Despite the high prevalence of
obesity among middle-aged subjects, it is unclear if sex differences in middle age affect the metabolic outcomes of
obesity therapies. Accordingly, in this study, middle-aged obese female and male mice were randomized to one of three groups: sleeve
gastrectomy (SG),
sham surgery ad libitum (SH-AL), or
sham surgery with weight matching to SG through intermittent fasting with calorie restriction (SH-IF). Comprehensive measures of energy and
glucose homeostasis, including energy intake,
body weight, energy expenditure,
glucose and
insulin tolerance, and interscapular brown adipose tissue (iBAT) sympathetic innervation density were obtained. At the end of 8 wk, SG and SH-IF females had better metabolic outcomes than their male counterparts. SG females had improved
weight loss maintenance, preservation of fat-free mass (FFM), higher total energy expenditure (TEE), normal locomotor activity, and reduced plasma
insulin and white adipose tissue (WAT) inflammatory markers. SH-IF females also had lower plasma
insulin and WAT inflammatory markers, and higher TEE than SH-IF males, despite their lower FFM. In addition, SH-IF females had higher iBAT sympathetic nerve density than SG and SH-AL females, whereas there were no differences among males. Notably, SH-IF mice of both sexes had the most improved
glucose tolerance, highlighting the benefits of fasting, irrespective of
weight loss. Results from this study demonstrate that in middle-aged obese mice, female sex is associated with better metabolic outcomes after SG or IF with calorie restriction. Clinical studies are needed to determine if sex differences should guide the choice of
obesity therapies.NEW & NOTEWORTHY SG or IF with calorie restriction produces better metabolic outcomes in females than in males. IF with calorie restriction prevents metabolic adaptation, even in the face of fat-free mass loss. IF with calorie restriction in females only, is associated with increased iBAT sympathetic innervation, which possibly mitigates reductions in energy expenditure secondary to fat-free mass loss. Lastly, IF leads to better
glucose homeostasis than SG, irrespective of sex.