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When fasting results in metabolic damage: a matter of sex

Behavioural and environmental changes in the past decades have caused the population to become obese. Sedentarism accompanied by high-caloric food intake is the major factor in obesity development worldwide. With increasing numbers of obese people, several comorbidities emerge such as insulin resistance, type 2 diabetes and the risk of cardiovascular diseases (CVD). To reverse the body weight gain and improve metabolic health, different nutritional changes are proposed. Recently, emerging studies have focused on nutritional interventions that favour fasting periods, such as caloric restriction (CR), time-restricted feeding (TRF) and intermittent fasting (IF). CR reduces 15–40% of daily caloric intake without malnutrition, TRF confines daily food consumption to a 4–12 h window, and IF alternates 24 h fasting periods (or periods of very low caloric intake) with 24 h of ad libitum food consumption. All of these interventions seem to protect against obesity, diabetes and CVD in mammals through improved peripheral insulin sensitivity, decreased brain inflammation, decreased triglycerides and higher ketone bodies (Di Francesco et al. 2018). Most of these characteristics have been described in mice and non-human primates; however, human studies are necessary to elucidate the clinical outcomes of fasting protocols. In short-term trials involving humans, the multicentre CALERIE (Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy) trial, as well as observational studies in Okinawa centenarians and the Caloric Restriction Society (CRONies), have found results similar to those in long-lived animals under CR including decreased body weight, metabolic rate and oxidative damage. Moreover, the incidence of cardiovascular outcomes and cancer decreases with CR (Di Francesco et al. 2018). In contrast, people today seek high caloric foods throughout the day, making CR a non-viable strategy for most individuals. Moreover, additional studies are necessary to ensure the safety of CR in specific populations with comorbidities. Because of this, studies have sought to show the importance of feeding–fasting period control, thereby highlighting the benefits of TRF or IF as alternatives to CR. One plausible reason for improved metabolic health in TRF is synchronization with the circadian rhythm. Almost every cell in our body has a clock that endogenously orchestrates metabolism with a period of 24 h, anticipating the feeding/fasting periods and optimizing metabolic efficiency (Manoogian & Panda, 2017). However, environmental factors such as light exposure, food intake, sleep/wake time, physical activity and hormones can alter the circadian rhythmicity. The disruption of circadian rhythm by genetic or behavioural strategies has negative consequences (Manoogian & Panda, 2017). Taken together, studies involving fasting protocols coordinated with the circadian rhythm have shown positive health aspects. On the other hand, aberrant sleeping and eating patterns, shift work and chronic jet-lag exposure contribute to the disruption of the circadian rhythm and to metabolic disorders, including higher CVD risk. The elegant study of Freire et al. in this issue of The Journal of Physiology investigated the influence of a 6 h fasting period during the active phase on metabolic parameters in male and female mice (Freire et al. 2020). The authors defined this protocol as a short daily fast (SDF) that was applied for 4 weeks. Compared to the ad libitum (AL) group, SDF reduced food intake in female mice. When the authors analysed this over time, the SDF group showed a lower food intake in the dark cycle and a higher food intake in the light cycle. After 4 weeks of SDF, both male and female mice showed increased body weight and lean mass, but this effect was greater in male mice. Taking these results together, the authors suggest that the change in the food intake pattern observed in the SDF female mice may disrupt the circadian cycle. Further, liver mass was increased in the SDF male group compared to AL; however, liver triglycerides per gram of tissue was higher in the SDF female group compared to their AL counterpart, with no effect of SDF on this parameter in male mice. To address proteins that might be involved in hepatic fat accumulation, the authors measured fatty acid synthase (FASN), acetyl-CoA carboxylase 1, ATP-citrate lyase and stearoyl-CoA desaturase 1 in the liver. The content of FASN protein in female groups was higher compared to that in male groups. Acyl-CoA thioesterase 2 (Acot2) and enoyl-CoA hydratase–3-hydroxyacyl CoA dehydrogenase (Ehhadh) mRNA in the liver were also higher in female compared to male groups, suggesting higher fat oxidation in the liver of female animals. No changes were found for perilipin 2 (Plin2) mRNA, a lipid accumulation marker. Regarding glucose homeostasis, females showed lower basal insulin and glucose levels compared to male mice. When a glucose tolerance test (GTT) was performed, there was a diet effect showing a higher area under the curve for the GTT in SDF groups compared to AL, both in males and females (Fig. 1). The experiments reported by Freire and co-workers emphasizes the metabolic differences in male and female mice, the effect of 6 h of fasting during the active phase and a possible disruption of the circadian rhythm. Combining these factors, they observed a sex-specific response, highlighting the importance of investigating the effects of nutritional interventions in both males and females. Regarding this study, we believe that the evaluation of other metabolic parameters could further corroborate the findings reported, such as circulating markers (triglycerides, high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein (VLDL) and ketone bodies). In addition, applying the same experimental design to a high fat diet-fed group could exacerbate the hepatic fat accumulation observed in female mice. Nevertheless, the findings of the study remain important to the field. Another practical question is that people often introduce nutritional regimes