Sex-specific differences in adipose tissue lipolysis during body weight cycling

Sex-specific differences in the regulation of body weight (BW) and adipose tissue (AT) distribution have been described recently. The underlying mechanisms are still largely unclear but point towards differences in AT metabolism. In a diet-induced obesity (DIO) mouse model we investigated sex-specific differences during BW cycling (reduction-maintenance-regain) and changes in AT lipolytic activity.

Obesity was induced in C57BL/6J male (m) and female (f) mice (n=10 per group) by 15 weeks of high-fat diet (HFD) feeding (60% kcal from fat). Subsequently BW was reduced (-25%) by caloric restriction with a low-fat diet (LFD, 10% kcal from fat). This reduced BW was maintained with adaptive feeding, and regain of BW was induced by ad libitum re-feeding of HFD. Measurement of energy expenditure (EE), body composition, and organ sampling were performed after each feeding period. An ex-vivo lipolysis assay (±forskolin) was carried out in gonadal fat pads for detecting changes in AT lipolysis.

Male mice exhibited accelerated BW gain under HFD reaching a plateau after 15 weeks, while females gained BW more slowly and constantly (BW gain week 0 to 15; m 134.6±1.7%, f 79.2±3.7%; p<0.001). In this DIO state, lean mass-specific EE was significantly higher in females compared to males (p<0.001) but was strongly reduced to the level of male mice EE after BW loss. Under caloric restriction females reached the -25% reduced BW faster than males (m 14.9±0.8; f 10.8±0.6 days). In both sexes reduction of BW was mainly mediated by a loss of AT (-50% of initial AT-mass). Interestingly, relative loss of gonadal AT was higher in females than in males. In consonance, the ex-vivo lipolysis assay during BW loss showed significantly higher rates of forskolin-stimulated lipolysis in females. In this phase females exhibited a lower respiratory quotient (RQ) supporting the hypothesis of enhanced lipolysis and lipid oxidation (RQ; m 0.87±0.02, f 0.84±0.02; p<0.01). Analysis of AT lipolysis in estrogen receptor alpha (ERα) knock out mice indicated that sex-dependent regulation of lipolysis depends on the presence of ERα in AT. Finally, re-feeding caused faster BW regain in males which could be explained by higher BW gain per kcal positive energy balance (m 0.11±0.01g; f 0.08±0.03g; p<0.05).

The present study shows a sex-specific regulation of BW cycling. Female mice responded to caloric restriction with higher lipolytic activity, enhanced loss of gonadal AT and augmented metabolic changes. Sexual dimorphisms in BW cycling likely involve ERα-dependent regulation of AT metabolism providing a potential therapeutic target.

Funding: DFG (KFO 218/0)