The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

Abstract

Caloric restriction (CR) is a nutritional intervention that reduces the risk of age-related diseases in numerous species, including humans. CR's metabolic effects, including decreased fat mass and improved insulin sensitivity, play an important role in its broader health benefits. However, the extent and basis of sex differences in CR's health benefits are unknown. We found that 30% CR in young (3-month-old) male mice decreased fat mass and improved glucose tolerance and insulin sensitivity, whereas these effects were blunted or absent in young female mice. Resistance to fat and weight loss in females was not explained by decreased energy expenditure compared to males. Positron emission tomography-computed tomography (PET/CT) with 18F-fluorodeoxyglucose (18F-FDG) showed that peripheral glucose uptake was comparable between sexes. Instead, CR caused a pronounced suppression of hepatic gluconeogenesis and altered liver ceramide content in males but not in females. In aged mice (18-months old), when females are anoestrus, CR decreased fat mass and improved glucose homeostasis to a similar extent in both sexes. CR-induced fat loss in humans was also sex- and age-dependent: younger females (<45 years) resisted fat loss compared to younger males while in older subjects (>45 years) this sex difference was absent. Collectively, these studies identify age-dependent sex differences in the metabolic effects of CR and highlight adipose tissue, the liver and oestrogen as key determinants of CR's metabolic benefits. This has important implications for understanding the interplay between diet and health and for maximising the benefits of CR in humans.

The effects of caloric restriction on adipose tissue and metabolic health are sex- and age-dependent

“…Consistent with this, we find that CR suppresses energy expenditure more in young females than in young males, at least during the first week of CR ( Figure 3A–B ). In contrast, CR males and females have similar energy expenditure at week 3 of CR ( Figure 3A–B ), similar to our previous findings at week 4 of CR ( Suchacki et al, 2022 ). Consistent with this, BAT activity is similar between AL and CR mice after 6 weeks of CR ( Figure 5 ).…”

“…Another advance over our previous calorimetry studies ( Suchacki et al, 2022 ) is that, by using the higher-sensitivity Promethion system, we were able to measure RER and thereby identify sex differences in lipid metabolism. We find that, compared to CR males, CR females have greater postprandial lipogenesis but lower FA oxidation and lipolysis.…”

The Effects of Intermittent Fasting and Continuous Energy Restriction with Exercise on Cardiometabolic Biomarkers, Dietary Compliance, and Perceived Hunger and Mood: Secondary Outcomes of a Randomised, Controlled Trial

“…It is not readily apparent why women in the IFT group experienced greater changes compared to those in the CERT group. Some previous studies in animal models have demonstrated sex-specific changes in response to calorie restriction [ 28 , 29 ], and it is possible that hormonal, divergent nutrient-sensing pathway activation in response to energy restriction and other mechanisms may be at play [ 30 ]. Nonetheless, in humans, research comparing CER and IF in females specifically have shown no differences in changes to TC or LDL-C (albeit utilizing endurance rather than resistance training) [ 31 , 32 ].…”

Sex-specific resilience of neocortex to food restriction

“…Indeed, the duration, magnitude, and pattern of food restriction, as well as macronutrient composition are known to impact the physiological responses to dietary manipulations 22,[37][38][39] . Moreover, whilst we focussed our study on the adult visual cortex, it remains unclear if the brain shows similar sex-specific energy-saving adaptations in other cortical areas, and how such adaptations change with age 6,40 .…”

“…These adaptations have been well documented for peripheral tissues and are sex-specific. For example, females, as compared to males, readily lose muscle and bone mass to reduce peripheral energy expenditure during food restriction, but lose less fat mass and overall bodyweight [1][2][3][4][5][6] . Moreover, females are more likely to suppress energy-costly, reproductive functions during food restriction than males, evidenced by substantive reductions in uterine and ovarian mass, as well as a cessation of reproductive function and behaviour [7][8][9] .…”