Understanding the role of obesity-mediated white adipose tissue and liver crosstalk

Obesity drives white adipose tissue (WAT) changes which can lead to its dysregulation and insulin resistance. The obesity-mediated loss of WAT homeostasis can trigger liver steatosis through dysregulated lipid pathways such as those related to polyunsaturated fatty acid (PUFA)-derived oxylipins. Cross-tissue dynamics of the WAT and liver in progressive obesity remains elusive and the exact relationship between oxylipins, metabolic syndrome and metabolic dysfunction-associated liver disease (MASLD) is ill-defined. My aim was to understand the transition from adaptive to maladaptive WAT homeostasis in humans and its repercussion on liver homeostasis. Using oxylipins as potential messengers between WAT and the liver, my objective was to clarify their role in obesity-related T2DM/MASLD. Methods: I phenotyped the omental WAT (oWAT) of N=88 patients with obesity undergoing bariatric surgery and n=9 control patients and correlated the obesity-related phenotype with MASLD progression in N=41 paired liver biopsy, plasma and oWAT samples. I integrated these finding with multi-tissue profiling (liver, oWAT and plasma) of PUFA-derived oxylipins during progression toward insulin resistance and MASH. Potential drug-effects were investigated through analysis of Metformin-treated fat explants ex vivo. Findings: Obesity-mediated adipocyte hypertrophy is associated with down-regulation of PPAR and CEBP independently of T2DM, increased macrophage infiltration and reduction in Collagen type I and VI. Obese oWAT explants treated with Metformin demonstrated increased adipogenic markers (PPARY, FABP4, CD36). Multi-tissue oxylipin profiling revealed a generalized down-regulation of cytochrome P450 (CYP)-derived diols during obesity conserved between the oWAT and plasma. Notably, epoxide:diol ratio, indicative of soluble epoxide hydrolyse (sEH) activity, increased with hepatic steatosis and T2DM. Interpretation: These results reveal a distinct oWAT phenotype occurring with obesity and metabolic syndrome and propose Metformin is adipogenic. The oxylipin signature in obesity suggests a possible role of fatty acid diols during metabolic syndrome and a dampened sEH activity in WAT and liver in T2DM/MASLD.