Infection and inflammation affect adipose triglyceride metabolism, resulting in increased plasma free fatty acid (FFA) and VLDL levels during the acute-phase response (APR). Lipin-1, a multifunctional protein, plays a critical role in adipose differentiation, mitochondrial oxidation, and triglyceride synthesis. Here, we examined if LPS, a TLR4 activator, zymosan, a TLR2 activator, and proinflammatory cytokines regulate lipin-1 in adipose tissue. LPS administration caused a marked decrease in the levels of lipin-1 mRNA and protein in adipose tissue. The decrease in lipin-1 mRNA levels occurred rapidly and lasted for at least 24 h. In contrast, lipin-2 and -3 mRNA levels did not change, suggesting specific repression of lipin-1. Zymosan similarly decreased lipin-1 mRNA without affecting lipin-2 or lipin-3 mRNA levels. To determine the pathways by which LPS repressed lipin-1, we examined the effect of proinflammtory cytokines on adipocytes. In 3T3-L1 adipocytes, TNF/IL-1, and INF, but not LPS/IL-6, caused a decrease in lipin-1 mRNA levels. Furthermore, TNF/IL-1 administration also decreased mRNA levels of lipin-1 in adipose tissue in mice. Importantly, the LPS-induced decrease in lipin-1 mRNA levels was significantly but not totally blunted in TNF/IL-1 receptor-null mice, suggesting key roles for TNF/IL-1 and other cytokines in mediating LPS-induced repression of lipin-1. Together, our results demonstrate that expression of lipin-1, one of the essential triglyceride synthetic enzymes, was suppressed by LPS, zymosan and proinflammatory cytokines in mouse adipose tissue and in cultured 3T3-L1 adipocytes, which could be an important mechanism for limiting FFA usage to synthesize triglycerides, thus promoting release of FFA into the circulation.