Statnick MA. Genetic ablation of myelin protein zero-like 3 in mice increases energy expenditure, improves glycemic control, and reduces hepatic lipid synthesis. Am J Physiol Endocrinol Metab 305: E282-E292, 2013. First published May 28, 2013; doi:10.1152/ajpendo.00228.2013.-Obesity continues to be a global health problem, and thus it is imperative that new pathways regulating energy balance be identified. Recently, it was reported: (Hayashi K, Cao T, Passmore H, Jourdan-Le Saux C, Fogelgren B, Khan S, Hornstra I, Kim Y, Hayashi M, Csiszar K. J Invest Dermatol 123: 864 -871, 2004) that mice carrying a missense mutation in myelin protein zero-like 3 (Mpzl3 rc ) have reduced body weight. To determine how Mpzl3 controls energy balance in vivo, we generated mice deficient in myelin protein zero-like 3 (Mpzl3-KO). Interestingly, KO mice were hyperphagic yet had reduced body weight and fat mass. Moreover, KO mice were highly resistant to body weight and fat mass gain after exposure to a high-fat, energydense diet. These effects on body weight and adiposity were driven, in part, by a pronounced increase in whole body energy expenditure levels in KO mice. KO mice also had reduced blood glucose levels during an intraperitoneal glucose challenge and significant reductions in circulating insulin levels suggesting an increase in insulin sensitivity. In addition, there was an overall increase in oxidative capacity and contractile force in skeletal muscle isolated from KO mice. Hepatic triglyceride levels were reduced by 92% in livers of KO mice, in part due to a reduction in de novo lipid synthesis. Interestingly, Mpzl3 mRNA expression in liver was increased in diet-induced obese mice. Moreover, KO mice exhibited an increase in insulin-stimulated Akt signaling in the liver, further demonstrating that Mpzl3 can regulate insulin sensitivity in this tissue. We have determined that Mpzl3 has a novel physiological role in controlling body weight regulation, energy expenditure, glycemic control, and hepatic triglyceride synthesis in mice. skeletal muscle; rough coat (rc/rc), Akt; immunoglobulin-like V-type domain; nonalcoholic fatty liver disease OBESITY CONTINUES TO BE a major healthcare challenge in the United States and developing countries all over the world. The overall prevalence of overweight and obese individuals with a body mass index of Ն25 kg/m 2 in the United States is 68%, and this number is expected to rise (16). The limited availability of safe and clinically efficacious pharmacological agents for weight loss can be attributed in part to the relative scarcity of knowledge about body weight regulatory mechanisms. Thus, there is an urgent need to understand the complexity of energy balance and to identify novel pathways regulating body weight.Myelin protein zero-like 3 (Mpzl3) encodes a predicted type I transmembrane protein and was named after its closest homolog Mpzl2 (also referred to as EVA1). MPZL3 and EVA1 share roughly 60% similarity in their amino acid sequences (7). Similar to EVA1, MPZL3 has a predicted extr...