Sex-specific differences in metabolic hormone and adipose tissue dynamics induced by moderate low-carbohydrate and ketogenic diet

Abstract

Low-carbohydrates diets are increasingly used to treat obesity and metabolic disorders. A very low-carbohydrate, ketogenic diet is hard to follow and, due to the very high fat content, linked to severe side effects, like hyperlipidemia and atherogenesis. Therefore, a less restrictive, unsaturated fat-based low-carbohydrate diet appears as a promising alternative. Since neither sex differences, nor their effect on specific metabolic hormones and adipose tissue compartments have been investigated thoroughly in these diets, we aimed to analyze their dynamics and metabolic factors in mice. We found a significant sexual dimorphism with decreased body weight and subcutaneous fat only in males on ketogenic diet, while diminished insulin, elevated ghrelin and FGF-21 were present with a differential time course in both sexes. The non-ketogenic moderate low-carbohydrate diet increased body weight and perigonadal fat in females, but induced leptin elevation in males. Both diets enhanced transiently TNFɑ only in males and had no impact on behavior. Altogether, these results reveal complex sex-dependent effect of dietary interventions, indicating unexpectedly females as more prone to unfavorable metabolic effects of low-carbohydrate diets.

Figure 1

Design of the experiment.

Figure 2

Serum ketone bodies concentration after 1 month on diet. (A) β-hydroxybutyrate, (B) acetoacetate. Mean ± SEM, two-way ANOVA (diet × sex), *significant difference from RC, p < 0.05, ****p < 0.0001, ^#significant sex differences, p < 0.05, Tukey test.

Figure 3

Body weight of male (A) and female (B) mice during 8 weeks on diet. Mean ± SEM, two-way repeated measures ANOVA (week × diet), *significant difference from RC, p < 0.05, **p < 0.01. ***p < 0.001, Tukey test.

Figure 4

Inguinal (A, B) and perigonadal (C, D) fat mass after 1 and 2 months on diet. (A, C) males, (B, D) females. Mean ± SEM, two-way ANOVA (time × diet), *significant difference from RC, p < 0.05, **p < 0.01. ***p < 0.001, Tukey test. Analysis of fat samples was not performed in all mice.

Figure 5

Insulin (A), FGF-21 (B), total ghrelin (C) and leptin (D) in serum, Mean ± SEM, two-way ANOVA (diet × sex), *significant difference from RC, p < 0.05, **p < 0.01. ***p < 0.001, ****p < 0.0001, ^##significant sex differences, p < 0.01, ^###p < 0.001, Tukey test.

Figure 6

TNFɑ (A), IL-6 (B), IL-10 (C) in serum, Mean ± SEM, Two-way ANOVA (diet × sex), *significant difference from RC or between KD groups, p < 0.05, **p < 0.01. ***p < 0.001, ****p < 0.0001, Tukey test.

Figure 7

Behavioral effects of diets. (A) depressive like behavior in sucrose preference test, (B) anxiety in elevated plus maze, (C) social behavior in non-reciprocal social interaction test, (D) spatial memory in Barnes maze. Mean ± SEM, two-way (A–C, diet × sex) or three-way repeated measures (D, trial × diet × sex) ANOVA.