Obesity is associated with ectopic deposition of lipid (steatosis) in different organs including pancreas, kidneys, blood vessels, liver, skeletal muscle, and heart. The accumulation of excessive toxic lipid species alters cellular signaling, promote mitochondrial dysfunction and increase cellular death in all these organs. We became interested in uncovering the molecular function of Sigma-1 receptor (Sigmar1) proteins in metabolism as it was reported to be associated with lipid-containing micro-domains suggesting a potential role in the pathophysiology of metabolic diseases. We found that Sigmar1 is abundantly expressed in the heart, where fatty acid oxidation (FAO) serves as the primary source of energy (approximately 70%). Preliminary data central to this proposal identify tissue-intrinsic function of Sigmar1 as an essential regulator of lipid metabolism under the normal physiological condition and in response to diet induced obesity stress. Hearts from Sigmar1 global knockout mouse demonstrate an increased level of triglycerides, accumulation of lipid droplets and suppression of mitochondrial respiration suggesting a potential function of Sigmar1 in lipid metabolism. To elucidate the molecular function of Sigmar1 under physiological and pathophysiological conditions, my laboratory recently generated cardiac-specific Sigmar1 transgenic mouse for overexpression and cardiac-specific Sigmar1 conditional knockout mouse models. The central hypothesis of this proposal is Sigmar1-dependent activation of lipid metabolism is protective against metabolic stress-induced cardiac dysfunction and pathological remodeling. Guided by strong preliminary data, this hypothesis will be tested by pursuing 3 specific aims: i) Aim 1 will determine a novel function for Sigmar1 in regulating lipid metabolism, ii) Aim 2 will determine the role of Sigmar1 in metabolic stress in mouse model of diet-induced obesity (DIO), and iii) Aim 3 will determine the molecular mechanism of Sigmar1’s function in lipid metabolism through mitochondrial fatty acid (FA) uptake and oxidation. We will use integrated molecular, genetic, and functional approaches in conjunction with genetically modified mice to determine the direct involvement and define the molecular mechanisms of Sigmar1’s role in lipid metabolism. This proposed project will identify a novel therapeutic target to regulate mitochondrial FAO and discover a novel molecular mechanism of cellular protection in DIO.