Estradiol-dependent and independent effects of FGF21 in obese female mice
T V Jakovleva1, A Yu Kazantseva1, A D Dubinina1
1Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
Abstract:
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.
Insights
Fibroblast growth factor 21 (FGF21) impacts metabolism, but its effects differ between sexes. Estradiol (E2) modifies FGF21
Area of Science:
- Endocrinology
- Metabolic research
- Molecular biology
Background:
- Fibroblast growth factor 21 (FGF21) is a hormone that enhances insulin sensitivity and energy expenditure, showing therapeutic potential for obesity and diabetes.
- FGF21's beneficial effects are often less pronounced in females, with sex-specific gene expression patterns observed.
- Estradiol (E2) is hypothesized to contribute to these sex-specific differences in FGF21 response.
Purpose of the Study:
- To investigate how estradiol influences the metabolic effects of FGF21 in female mice with diet-induced obesity.
- To examine FGF21's impact on food intake, body weight, glucose metabolism, and gene expression in liver, adipose tissue, and hypothalamus.
- To determine the role of estradiol levels (low vs. high) in mediating FGF21's actions.
Main Methods:
- Female mice with diet-induced obesity were ovariectomized (OVX) to create low estradiol conditions, with some receiving E2 supplementation.
- FGF21 was administered to OVX mice, both with and without E2, for 13 days.
- Metabolic parameters (body weight, glucose tolerance, food intake) and gene expression in key metabolic tissues were analyzed.
Main Results:
- FGF21 did not alter body weight, adipose tissue weight, or glucose tolerance in OVX obese females, irrespective of E2 treatment.
- FGF21 increased standard chow intake, reduced blood glucose, and suppressed hepatic Fgf21, G6pc, and Acacα gene expression.
- Estradiol modulated FGF21's effects on gene expression in the liver (Irs2, Pklr), hypothalamus (Lepr, Klb), and subcutaneous white adipose tissue (scWAT; Cpt1α).
Conclusions:
- Estradiol does not appear to be responsible for the lack of FGF21 effects on body and adipose tissue weight in OVX obese females.
- Estradiol significantly influences the transcriptional effects of FGF21 in the liver, adipose tissue, and hypothalamus.
- These estradiol-mediated modifications in gene expression may explain sex differences in FGF21's pharmacological actions.
