Jakovleva T V, Kazantseva A Yu, Dubinina A D, Balybina N Yu, Baranov K O, Makarova E N, Bazhan N M
Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Institute of Molecular and Cellular Biology of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2022 Mar;26(2):159-168. doi: 10.18699/VJGB-22-20.
The f ibroblast growth factor 21 (FGF21) synthesized in the liver, acting as a hormone, increases insulin sensitivity and energy expenditure. FGF21 administration has potent benef icial effects on obesity and diabetes in humans, cynomolgus monkey, and rodents. The therapeutic effects of FGF21 have been studied mainly in males. They are not always manifested in females, and they are accompanied by sex-specif ic activation of gene expression in tissues. We have suggested that one of the causes of sexual dimorphism in response to FGF21 is the effect of estradiol (E2). Currently, it is not known how estradiol modif ies the pharmacological effects of FGF21. The objec tive of this study was to study the inf luence of FGF21 on metabolic characteristics, food intake, and the expression of carbohydrate and fat metabolism genes in the liver, adipose tissue, and hypothalamus in female mice with alimentary obesity and low (ovariectomy) or high (ovariectomy + E2) blood estradiol level. In ovariectomized (OVX) females, the development of obesity was induced by the consumption of a high sweet-fat diet (standard chow, lard, and cookies) for 8 weeks. We investigated the effects of FGF21 on body weight, blood levels, food preferences and gene expression in tissues when FGF21 was administered separately or in combination with E2 for 13 days. In OVX obese females, FGF21, regardless of E2-treatment, did not affect body weight, and adipose tissue weight, or glucose tolerance but increased the consumption of standard chow, reduced blood glucose levels, and suppressed its own expression in the liver (Fgf21), as well as the expression of the G6pc and Acacα genes. This study is the f irst to show the modif ication of FGF21 effects by estradiol: inhibition of FGF21-inf luence on the expression of Irs2 and Pklr in the liver and potentiation of the FGF21-stimulated expression of Lepr and Klb in the hypothalamus. In addition, when administered together with estradiol, FGF21 exerted an inhibitory effect on the expression of Cpt1α in subcutaneous white adipose tissue (scWAT), whereas no stimulating FGF21 effects on the expression of Insr and Acacβ in scWAT or inhibitory FGF21 effect on the plasma insulin level were observed. The results suggest that the absence of FGF21 effects on body and adipose tissue weights in OVX obese females and its benef icial effect on food intake and blood glucose levels are not associated with the action of estradiol. However, estradiol affects the transcriptional effects of FGF21 in the liver, white adipose tissue, and hypothalamus, which may underlie sex differences in the FGF21 effect on the expression of metabolic genes and, possibly, in pharmacological FGF21 effects.
肝脏合成的成纤维细胞生长因子21（FGF21）作为一种激素，可提高胰岛素敏感性并增加能量消耗。给予FGF21对人类、食蟹猴和啮齿动物的肥胖和糖尿病具有显著的有益作用。FGF21的治疗作用主要在雄性动物中进行了研究。这些作用在雌性动物中并不总是表现出来，并且伴随着组织中基因表达的性别特异性激活。我们认为，对FGF21反应存在性别差异的原因之一是雌二醇（E2）的作用。目前，尚不清楚雌二醇如何改变FGF21的药理作用。本研究的目的是研究FGF21对饮食性肥胖且血液雌二醇水平低（卵巢切除）或高（卵巢切除+E2）的雌性小鼠的代谢特征、食物摄入量以及肝脏、脂肪组织和下丘脑中碳水化合物和脂肪代谢基因表达的影响。在卵巢切除（OVX）的雌性小鼠中，通过食用高糖高脂饮食（标准饲料、猪油和饼干）8周诱导肥胖。我们研究了单独给予FGF21或与E2联合给予13天时，FGF21对体重、血液水平、食物偏好和组织中基因表达的影响。在OVX肥胖雌性小鼠中，无论是否进行E2治疗，FGF21均不影响体重、脂肪组织重量或葡萄糖耐量，但增加了标准饲料的消耗量，降低了血糖水平，并抑制了其自身在肝脏中的表达（Fgf21）以及G6pc和Acacα基因的表达。本研究首次表明雌二醇可改变FGF21的作用：抑制FGF21对肝脏中Irs2和Pklr表达的影响，并增强FGF21刺激的下丘脑中Lepr和Klb的表达。此外，与雌二醇一起给药时，FGF21对皮下白色脂肪组织（scWAT）中Cpt1α的表达具有抑制作用，而未观察到FGF21对scWAT中Insr和Acacβ表达的刺激作用或对血浆胰岛素水平的抑制作用。结果表明，OVX肥胖雌性小鼠中FGF21对体重和脂肪组织重量无影响及其对食物摄入量和血糖水平的有益作用与雌二醇的作用无关。然而，雌二醇会影响FGF21在肝脏、白色脂肪组织和下丘脑中的转录作用，这可能是FGF21对代谢基因表达以及可能对FGF21药理作用产生性别差异的基础。
