Resistance to Diet-Induced Obesity and Associated Metabolic Perturbations in Haploinsufficient Monocarboxylate Transporter 1 Mice

<div><p>The monocarboxylate transporter 1 (MCT1 or SLC16A1) is a carrier of short-chain fatty acids, ketone bodies, and lactate in several tissues. Genetically modified C57BL/6J mice were produced by targeted disruption of the <i>mct1</i> gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but <i>MCT1</i>^+/− mice developed normally. However, when fed high fat diet (HFD), <i>MCT1</i>^+/− mice displayed resistance to development of diet-induced obesity (24.8% lower body weight after 16 weeks of HFD), as well as less insulin resistance and no hepatic steatosis as compared to littermate <i>MCT1</i>^+/+ mice used as controls. Body composition analysis revealed that reduced weight gain in <i>MCT1</i>^+/− mice was due to decreased fat accumulation (50.0% less after 9 months of HFD) notably in liver and white adipose tissue. This phenotype was associated with reduced food intake under HFD (12.3% less over 10 weeks) and decreased intestinal energy absorption (9.6% higher stool energy content). Indirect calorimetry measurements showed ∼ 15% increase in O₂ consumption and CO₂ production during the resting phase, without any changes in physical activity. Determination of plasma concentrations for various metabolites and hormones did not reveal significant changes in lactate and ketone bodies levels between the two genotypes, but both insulin and leptin levels, which were elevated in <i>MCT1</i>^+/+ mice when fed HFD, were reduced in <i>MCT1</i>^+/− mice under HFD. Interestingly, the enhancement in expression of several genes involved in lipid metabolism in the liver of <i>MCT1</i>^+/+ mice under high fat diet was prevented in the liver of <i>MCT1</i>^+/− mice under the same diet, thus likely contributing to the observed phenotype. These findings uncover the critical role of MCT1 in the regulation of energy balance when animals are exposed to an obesogenic diet.</p>