Peroxisome Proliferator-Activated Receptors (PPAR)γ, a nuclear receptor, predominantly expressed in adipocyte, is a key transcription factor regulating lipid and glucose metabolism, cell differentiation, and energy homeostasis. Endogenous ligands, including long-chain fatty acids and prostaglandin (PG) D₂ and its derivatives, activate PPARγ. PGD₂ biosynthesis occurs via the arachidonic acid cascade involving cyclooxygenase-2 (COX-2) and lipocalin-type PGD synthase (LPGDS). Our earlier studies demonstrated that pro-adipogenic PGD₂ and its metabolites are generated through the COX pathway in mature adipocytes. We further showed that selective and non-selective COX inhibitors reduce adipocyte size, fat accumulation, serum lipids, and adipogenic gene expression in obese mice, implicating the COX pathway in adipogenesis. Given the limitations of synthetic drugs and safety concerns, natural products are emerging as safe, and alternative modulators of metabolic pathways.

Through integrative approaches of in-vivo animal studies, network pharmacology and bioinformatics, we are investigating functional foods as potential interventions in reprograming metabolic gene networks, and restoring physiological balance associated with adipose tissue functions by targeting the COX-2/PPARγ axis.

Network pharmacology analyses demonstrated that plant-derived flavonoids, polyphenols, interact with key proteins regulating adipose tissue functions via PPARγ, MAPK, and TNFα signaling pathways. Biochemical, histological, and Oil-Red-O staining assessments revealed the improvements in lipid profile, insulin sensitivity, hepatic steatosis, cardiac risks in diet induced obese mice. Supporting the biochemical data, and computational predictions, our data validated the downregulation of mRNA expression of adipogenic, pro-inflammatory genes like COX-2, PPARγ, MCP-1, TNFα, IL-6, upregulation of thermogenic gene UCP-1 in high-fat diet-induced obese mice in response to different plant extracts.

These results provide compelling evidence that natural compounds can reprogram metabolic gene networks, suppress adipogenesis, and restore adipose tissue homeostasis. Targeting the COX-2/PPARγ axis with bioactive foods offers a promising, mechanistically supported strategy to counteract the genomic and biochemical drivers of obesity and its related complications.