Carbohydrate restriction is a widely used dietary intervention to treat chronic diseases like metabolic syndrome. The ketogenic diet represents a severe type of carbohydrate restriction and is being rapidly adopted by metabolically healthy individuals. Recently, different responses to American (35% of energy from fat, 50% from carbohydrate) and ketogenic (80% of energy from fat, and 0% from carbohydrate) were observed between C57BL/6 J and FVB/NJ mice suggesting that genetic background effects response and non-response to carbohydrate restriction.To further investigate the apparent response and non-response to carbohydrate restriction, we generated a C57BL/6 J x FVB/NJ intercross (F2) population (250 females and 264 males) to identify quantitative trait loci (QTL) involved in response to these two high fat diets. All animals were genotyped on the Mouse Universal Genotyping Array.Genetic analyses for fat gain during 3 months on diet revealed a diet and sex dependent (pdiet: Chr5 = 0.0013, psex: Chr5 = 0.0087) QTL on Chromosome (Chr) 5 at 73.7 Mb that results in a male-specific response to the ketogenic diet. There is an additional QTL on distal Chr1 at 191.6 Mb for fat mass gain in both males and females, on on both diets that overlaps with a QTL for serum HDL cholesterol concentration after 3 months on diet at 168.6 Mb.This distal locus on Chr1 has previously been associated with Apoa2 and serum HDL cholesterol concentration in these strains. Additional candidate genes in these regions include Hsd11b1 and Srd5a3 and are associated with steroid hormone biosynthesis. These candidates are of primary interest given the relationship between cholesterol and synthesis of steroid hormones. These results demonstrate that the response to American and ketogenic diets is strain and sex specific. Our ongoing efforts to validate the regulatory role of these loci in response to carbohydrate restriction will be used to assess the utility of the relevant genotypes and analytes as biomarkers for response to carbohydrate restriction.National Institutes of Health.