Sex Differences in Metabolic Recuperation After Weight Loss in High Fat Diet-Induced Obese Mice

Abstract

Dietary intervention is a common tactic employed to curtail the current obesity epidemic. Changes in nutritional status alter metabolic hormones such as insulin or leptin, as well as the insulin-like growth factor (IGF) system, but little is known about restoration of these parameters after weight loss in obese subjects and if this differs between the sexes, especially regarding the IGF system. Here male and female mice received a high fat diet (HFD) or chow for 8 weeks, then half of the HFD mice were changed to chow (HFDCH) for 4 weeks. Both sexes gained weight (p < 0.001) and increased their energy intake (p < 0.001) and basal glycemia (p < 0.5) on the HFD, with these parameters normalizing after switching to chow but at different rates in males and females. In both sexes HFD decreased hypothalamic NPY and AgRP (p < 0.001) and increased POMC (p < 0.001) mRNA levels, with all normalizing in HFDCH mice, whereas the HFD-induced decrease in ObR did not normalize (p < 0.05). All HFD mice had abnormal glucose tolerance tests (p < 0.001), with males clearly more affected, that normalized when returned to chow. HFD increased insulin levels and HOMA index (p < 0.01) in both sexes, but only HFDCH males normalized this parameter. Returning to chow normalized the HFD-induced increase in circulating leptin (p < 0.001), total IGF1 (p < 0.001), IGF2 (p < 0.001, only in females) and IGFBP3 (p < 0.001), whereas free IGF1 levels remained elevated (p < 0.01). In males IGFBP2 decreased with HFD and normalized with chow (p < 0.001), with no changes in females. Although returning to a healthy diet improved of most metabolic parameters analyzed, fIGF1 levels remained elevated and hypothalamic ObR decreased in both sexes. Moreover, there was sex differences in both the response to HFD and the switch to chow including circulating levels of IGF2 and IGFBP2, factors previously reported to be involved in glucose metabolism. Indeed, glucose metabolism was also differentially modified in males and females, suggesting that these observations could be related.

Impact of Calorie-Restricted Cafeteria Diet and Treadmill Exercise on Sweet Taste in Diet-Induced Obese Female and Male Rats

“…Another interesting finding of the present study was the differential effect of CAFR diet on decreasing BWG in females but not in males, despite CAFR females maintaining a higher proportion of non-chow food intake than CAFR males. It has been previously reported in mice that, when switching from HFD to chow, females lose body weight faster than males [ 55 ], which is in accordance with our results, since our animals were switched from CAF to CAFR diet, which increased chow intake. The CAFR diet shifted the intake of the animals toward a healthier profile that included increased chow intake, which is considered a healthier food choice than CAF, and decreased cafeteria diet intake in both sexes, which is consistent with previous observations in animals fed this diet [ 29 , 56 ].…”

“…This might be explained by the fact that females presented a higher CAF intake and a lower chow intake than males, which has also been reported in a model of high-fat diet (HFD) [ 54 ]. Previous studies reported that rodent males under HFD gained body weight more rapidly than females, which presented a delayed response [ 54 , 55 ]. These results partially contrast with ours; however, the fact that these studies used a HFD while ours used the CAF diet might partially explain the different results we obtained here.…”

Sex-Specific Appetite Regulation of Lipocalin-2 in High-Fat-Diet-Induced Obese Mice

“…There were no significant differences observed in terms of body weight or food consumption between the HFD-fed Lcn2 −/− male mice and WT mice, as well as between the ND-fed Lcn2 −/− female mice and WT mice. This is consistent with the findings of numerous rodent studies, which have shown that males are typically more vulnerable to the negative effects of HFD [2,25]. Lcn2 acts as a satiety signal, and its rise allies with a decrease in hunger.…”

Sex Differences in Hypothalamic Changes and the Metabolic Response of TgAPP Mice to a High Fat Diet

“…One caveat that must be taken into consideration is that the intake of HFD was compared to that of an LFD; although this diet has been commercialized as a control diet to be used in conjunction with the HFD, it has a higher level of carbohydrates than a normal rodent chow diet. This diet also has some metabolic effects when compared to chow intake (Guerra-Cantera et al, 2021 ). Another limitation of the study is that it was not designed for a strict metabolic study, where the animals are usually individually caged, allowing the food intake to be singly monitored.…”