Sex differences in response to short-term high fat diet in mice

Abstract

Background: Consumption of high-fat diet (HF) leads to hyperphagia and increased body weight in male rodents. Female rodents are relatively resistant to hyperphagia and weight gain in response to HF, in part via effects of estrogen that suppresses food intake and increases energy expenditure. However, sex differences in energy expenditure and activity levels with HF challenge have not been systemically described. We hypothesized that, in response to short-term HF feeding, female mice will have a higher energy expenditure and be more resistant to HF-induced hyperphagia than male mice.

Methods: Six-week-old male and female C57BL/6 J mice were fed either low fat (LF, 10% fat) or moderate HF (45% fat) for 5 weeks, and energy expenditure, activity and meal pattern measured using comprehensive laboratory animal monitoring system (CLAMS).

Results: After 5 weeks, HF-fed male mice had a significant increase in body weight and fat mass, compared with LF-fed male mice. HF-fed female had a significant increase in body weight compared with LF-fed female mice, but there was no significant difference in fat mass. HF-fed male mice had lower energy expenditure compared to HF-fed female mice, likely due in part to reduced physical activity in the light phase. HF-fed male mice also had increased energy intake in the dark phase compared to LF-fed male mice and a reduced response to exogenous cholecystokinin-induced inhibition of food intake. In contrast, there was no difference in energy intake between LF-fed and HF-fed female mice.

Conclusions: The data show that female mice are generally protected from short-term HF-induced alterations in energy balance, possibly by maintaining higher energy expenditure and an absence of hyperphagia. However, HF-feeding in male mice induced weight and fat mass gain and hyperphagia. These findings suggest that there is a sex difference in the response to short-term HF-feeding in terms of both energy expenditure and control of food intake.

Keywords: Energy expenditure; Energy intake; High-fat diet; Meal patterns; Physical activity; Sex differences.

Figure 1.. Schematic representation of the experimental design.

The study 1: mice were fed with semisynthetic diet for 4 weeks and transferred to CLAMS system facility. Prior to the data collection by CLAMS system, mice were allowed to acclimate to the facility and CLAMS chamber. After 3 days of data collection, body composition was measured and mice were terminated for tissue dissection. The study 2: mice were fed with semisynthetic diet for 4 weeks and the feeding study was performed on male mice.

Figure 2.. High-fat diet led to an increase in body weight gain, fat mass and hyperphagia in male mice.

Male and female C57BL/6J mice were fed with either high-fat diet (HF) or low-fat control diet (LF) for 5 weeks. (A) Weekly body weight, (B) weekly body weight change, statistical differences determined using two-way ANOVA, and (C) weekly food intake were measured (N = 12–13 per group, combined data from mice in Study 1 and Study 2). (D) Comparison of food intake between 2^nd week and 4^th week, statistical differences were determined using paired t-test. (E) Fat pad mass and (F) body composition at 5^th week of HF, statistical differences were determined using unpaired t-test for fat pad mass and two-way ANOVA for body composition (N = 7–8 per group; Study 1). Data are presented as mean ± SEM. *p < 0.05, **p < 0.01, ***p < 0.001.

Figure 3.. Male mice ingesting a high-fat diet had decreased energy expenditure.

Metabolic phenotype was measured continuously for 48 hours in the 5^th week of feeding either the LF or HF diet in male and female mice. (A) Respiratory exchange ratio (RER) and (B) energy expenditure, statistical differences were determined by using two-way ANOVA (N = 7–8 per group, Study 1). Data are presented as mean ± SEM. ***p < 0.001.

Figure 4.. Female mice ingesting a high-fat diet had increased physical activity in the light phase.

Physical activity was measured continually for 48 hours in male and female mice in 5^th week of feeding either the LF or HF diets. (A) Z-axis movement and (B) X-axis movement, statistical differences were determined by using two-way ANOVA (N = 7–8 per group, Study 1). Data are presented as mean ± SEM. ** < 0.01.

Figure 5.. Male mice ingesting a high-fat diet had an increase in food intake during the dark phase.

Food intake and meal patterns were measured continually for 48 hours in male and female mice after in the 5^th week of ingesting either the LF or HF diet. (A) Food intake, (B) meal size and (C) meal number, statistical differences were determined by using two-way ANOVA (N = 7–8 per group, Study 1). Data are presented as mean ± SEM. *p < 0.05.

Figure 6.. Male mice ingesting a high-fat diet had a decrease in cholecystokinin-induced satiation.

Cholecystokinin (CCK) feeding study in male mice after 5 weeks of HF and LF diet, statistical differences were determined by using paired t-test (N = 5 per group, Study 2). Mice were fasted for 12 hours and injected intraperitoneally either saline or CCK (1 μg/kg) at the onset of the dark phase. Food intake was measured every 20 min for 1 hour. Data are presented as mean ± SEM. *p < 0.05, ***p < 0.001.