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Published on: May 19, 2023
Whole transcriptome analysis and validation of metabolic pathways in subcutaneous adipose tissues during
Sara A Murray1, Louise S Dalbøge2, Karalee Baquero3
1Novo Nordisk Research Center Seattle, Inc, Seattle, WA, USA. zsmy@novonordisk.com.
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.
Insights
Fibroblast growth factor 21 (FGF21) causes weight loss in primates by altering lipid metabolism, not primarily through thermogenesis. Gene expression changes in adipose tissue reveal shifts in triglyceride synthesis and adipogenesis, with immune cell markers increasing alongside weight loss.
Area of Science:
- Metabolic Regulation
- Endocrinology
- Primate Physiology
Background:
- Fibroblast growth factor 21 (FGF21) is known to induce weight loss in various species.
- While FGF21's role in thermogenesis is established in rodents, its effect on energy expenditure (EE) in primates remains unclear.
- Understanding FGF21's mechanism in non-human primates is crucial for translating findings to human metabolic studies.
Purpose of the Study:
- To investigate the transcriptional response and gene networks in primate adipose tissue following FGF21-induced weight loss.
- To determine if FGF21 increases energy expenditure in rhesus macaques.
- To explore the relationship between gene expression changes and the extent of weight loss.
Main Methods:
- Analysis of adipose tissue transcriptional response in rhesus macaques treated with FGF21.
- Examination of gene networks related to thermogenesis, triglyceride synthesis, adipogenesis, and immune cell markers.
- Functional evaluation of specific lipogenesis genes (NRG4, ANGPTL8) in diet-induced obese and lean mice.
Main Results:
- Thermogenesis-related genes showed inconsistent responses to FGF21 treatment and weight loss.
- Gene modules involved in triglyceride synthesis and adipogenesis decreased, correlating with greater weight loss.
- Expression of innate immune cell markers increased post-treatment, also associated with greater weight loss.
- Overexpression of NRG4 reduced weight gain in obese mice, while ANGPTL8 overexpression elevated TG levels in lean mice.
Conclusions:
- FGF21-induced weight loss in rhesus macaques involves a shift in lipid storage and metabolism, rather than solely increased energy expenditure via thermogenesis.
- Observed effects in primates do not fully align with increased EE seen in rodent models, suggesting potential inter-species differences.
- Complex interplay between FGF21 activity and counter-regulatory mechanisms may influence its metabolic effects across species.
