Geraniin alleviates pathological visceral adipose tissue expansion through modulation of β-adrenergic receptor-associated cAMP-LKB1-AMPK signaling in high-fat diet-fed mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Geranium (Geranium wilfordii Maxim.) has traditionally been used as a folk medicine in East Asia and Europe. Geraniin, the major bioactive constituent of geranium, has been reported to ameliorate dyslipidemia and insulin resistance, but its effects against adipose metabolic dysfunction remain unclear. AIM OF THE STUDY: To investigate the protective effects of geraniin against pathological visceral adipose tissue (VAT) expansion in high-fat diet-fed (HFD-fed) mice and to elucidate the underlying mechanisms. METHODS: Adipose tissue content was detected using micro-CT. Adipocyte morphology and macrophage infiltration in VAT were evaluated by HE staining and immunohistochemistry. Target gene and protein expression were analyzed by qPCR, western blot, and immunofluorescence staining. Circulating free fatty acid (FFA) profiles were quantified using GC-MS. RESULTS: Geraniin markedly attenuated body weight gain and pathological VAT expansion in HFD-fed mice without affecting food intake. Geraniin reduced adipocyte hypertrophy and inflammatory responses in VAT. Mechanistically, geraniin suppressed the SREBP-1/FAS-associated lipogenic program while enhancing PGC-1α/ATGL-associated lipolytic program. These metabolic changes were accompanied by increased cAMP level and enhanced LKB1 and AMPK phosphorylation. Importantly, propranolol reversed geraniin-induced cAMP accumulation and LKB1-AMPK activation, as well as lipid metabolic remodeling in VAT. Consistent findings were observed in 3T3-L1 adipocytes. In addition, geraniin partially normalized circulating FFA profiles, particularly by reducing palmitic acid levels. CONCLUSION: Geraniin alleviated pathological VAT expansion in HFD-fed mice through lipid metabolic remodeling. Our findings suggest that β-adrenergic receptor (ADRB)-associated signaling and downstream cAMP-LKB1-AMPK activation may contribute to the protective effects of geraniin, supporting its therapeutic potential for abdominal obesity and related metabolic disorders.