Makarova E N, Yakovleva T V, Balyibina N Yu, Baranov K O, Denisova E I, Dubinina A D, Feofanova N A, Bazhan N M
Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Novosibirsk State University, Novosibirsk, Russia.
Vavilovskii Zhurnal Genet Selektsii. 2020 Mar;24(2):200-208. doi: 10.18699/VJ20.40-o.
Hypothalamic melanocortin 4 receptors (MC4R) regulate energy balance. Mutations in the MC4R gene are the most common cause of monogenic obesity in humans. Fibroblast growth factor 21 (FGF21) is a promising antiobesity agent, but its effects on melanocortin obesity are unknown. Sex is an important biological variable that must be considered when conducting preclinical studies; however, in laboratory animal models, the pharmacological effects of FGF21 are well documented only for male mice. We aimed at investigating whether FGF21 affects metabolism in male and female mice with the lethal yellow (A) mutation, which results in MC4R blockage and obesity development. Obese C57Bl-A male and female mice were administered subcutaneously for 10 days with vehicle or FGF21 (1 mg per 1 kg). Food intake (FI), body weight (BW), blood parameters, and gene expression in the liver, muscles, brown adipose tissue, subcutaneous and visceral white adipose tissues, and hypothalamus were measured. FGF21 action strongly depended on the sex of the animals. In the males, FGF21 decreased BW and insulin blood levels without affecting FI. In the females, FGF21 increased FI and liver weight, but did not affect BW. In control A-mice, expression of genes involved in lipid and glucose metabolism (Ppargc1a, Cpt1, Pck1, G6p, Slc2a2) in the liver and genes involved in lipogenesis (Pparg, Lpl, Slc2a4) in visceral adipose tissue was higher in females than in males, and FGF21 administration inhibited the expression of these genes in females. FGF21 administration decreased hypothalamic POMC mRNA only in males. Thus, the pharmacological effect of FGF21 were significantly different in male and female A-mice; unlike males, females were resistant to catabolic effects of FGF21.
下丘脑黑皮质素4受体（MC4R）调节能量平衡。MC4R基因的突变是人类单基因肥胖最常见的原因。成纤维细胞生长因子21（FGF21）是一种很有前景的抗肥胖药物，但其对黑皮质素性肥胖的影响尚不清楚。性别是临床前研究中必须考虑的一个重要生物学变量；然而，在实验动物模型中，FGF21的药理作用仅在雄性小鼠中有充分记录。我们旨在研究FGF21是否会影响携带致死黄色（A）突变的雄性和雌性小鼠的新陈代谢，该突变会导致MC4R阻断和肥胖发展。给肥胖的C57Bl-A雄性和雌性小鼠皮下注射载体或FGF21（每1千克1毫克），持续10天。测量食物摄入量（FI）、体重（BW）、血液参数以及肝脏、肌肉、棕色脂肪组织、皮下和内脏白色脂肪组织及下丘脑的基因表达。FGF21的作用很大程度上取决于动物的性别。在雄性小鼠中，FGF21降低了体重和胰岛素血液水平，而不影响食物摄入量。在雌性小鼠中，FGF21增加了食物摄入量和肝脏重量，但不影响体重。在对照A小鼠中，雌性肝脏中参与脂质和葡萄糖代谢的基因（Ppargc1a、Cpt1、Pck1、G6p、Slc2a2）以及内脏脂肪组织中参与脂肪生成的基因（Pparg、Lpl、Slc2a4）的表达高于雄性，而给予FGF21可抑制雌性小鼠中这些基因的表达。给予FGF21仅在雄性小鼠中降低了下丘脑POMC mRNA水平。因此，FGF21在雄性和雌性A小鼠中的药理作用显著不同；与雄性不同，雌性对FGF21的分解代谢作用具有抗性。
