Abstract
FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the Ay mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese Ay males and females. Ay mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of Fgf21 and Ucp1 in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of Cpt1 and Irs1 only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.
Highlights
Fibroblast growth factor 21 (FGF21) is an endocrine messenger that regulates multiple aspects of energy homeostasis [1,2]
The therapeutic effects of FGF21 were observed in mice with both diet-induced and genetic obesity caused by the absence of leptin or its functional receptor [6,7,13–22]
The aim of the present study is to compare the effects of exogenous FGF21 on energy intake, locomotor activity, metabolic characteristics, liver state, and expression of genes related to the regulation of energy homeostasis and glucose and lipid metabolism in obese Ay males and females
Summary
Fibroblast growth factor 21 (FGF21) is an endocrine messenger that regulates multiple aspects of energy homeostasis [1,2]. It is synthesized and secreted into the bloodstream mainly by the liver in response to various metabolic stresses and coordinates the response from adipose tissues, liver, and muscle to restore metabolic homeostasis [3]. FGF21 is considered an attractive therapeutic target to treat obesity and obesity-associated metabolic disorders, including non-alcoholic fatty liver disease (NAFLD) [1,4,5]. It was shown in preclinical models that administration of FGF21 or its mimetics and analogs reduces body weight, blood glucose levels, improves blood lipid profiles, increases insulin sensitivity [6–8], and protects from fatty liver disease [9,10] in obese animals. The ability of FGF21 to improve glucose and lipid metabolism in animal
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