# Cycloastragenol Improves Fatty Acid Metabolism Through NHR-49/FAT-7 Suppression and Potent AAK-2 Activation in Caenorhabditis elegans Obesity Model

## TL;DR

Cycloastragenol reduces obesity in worms by altering lipid metabolism through specific gene pathways.

## Contribution

Cycloastragenol's novel role in reprogramming lipid metabolism via NHR-49/FAT-7 suppression and AAK-2 activation is identified.

## Key findings

- Cycloastragenol decreases body area and lipid accumulation in glucose-induced C. elegans obesity.
- Cycloastragenol suppresses NHR-49 and FAT-7 while activating AAK-2 and SKN-1 signaling.
- The compound modulates the daf-2/age-1/NHR-49 and AAK-2/SIR-2.1 pathways to improve lipid metabolism.

## Abstract

Obesity is among the top contributing factors for non-communicable chronic disease development and has attained menacing global proportions, affecting approximately one of eight adults. Phytochemicals that support energy metabolism and prevent obesity development have been the subject of intense research endeavors over the past several decades. Cycloastragenol is a natural triterpenoid compound and aglycon of astragaloside IV, known for activating telomerase and mitigating cellular aging. Here, we aim to characterize the effect of cycloastragenol on lipid metabolism in a glucose-induced obesity model in Caenorhabditis elegans. We assessed the changes in the body length, width, and area in C. elegans maintained under elevated glucose through automated WormLab system. Lipid accumulation in the presence of either cycloastragenol (100 μM) or orlistat (12 μM), used as a positive anti-obesity control drug, was quantified through Nile Red fluorescent staining. Furthermore, we evaluated the changes in key energy metabolism molecular players in GFP-reporter transgenic strains. Our results revealed that cycloastragenol treatment decreased mean body area and reduced lipid accumulation in the C. elegans glucose-induced model. The mechanistic data indicated that cycloastragenol suppresses the nuclear hormone receptor family member NHR-49 and the delta(9)-fatty-acid desaturase 7 (FAT-7) enzyme, and activates the 5′-AMP-activated protein kinase catalytic subunit alpha-2 (AAK-2) and the protein skinhead 1 (SKN-1) signaling. Collectively, our findings highlight that cycloastragenol reprograms lipid metabolism by down-regulating the insulin-like receptor (daf-2)/phosphatidylinositol 3-kinase (age-1)/NHR-49 signaling while simultaneously enhancing the activity of the AAK-2/NAD-dependent protein deacetylase (SIR-2.1) pathway. The anti-obesogenic potential of cycloastragenol rationalizes further validation in the context of metabolic diseases and obesity management.