Abstract
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 mct1 gene in order to understand the role of this transporter in energy homeostasis. Null mutation was embryonically lethal, but MCT1 +/− mice developed normally. However, when fed high fat diet (HFD), MCT1 +/− 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 MCT1 +/+ mice used as controls. Body composition analysis revealed that reduced weight gain in MCT1 +/− 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 MCT1 +/+ mice when fed HFD, were reduced in MCT1 +/− mice under HFD. Interestingly, the enhancement in expression of several genes involved in lipid metabolism in the liver of MCT1 +/+ mice under high fat diet was prevented in the liver of MCT1 +/− 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.
Highlights
Short-chain monocarboxylates such as lactate or the ketone bodies ß-hydroxybutyrate and acetoacetate are metabolic substrates that play crucial roles in body energy homeostasis under various conditions
MCT12/2 mice die at an early embryonic stage but MCT1+/2 mice are viable A transgenic mouse was produced by disruption of the mct1 locus
Replacement of a 640 bp sequence including the first exon within the mct1 gene by a sequence coding for ß-galactosidase (LacZ gene) in frame with the mct1 promoter was obtained by homologous recombination (Fig. 1A)
Summary
Short-chain monocarboxylates such as lactate or the ketone bodies ß-hydroxybutyrate and acetoacetate are metabolic substrates that play crucial roles in body energy homeostasis under various conditions (e.g. exercise or fasting). Lactate represents an important oxidative energy substrate for various tissues such as the heart [1], the brain [2] or the oxidative fibers of muscles [3]. Lactate is used by the liver for gluconeogenesis, as part of the Cori cycle [4] Lactate regulates both food intake and blood glucose levels by acting directly on fuelsensitive neurons in the hypothalamus [5,6,7]. Ketone bodies produced during periods of fasting or under high fat diets [8,9] are used as energy substrates by several tissues including the brain [10], the heart [11] and skeletal muscles [12]. From a clinical point of view, it has been suggested that both lactate [15] and ketone bodies [16] metabolism could play an important role in the development of obesity the underlying mechanisms remain obscure
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