Abstract
Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. In mice, FGF21 is thought to cause weight loss by stimulating thermogenesis, but whether FGF21 increases energy expenditure (EE) in primates is unclear. Here, we explore the transcriptional response and gene networks active in adipose tissue of rhesus macaques following FGF21-induced weight loss. Genes related to thermogenesis responded inconsistently to FGF21 treatment and weight loss. However, expression of gene modules involved in triglyceride (TG) synthesis and adipogenesis decreased, and this was associated with greater weight loss. Conversely, expression of innate immune cell markers was increased post-treatment and was associated with greater weight loss. A lipogenesis gene module associated with weight loss was evaluated by testing the function of member genes in mice. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice. These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. These discrepancies may reflect inter-species differences or complex interplay of FGF21 activity and counter-regulatory mechanisms.
Highlights
Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies
In order to gain insight into metabolic changes that occur as a result of FGF21-induced weight loss, we examined gene expression in adipose tissue (AT) and skeletal muscle (SM) of diet-induced obese (DIO) non-human primate (NHP) undergoing treatment with FGF21
Variation in the amount of weight the animals lost over the course of the study [8–28%]21 allowed us to determine whether any gene expression changes were associated with greater weight loss
Summary
Fibroblast growth factor 21 (FGF21) induces weight loss in mouse, monkey, and human studies. Overexpression of NRG4 reduced weight gain in diet-induced obese mice, while overexpression of ANGPTL8 resulted in elevated TG levels in lean mice These observations provide evidence for a shifting balance of lipid storage and metabolism due to FGF21-induced weight loss in the non-human primate model, and do not fully recapitulate increased EE seen in rodent and in vitro studies. In adipose tissue we observe transcriptional changes in adipogenesis, lipid synthesis, and neuronal signaling gene networks, as well as changes in immune cell markers and genes involved in thermogenesis that were associated with greater weight loss Together these observations provide evidence for a shifting balance of lipid storage and metabolism related to FGF21 treatment and resulting weight loss in NHP that is distinct from previously described effects in rodent and in vitro models
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