Abstract:
Introduction: Estradiol is a central regulator of lipid homeostasis and adipose tissue metabolism in females, exerting anti-adipogenic effects by suppressing de novo lipogenesis and promoting lipolysis. Estrogen deficiency, as observed during ovarian insufficiency, is strongly associated with increased adiposity and weight gain. Chronic low-grade inflammation has been shown to disrupt ovarian endocrine function, leading to reduced estradiol availability and metabolic imbalance. Lipopolysaccharide (LPS) induced endotoxemia is a well-established model of chronic inflammation; however, its role in modulating estrogen-dependent adipogenic metabolic pathways in females remains incompletely understood. Given that estradiol regulates key lipid metabolic enzymes such as fatty acid synthase (FASN) and adipose triglyceride lipase (ATGL), the present study aimed to determine whether chronic LPS exposure induces estrogen deficiency–driven adipogenic remodeling by enhancing lipogenesis and suppressing lipolysis in female adipose tissue.
Results: Chronic-phase LPS treatment in female rats resulted in a significant reduction in circulating serum estradiol levels compared with controls, indicating inflammation-induced ovarian endocrine dysfunction. This estrogen decline was accompanied by marked alterations in adipose tissue lipid metabolism. Expression of fatty acid synthase (FASN), a key enzyme regulating de novo lipogenesis, was increased in white adipose tissue of chronic LPS-treated females. In contrast, adipose triglyceride lipase (ATGL), the rate-limiting enzyme for triglyceride hydrolysis and lipolysis, was profoundly suppressed to LPS treated female relative to controls. These reciprocal changes indicate a metabolic shift favoring lipid synthesis and storage while severely impairing lipid mobilization. Consistent with this metabolic reprogramming, chronic LPS-treated females exhibited significant white adipose tissue expansion and progressive body-weight gain during the chronic phase of endotoxemia and Neuropeptide Y (NPY), a key hypothalamic orexigenic signal was elevated suggesting activation of hyperphagic feeding pathways.
Conclusion: Our findings demonstrate that chronic LPS-induced inflammation promotes adipogenic obesity in females by inducing a functional estrogen-deficient state that disrupts adipose tissue lipid metabolism and orexigenic signals. Reduced circulating estradiol is associated with enhanced lipogenesis, evidenced by increased FASN expression, and markedly suppressed lipolysis, as reflected by profound ATGL downregulation. This imbalance between lipid synthesis and orexigenic signals breakdown drives white adipose tissue expansion, body-weight gain and hyperphagia during chronic endotoxemia. Collectively, the study highlights an inflammation–estrogen–lipid metabolism axis underlying female-specific susceptibility to adipogenic obesity and provides mechanistic insight into how chronic inflammatory stress contributes to obesity associated with ovarian insufficiency.
