TY - JOUR

T1 - Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation

AU - Makarova, E. N.

AU - Yakovleva, T. V.

AU - Balyibina, N. Yu

AU - Baranov, K. O.

AU - Denisova, E. I.

AU - Dubinina, A. D.

AU - Feofanova, N. A.

AU - Bazhan, N. M.

N1 - Макарова Е.Н., Яковлева Т.В., Балыбина Н.Ю., Баранов К.О., Денисова Е.И., Дубинина А.Д., Феофанова Н.А., Бажан Н.М. У мышей с мутацией lethal yellow (Ay) фармакологические эффекты фактора роста фибробластов 21 зависят от пола // Вавиловский журнал генетики и селекции. - 2020. - Т. 24. - № 2. - C. 200-208

PY - 2020/2/1

Y1 - 2020/2/1

N2 - 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 (Ay) mutation, which results in MC4R blockage and obesity development. Obese C57Bl-Aymale 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 Ay-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 Ay-mice; unlike males, females were resistant to catabolic effects of FGF21.

AB - 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 (Ay) mutation, which results in MC4R blockage and obesity development. Obese C57Bl-Aymale 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 Ay-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 Ay-mice; unlike males, females were resistant to catabolic effects of FGF21.

KW - A-mice

KW - FGF21

KW - Hypothalamus

KW - Liver

KW - Melanocortin obesity

KW - Sex differences

KW - IMPROVES INSULIN SENSITIVITY

KW - melanocortin obesity

KW - liver

KW - AGOUTI GENE

KW - TISSUE

KW - A(y)-mice

KW - OBESITY

KW - ENERGY-EXPENDITURE

KW - LIVER

KW - GENE-EXPRESSION

KW - WEIGHT

KW - sex differences

KW - hypothalamus

KW - MELANOCORTIN-4 RECEPTOR

UR - http://www.scopus.com/inward/record.url?scp=85088708507&partnerID=8YFLogxK

UR - https://elibrary.ru/item.asp?id=42709613

U2 - 10.18699/VJ20.40-O

DO - 10.18699/VJ20.40-O

M3 - Article

C2 - 33659800

AN - SCOPUS:85088708507

VL - 24

SP - 200

EP - 208

JO - Вавиловский журнал генетики и селекции

JF - Вавиловский журнал генетики и селекции

SN - 2500-0462

IS - 2

ER -