Obese or not? Reconsidering Sex Differences in the Characterization of Western Diet-Induced Obesity in a Murine Model

BACKGROUND: In the United States, consumption of a Western diet (WD), high in sugar and fat, has largely contributed to the epidemic of obesity, a major public health problem affecting both males and females. Body mass index (BMI) is a simple index of weight-for-height utilized to classify overweight and obesity in humans. However, this index alone is not translational in determining obesity in rodents. Moreover, sex differences in diet-induced obesity in mice are not well-characterized. We aim to study temporal metabolic changes in association with body weight gain caused by WD in males and females. METHODS: Our lab has established a model of WD-induced obesity in mice. Adult C57BL6 male and female mice were randomized into two experimental groups. The control group (n=7) was fed a standard chow diet (5% fat, 48.7% carbohydrates [3.2% sucrose], and 24.1% protein) and the WD group (n=11) was fed a WD (40% fat, 43% carbohydrates [34% sucrose], and 17% protein) for 20 weeks. Body weight, BMI, Lee Index (calculated as the cube root of body weight (g)/body length (cm)), intraperitoneal glucose tolerance test (IPGTT), and metabolic cage studies were performed every 4 weeks to study the temporal metabolic changes caused by WD. RESULTS: While males showed significant increase in body weight after 3 weeks on WD (31.72g vs. 29.01g control, p<0.05), the obesity state was only confirmed after 8 weeks on WD as shown by increased BMI (4.04 kg/m2 vs. 3.62 kg/m2 control, p<0.05). Lee index was significant after 20 weeks on WD (0.34 g/cm vs. 0.33 g/cm control, p<0.05). In comparison to males, female weight gain was delayed and significant after 5 weeks on WD (24.39g vs. 22.00g control, p<0.05). No differences in BMI (3.49 kg/m2 vs. 3.34 kg/m2 control, p=0.43) and Lee index (0.34 g/cm vs. 0.35 g/cm control, p=0.50) were observed even after 16 weeks on WD. Intriguingly, both male and female mice on WD for 20 weeks exhibited decrease in food intake (Male: 2.37 g/day vs. 3.16 g/day control, p<0.05; Female: 2.88 g/day vs. 3.81 g/day control, p<0.05) and caloric intake (Male: 8.98 kcal/day vs. 12.94 kcal/day control, p<0.05; Female: 14.81 kcal/day vs. 15.60 kcal/day control, p=0.60), as well as decreased fecal output (Male: 0.42 wet g/day vs. 2.00 wet g/day control, p<0.05; Female: 0.37 wet g/day vs. 2.17 wet g/day control, p<0.05) and urine output (Male: 1.43 ml/day vs. 2.43 ml/day control, p<0.05; Female: 0.57 ml/day vs. 0.69 ml/day control, p=0.32) compared to their respective controls. Interestingly, males showed significant intolerance to glucose after 2 months on WD (9542 ± 4375 a.u, p<0.05), while females did not show changes in glucose metabolism within 20 weeks of WD protocol. CONCLUSION: Obesity is a complex metabolic disorder whose determination, in murine models, has been simplified to body weight gain. Our results show that significant weight gain alone may not fully characterize the obesity state in mice. Inclusion of other parameters such as BMI, Lee Index, and metabolic profile may better determine experimental obesity in a sex-difference manner. This research can be translationally expanded to reconsider human obesity by taking into consideration sex differences. © FASEB.