It is becoming evident that insulin resistance of white adipose tissue is a major factor underlying the cardiovascular risk of obesity. Impaired fat storage rather than altered glucose metabolism in adipocytes probably contributes to development of insulin resistance in muscle and other tissues, in particular via increased delivery of nonesterified fatty acids into circulation. Lipid metabolism of adipose tissue is affected by the energy status of fat cells. In vitro experiments indicated the dependence of both lipogenesis and lipolysis on ATP levels in adipocytes. Thus, respiratory uncoupling in adipocytes that results in stimulation of energy dissipation and depression of ATP synthesis may contribute to the control of lipid metabolism, adiposity, and insulin sensitivity. This notion is supported by the expression of UCPs in adipocytes, for example, UCP2, UCP5, as well as some protonophoric anion transporters, and by induction of UCP1 and UCP3 in white fat by pharmacological treatments that reduce adiposity. A negative correlation between expression of UCPs in adipocytes and accumulation of white fat was also found. Expression of UCP1 from the adipose-specific promoter in the aP2-Ucp1 transgenic mice mitigated obesity induced by genetic or dietary factors. The obesity resistance, accompanied by respiratory uncoupling in adipocytes and increased energy expenditure, resulted from ectopic expression of UCP1 in white, but not brown fat. Probably due to depression of the ATP/ADP ratio, both fatty acid synthesis and lipolytic action of norepinephrine in adipocytes of transgenic mice were relatively low. Expression of regulatory G-proteins, which are essential for both catecholamine and insulin signaling in adipocytes, was also altered by ectopic UCP1. These results support the role of protonophoric proteins in adipocytes in the control of adiposity and insulin sensitivity. Antidiabetic effects of thiazolidinediones, fibrates, beta(3)-adrenoreceptor agonists, dietary n-3 PUFAs, and leptin may be explained at least partially by their effects on the energy and hence also the lipid metabolism of fat cells.