Differential physiological responses to central leptin overexpression in male and female rats

Abstract

Brains of females are more sensitive to the acute catabolic actions of leptin. However, sex differences in the long-term physiological responses to central leptin receptor modulation are unknown. To this end, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist), or a green fluorescence protein (Control). We examined chronic changes in body weight and composition in male and female rats. Females displayed greater and sustained responses to Leptin whereas males rapidly lost physiological effects and developed leptin resistance confirmed by lower acute leptin-mediated phosphorylation of STAT3 (P-STAT3). Surprisingly, despite persistent physiological responses, Leptin-females also exhibited reduced acute leptin-mediated P-STAT3, suggesting an onset of leptin resistance near time of death. In line with this interpretation, Leptin-females and Control-females consumed the same amount of food on the last day of the experiment. Both Leptin-Antagonist groups gained similar percentages of their initial body weight and fat mass, whereas only Leptin-Antagonist-females gained lean body mass. Consequently, lean/fat mass ratio with Leptin-Antagonist was preserved in females and decreased in males, suggesting a deterioration of body composition in males. In summary, this study establishes that females are more responsive to long-term central leptin overexpression than males and that leptin antagonism has a greater physiological impact in males. The hormone environment may have played a role in these processes; however, future studies are needed to establish whether physiological responses are mediated by female or male sex hormones.

Oestradiol and leptin have separate but additive anorexigenic effects and differentially target fat mass in rats

“…Treating the males with estradiol did enhance and prolong Leptin-mediated fat mass loss but did not completely recapitulate the female phenotype. In our previous study, females receiving the same treatment maintained a fat mass loss of 22% of their initial fat mass [14] while males in the present study essentially regained their lost fat mass. Environment variables could have contributed to the inter-experiment differences; however, given the similarities of the animals (age, weight, and strain) and treatment (same vector batch, dose, and duration of the experiment), it is likely that other anabolic factors in males and/or other catabolic factors in females account for the differences.…”

“…To further explore this possibility, we compared Vehicle-treated versus Estradiol-treated males that were centrally delivered via AAV to overexpress either leptin or a control gene. As expected, Estradiol-Leptin male rats had the greatest and most sustained body weight loss, reminiscent of the female response to chronic overexpression of leptin in the brain [14]. In this experiment, estradiol treatment effectively suppressed circulating testosterone to values that were consistent with that of intact females, which limited potential interactions among testosterone and estradiol as a confounding variable in data interpretation [27].…”

“…Indeed, acute central leptin treatment induces stronger anorexia in females than in males [22]. In line with these findings, we recently demonstrated that females display greater and more persistent physiological responses to central leptin gene delivery [14]. Several sex differences in the hypothalamic feeding circuits controlled by leptin have been reported.…”

“…Similarly, in Study 2, leptin transgene expression relative to beta-actin in Leptin treated animals was 5,800-fold that of Control animals ( P < 0.001). Data were reported in previous publications [14,15].…”

Leptin Modulates the Response of Brown Adipose Tissue to Negative Energy Balance: Implication of the GH/IGF-I Axis

“…Attenuation of leptin signaling in BAT could be involved in the activation of the IGF-I pathway. Deletion of SOCS3 increases phosphorylation of IRS1 and Akt in other tissues [ 31 ] and central overexpression of leptin reduces STAT-3 activation in male rats [ 32 ]. We found a reduction in STAT-3 phosphorylation and SOCS-3, as well as a fall in the association of SOCS3 to IGF-IR in leptin-treated rats that may be explained, at least in part, by the increased phosphorylation of IGF-IR and the subsequent activation of this pathway.…”