Whereas adipose tissue possesses a local renin-angiotensin system, the synthesis and regulated release of renin has not been addressed. To that end we utilized differentiating 3T3-L1 cells and analyzed renin expression and secretion. Renin mRNA expression and protein enzymatic activity were not detectable in preadipocytes. However, upon differentiation, renin mRNA and both intracellular and extracellular renin activity were up regulated. In differentiated adipocytes, forskolin treatment resulted in a 28-fold increase in renin mRNA while TNF treatment decreased renin mRNA 4-fold. IL-6, insulin, and angiotensin II (Ang II) were without effect. In contrast, forskolin and TNF each increased renin protein secretion by 12- and 7-fold, respectively. Although both forskolin and TNF induce lipolysis in adipocytes, fatty acids, prostaglandin E2 or lipopolysaccharide had no effect on renin mRNA or secretion. To evaluate mechanism(s) by which forskolin and/or TNF are able to regulate renin secretion, a general lipase inhibitor (E600) and PKA inhibitor (H89) were used. Both inhibitors attenuated forskolin induced renin release while having no effect on TNF regulated secretion. In contrast, E600 potentiated forskolin-stimulated renin mRNA levels while H89 had no effect. Neither inhibitor had any influence on TNF regulation of renin mRNA. Relative to lean controls, renin expression was reduced 78% in the epididymal adipose tissue of obese male C57Bl/6J mice, consistent with TNF-mediated down regulation of renin mRNA in the culture system. In conclusion, the expression and secretion of renin are regulated under a complex series of hormonal and metabolic determinants in mature 3T3-L1 adipocytes.