High-salt (HS) intake contributes to hypertension and cardiopathy, but the effect of HS on fat deposition is controversial. Feed intake, fat mass, the percentage of abdominal fat, heat production, rate of oxygen consumption and the respiratory exchange ratio of mice on a HS diet were significantly decreased (P < 0.01 or 0.05) compared with mice on a normal-salt (NS) diet. An in vitro experiment with differentiating pre-adipocytes showed reduced fat deposition in the presence of high concentrations of NaCl (>0.05 M). Abdominal fat mRNA profiles and protein measurements showed that 5 known genes involved in lipolysis were up-regulated significantly and 9 genes related to lipogenesis were down-regulated in HS mice. Abundant genes and some proteins (ATP2a1, AGT, and ANGPTL4) related to calcium ion metabolism or the renin-angiotensin system (RAS) were differentially expressed between HS and NS mice. Of special interest, CREB1 phosphorylation (S133 and S142), a key factor involved in calcium signaling and other pathways, was up-regulated in HS mice. By IPA analysis, a network mediated by calcium was established providing the molecular mechanisms underlying the negative effect of HS on fat deposition.