Significance High salt intake is common in Western diets and likely contributes to hypertension and cardiovascular disease. Recently high salt intake has also been found to both be associated and predict the development of obesity, insulin resistance, and metabolic syndrome. Here we show that high-salt diet activates the aldose reductase (polyol) pathway in the liver, resulting in endogenous fructose production that then induces leptin resistance and the development of metabolic syndrome and fatty liver. Blocking fructose metabolism blocks the effects of high-salt diet. High salt intake also predicts diabetes and nonalcoholic fatty liver disease in Japanese adults. Thus, high-salt diet, an essential micronutrient with no intrinsic caloric value, may have a contributory role in driving obesity and diabetes.