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

E. N. Makarova; T. V. Yakovleva; N. Yu Balyibina; K. O. Baranov; E. I. Denisova; A. D. Dubinina; N. A. Feofanova; N. M. Bazhan

doi:10.18699/VJ20.40-O

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

Переведенное название: У мышей с мутацией lethal yellow (Ay) фармакологические эффекты фактора роста фибробластов 21 зависят от пола

E. N. Makarova, T. V. Yakovleva, N. Yu Balyibina, K. O. Baranov, E. I. Denisova, A. D. Dubinina, N. A. Feofanova, N. M. Bazhan

Результат исследования: Научные публикации в периодических изданиях › статья › рецензирование

Аннотация

Гипоталамические меланокортиновые рецепторы 4-го типа (МК4Р) принимают участие в поддержании баланса энергии. Мутации в гене, кодирующем МК4Р, - наиболее распространенная причина монолокусного ожирения у людей. Фактор роста фибробластов 21 (FGF21) рассматривают в качестве перспективного кандидата для медикаментозного лечения ожирения, однако неизвестно, влияет ли он на меланокортиновое ожирение. Пол особей необходимо учитывать при проведении доклинических исследований, но у лабораторных животных фармакологические эффекты FGF21 изучали только на самцах. В настоящей работе исследовано влияние FGF21 на метаболизм у самцов и самок мышей с мутацией lethal yellow в локусе агути (Ay), которая приводит к блокаде МК4Р в гипоталамусе и развитию ожирения. Самцам и самкам мышей Ay линии C57Bl с развитым ожирением вводили подкожно в течение 10 дней физиологический раствор или FGF21 (1 мг/кг). Измеряли потребление пищи (ПП), массу тела (МТ), показатели крови и экспрессию генов в печени, мышцах, бурой жировой ткани, подкожной и висцеральной белой жировой ткани и гипоталамусе. Эффекты FGF21 зависели от пола животных. У самцов FGF21 снижал МТ и уровень инсулина в крови и не влиял на ПП. У самок FGF21 увеличивал ПП и массу печени, но не влиял на МТ. У контрольных самок Ay экспрессия генов углеводно-жирового обмена (Ppargc1a, Cpt1, Pck1, G6p, Slc2a2) в печени и генов липогенеза (Pparg, Lpl, Slc2a4) в висцеральной жировой ткани была выше, чем у самцов, и введение FGF21 снижало экспрессию этих генов только у самок. Введение FGF21 уменьшало уровень мРНК ПОМК в гипоталамусе только у самцов. Полученные результаты демонстрируют, что фармакологический эффект FGF21 значительно различается у самцов и самок мышей с мутацией Ay: в отличие от самцов, самки проявляют устойчивость к катаболическому действию FGF21

Переведенное название	У мышей с мутацией lethal yellow (Ay) фармакологические эффекты фактора роста фибробластов 21 зависят от пола
Язык оригинала	английский
Страницы (с-по)	200-208
Число страниц	9
Журнал	Вавиловский журнал генетики и селекции
Том	24
Номер выпуска	2
DOI	https://doi.org/10.18699/VJ20.40-O
Состояние	Опубликовано - 1 февр. 2020

Предметные области OECD FOS+WOS

3 МЕДИЦИНСКИЕ НАУКИ И ЗДРАВООХРАНЕНИЕ
1.06 БИОЛОГИЧЕСКИЕ НАУКИ
4 СЕЛЬСКОХОЗЯЙСТВЕННЫЕ НАУКИ

ГРНТИ

76.29 Клиническая медицина

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Makarova, E. N., Yakovleva, T. V., Balyibina, N. Y., Baranov, K. O., Denisova, E. I., Dubinina, A. D., Feofanova, N. A., & Bazhan, N. M. (2020). Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation. Вавиловский журнал генетики и селекции, 24(2), 200-208. https://doi.org/10.18699/VJ20.40-O

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

abstract = "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.",

keywords = "A-mice, FGF21, Hypothalamus, Liver, Melanocortin obesity, Sex differences, IMPROVES INSULIN SENSITIVITY, melanocortin obesity, liver, AGOUTI GENE, TISSUE, A(y)-mice, OBESITY, ENERGY-EXPENDITURE, LIVER, GENE-EXPRESSION, WEIGHT, sex differences, hypothalamus, MELANOCORTIN-4 RECEPTOR",

author = "Makarova, {E. N.} and Yakovleva, {T. V.} and Balyibina, {N. Yu} and Baranov, {K. O.} and Denisova, {E. I.} and Dubinina, {A. D.} and Feofanova, {N. A.} and Bazhan, {N. M.}",

note = "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",

year = "2020",

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doi = "10.18699/VJ20.40-O",

language = "English",

volume = "24",

pages = "200--208",

journal = "Вавиловский журнал генетики и селекции",

issn = "2500-0462",

publisher = "Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences",

number = "2",

}

Makarova, EN, Yakovleva, TV, Balyibina, NY, Baranov, KO, Denisova, EI, Dubinina, AD, Feofanova, NA & Bazhan, NM 2020, 'Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation', Вавиловский журнал генетики и селекции, том. 24, № 2, стр. 200-208. https://doi.org/10.18699/VJ20.40-O

Pharmacological effects of fibroblast growth factor 21 are sex-specific in mice with the lethal yellow (Ay) mutation. / Makarova, E. N.; Yakovleva, T. V.; Balyibina, N. Yu и др.

В: Вавиловский журнал генетики и селекции, Том 24, № 2, 01.02.2020, стр. 200-208.

Результат исследования: Научные публикации в периодических изданиях › статья › рецензирование

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

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