Cardiac natriuretic peptides (NP) are involved in cardio-renal regulation and in lipolysis. The NP activity is largely dependent on the ratio between the signaling receptor NPRA and the clearance receptor NPRC. Lipolysis increases when NPRC is reduced by starving or very-low calorie diet. On the contrary, insulin is an anti-lipolytic hormone that increases sodium-retention, suggesting a possible functional link with NP. We examined the insulin-mediated regulation of NP receptors in differentiated human adipocytes and tested the association of NP receptors expression in visceral adipose tissue (VAT) with metabolic profiles of patients undergoing renal surgery. Differentiated human adipocytes from VAT and Simpson-Golabi-Behmel Syndrome (SGBS) adipocyte cell line were treated with insulin in the presence of high glucose or low-glucose media to study NP receptors and insulin/glucose regulated pathways. Fasting blood samples and VAT samples were taken from patients in the day of renal surgery. We observed a potent insulin-mediated and glucose-dependent up-regulation of NPRC, through the PI3K pathway, associated with lower lipolysis in differentiated adipocytes. No effect was observed on NPRA. Low-glucose medium, utilized to simulate in vivo starving conditions, hampered the insulin effect on NPRC through modulation of insulin/glucose regulated pathways, allowing ANP to induced lipolysis and thermogenic genes. An expression ratio in favor of NPRC in adipose tissue was associated with higher fasting insulinemia, HOMA-IR and atherogenic lipid levels. Insulin /glucose dependent NPRC induction in adipocytes might be a key factor linking hyperinsulinemia, metabolic syndrome and higher blood pressure by reducing NP effects on adipocytes.