Côté I, Green S M, Toklu H Z, Morgan D, Carter C S, Tümer N, Scarpace P J
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, USA.
Department of Psychiatry, University of Florida, Gainesville, FL, USA.
J Neuroendocrinol. 2017 Dec;29(12). doi: 10.1111/jne.12552.
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. Accordingly, we centrally delivered a viral vector to overexpress leptin (Leptin), a neutral leptin receptor antagonist (Leptin-Antagonist) or a green fluorescence protein (GFP) (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 as confirmed by lower acute leptin-mediated phosphorylation of signal transducer and activator of transcription 3 (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, the 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, the present 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 such physiological responses are mediated by female or male sex hormones.
雌性动物的大脑对瘦素的急性分解代谢作用更为敏感。然而，长期以来，中枢性瘦素受体调节的生理反应中的性别差异尚不清楚。因此，我们通过中枢给药一种病毒载体，以过表达瘦素（Leptin）、一种中性瘦素受体拮抗剂（Leptin-Antagonist）或绿色荧光蛋白（GFP）（对照）。我们研究了雄性和雌性大鼠体重和身体组成的长期变化。雌性对Leptin表现出更大且持续的反应，而雄性则迅速失去生理效应并产生瘦素抵抗，这通过较低的急性瘦素介导的信号转导和转录激活因子3（P-STAT3）磷酸化得到证实。令人惊讶的是，尽管有持续的生理反应，但Leptin处理的雌性大鼠也表现出急性瘦素介导的P-STAT3降低，这表明在接近死亡时出现了瘦素抵抗。与此解释一致的是，在实验的最后一天，Leptin处理的雌性大鼠和对照雌性大鼠消耗的食物量相同。两个Leptin-Antagonist组增加的初始体重和脂肪量百分比相似，而只有Leptin-Antagonist处理的雌性大鼠增加了瘦体重。因此，Leptin-Antagonist处理组的瘦体重/脂肪量比值在雌性中保持不变，而在雄性中降低，这表明雄性的身体组成恶化。总之，本研究表明，雌性对长期中枢性瘦素过表达的反应比雄性更敏感，并且瘦素拮抗对雄性具有更大的生理影响。激素环境可能在这些过程中发挥了作用；然而，需要进一步的研究来确定这些生理反应是否由雌性或雄性性激素介导。
