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Resistance to Diet-Induced Obesity in µ-Opioid Receptor–Deficient Mice

Evidence for a "Thrifty Gene"

¹ Laboratoire Homeostasie-Allostasie-Pathologie, University of Bordeaux 2, Bordeaux, France
² Department of Neuropharmacology, Scripps Research Institute, La Jolla, California
³ Neurobiologie et Métabolisme Energétique, Université Paul Sabatier, Toulouse, France
⁴ Department of Psychology, Wayne State University, Detroit, Michigan
⁵ Metabolisme Mitochondrial, Necker Faculty of Medicine, Paris, France
⁶ Nutrition et Signalisation Cellulaire, Université Bordeaux 1, Talence, France
⁷ Institute of Genetics, Molecular and Cellular Biology, Illkirch, France

Using pharmacological tools, a role for opioid receptors in the regulation of food intake has been documented. However, the involvement of specific receptor subtypes remains questionable, and little information is available regarding a role for opioid receptors in energy metabolism. Using adult male mice lacking the µ-opioid receptor (MOR) gene (MOR^–/–), we show that the MOR is not essential for the maintenance of normal levels of ad libitum food intake but does modulate the efficiency of energy storage during high-fat diets through the regulation of energy partitioning. When fed a regular diet, MOR^–/– mice displayed only subtle alterations in energy homeostasis, suggesting a relative overuse of fat as a fuel source in the fed state. When fed a high-fat diet, MOR^–/– mice were resistant to obesity and impaired glucose tolerance, despite having similar energy intake to wild-type mice. This resistance to obesity was associated with a strong induction of the expression of key mitochondrial enzymes involved in fatty acid oxidation within skeletal muscle. This metabolic role of the MOR, which is consistent with the properties of a "thrifty gene," suggests that the MOR pathway is a potential target for pharmacological intervention in the treatment of obesity associated with the intake of fatty diets.

Abbreviations: BAT, brown adipose tissue; COIV, cytochrome oxidase subunit IV; CPT-1, carnitine palmitoyl acetyl transferase 1; FFA, free fatty acid; MOR, µ-opioid receptor; PPAR-, peroxisome proliferator–activated receptor-; UCP, uncoupling protein

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