title: Resistance to diet-induced obesity and associated metabolic perturbations in haploinsufficient monocarboxylate transporter 1 mice.
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.
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland ; Laboratory of Neuroenergetic and Cellular Dynamics, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lengacher
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Touria
authors.initials: T
authors.lastname: Nehiri-Sitayeb
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Nadia
authors.initials: N
authors.lastname: Steiner
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Lionel
authors.initials: L
authors.lastname: Carneiro
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Favrod
authors.affiliation: Mouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Preitner
authors.affiliation: Mouse Metabolic Evaluation Facility, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Thorens
authors.affiliation: Mouse Pathology Facility, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Stehle
authors.affiliation: Mouse Pathology Facility, Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: Laure
authors.initials: L
authors.lastname: Dix
authors.affiliation: Service d'endocrinologie, diabétologie et métabolisme, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
authors.forename: François
authors.initials: F
authors.lastname: Pralong
authors.affiliation: Laboratory of Neuroenergetic and Cellular Dynamics, Brain and Mind Institute, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
authors.forename: Pierre J
authors.initials: PJ
authors.lastname: Magistretti
authors.affiliation: Department of Physiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Luc
authors.initials: L
authors.lastname: Pellerin
mesh_terms: D000818:Animals; D001823:Body Composition / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects; D004435:Eating / Q000502:physiology; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism; D000099233:Monocarboxylate Transport Protein 1
chemical_list: D027501:Monocarboxylic Acid Transporters; D027981:Symporters; D001616:beta-Galactosidase; D000099233:Monocarboxylate Transport Protein 1