Background and Aims: Changes in mitochondrial energy metabolism promoted by uncoupling proteins (UCPs) are often found in metabolic disorders. We have recently shown that hypertriglyceridemic (HTG) mice present higher mitochondrial resting respiration unrelated to UCPs. Here, we disclose the underlying mechanism and consequences, in tissue and whole body metabolism, of this mitochondrial response to hyperlipidemia. Methods: Oxidative metabolism and its response to K⁺ channel agonists and antagonists were measured in isolated mitochondria, livers and mice. Results: Mitochondria isolated from the livers of HTG mice presented enhanced respiratory rates compared to those from wild-type mice. Changes in oxygen consumption were sensitive to ATP, diazoxide and 5-hydroxydecanoate, indicating they are attributable to mitochondrial ATP-sensitive K⁺ channel (mitoK_ATP) activity. Indeed, mitochondria from HTG mice presented enhanced swelling in the presence of K⁺ ions, sensitive to mitoK_ATP agonists and antagonists. Furthermore, mitochondrial binding to fluorescent glibenclamide indicates that HTG mice expressed higher quantities of mitoK_ATP. The higher content and activity of liver mitoK_ATP resulted in a faster metabolic state, as evidenced by increased liver oxygen consumption, higher body CO₂ release and temperature in these mice. In agreement with higher metabolic rates, food ingestion was significantly larger in HTG mice, without enhanced weight gain. Conclusions: These results demonstrate that primary hyperlipidemia leads to an elevation in liver mitoK_ATP activity, which may represent a regulated adaptation to oxidize excess fatty acids in HTG mice. Furthermore, our data indicate that mitoK_ATP, in addition to UCPs, may be involved in the control of energy metabolism and body weight.