function studies and targeted interventions (NAC, ISRIB).

Main Results:

• B6J mice fed a 5% protein KD exhibited hypophagia, weight loss, and hypoglycemia, unlike B6NJ mice.
• Increased GDF15 and LCN2 levels in B6J mice correlated with weight loss; Nnt and Nlrp12 mutations were identified as strain-specific factors.
• Suppression of oxidative stress (NAC) reduced GDF15/LCN2 and prevented weight loss in B6J mice on the KD-5% diet.

Conclusions:

• Genetic background critically interacts with macronutrient composition to regulate KD efficacy.
• Increased GDF15 and LCN2 levels, driven by genetic factors and stress responses, induce hypophagia.
• Findings suggest personalized dietary interventions may be necessary due to genetic variability in human responses to diet.