The follicle-stimulating hormone receptor knockout (FORKO) female mouse provides a useful model to examine the role that lack of estrogen plays in the development of obesity and hypertension in postmenopausal women. Estrogen increases circulating levels of atrial natriuretic peptide (ANP), a hormone with renal and cardiovascular effects. It has been shown that atrial natriuretic peptide (ANP) is a potent stimulator of fat cell lipolysis in addition of its well established effect in the blood pressure. The aim of this study was to determine the status of natriuretic peptide system in female follitropin-receptor knockout mice (FORKO) that could be associated with obesity and hypertension observed in these mutants. FORKO and wild-type (WT) mice received daily injections of 17β-estradiol (E2) or vehicle, for 4 days. In the 5th day, blood was collected for determination of plasma ANP levels and some tissues were removed for determination of ANP, natriuretic peptide receptor type-A (NPr-A) and type-C (NPr-C) gene expression by RT-PCR. FORKO mice, that are obese, have lower circulating ANP levels and atria ANP gene expression and higher renal and adipocyte NPr-C gene expression than WT. E2 treatment induced a significant reduction of body weight and mesenteric adipose tissue weight only in FORKO. This reduction was accompanied by an increase of plasma ANP and atrial ANP gene expression in FORKO compared to WT. E2 treatment also induced a decrease of renal and adipocyte NPr-C gene expression in FORKO. In summary, this study shows that FORKO have an impaired natriuretic peptide system and that E2 treatment improved this condition by increasing atrial ANP synthesis as well as by decreasing ANP clearance receptors, resulting in enhancement of circulating ANP level. Thus, estrogen regulated ANP system could have multiple roles in modulating obesity and hypertension.