Resistance to Diet-Induced Obesity in μ-Opioid Receptor–Deficient Mice: Evidence for a “Thrifty Gene”

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 mu-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.

[1]  P. Brousset,et al.  Opioid receptor blockade reduces Fas‐induced hepatitis in mice , 2004, Hepatology.

[2]  R. van den Bos,et al.  Mu‐opioid receptor knockout mice show diminished food‐anticipatory activity , 2004, The European journal of neuroscience.

[3]  R. Bodnar.  Endogenous opioids and feeding behavior: a 30-year historical perspective , 2004, Peptides.

[4]  L. Rossetti,et al.  Minireview: nutrient sensing and the regulation of insulin action and energy balance. , 2003, Endocrinology.

[5]  J. Clapham,et al.  Increased fatty acid oxidation in transgenic mice overexpressing UCP3 in skeletal muscle , 2003, Diabetes, obesity & metabolism.

[6]  M. Rossmeisl,et al.  Paradoxical resistance to diet-induced obesity in UCP1-deficient mice. , 2003, The Journal of clinical investigation.

[7]  S. Woods,et al.  Combined Blockade of Both μ- and κ-Opioid Receptors Prevents the Acute Orexigenic Action of Agouti-Related Protein , 2002 .

[8]  J. Harrold,et al.  Diet-induced obesity increases μ opioid receptor binding in specific regions of the rat brain , 2002, Brain Research.

[9]  M. Yeomans,et al.  Opioid peptides and the control of human ingestive behaviour , 2002, Neuroscience & Biobehavioral Reviews.

[10]  G. Barsh,et al.  Genetic approaches to studying energy balance: perception and integration , 2002, Nature Reviews Genetics.

[11]  E. Air,et al.  Printed in U.S.A. Copyright © 2002 by The Endocrine Society Eating Elicited by Orexin-A, But Not Melanin- Concentrating Hormone, Is Opioid Mediated , 2022 .

[12]  Rachel Jones.  Now you see it... , 2002 .

[13]  S. Haber,et al.  Opioid modulation of taste hedonics within the ventral striatum , 2002, Physiology & Behavior.

[14]  Yuichiro Yamada,et al.  Inhibition of gastric inhibitory polypeptide signaling prevents obesity , 2002, Nature Medicine.

[15]  A. Genazzani,et al.  Effect of long-term naltrexone treatment on endocrine profile, clinical features, and insulin sensitivity in obese women with polycystic ovary syndrome. , 2002, Fertility and sterility.

[16]  C. Gaveriaux-Ruff,et al.  Opioid receptor genes inactivated in mice: the highlights , 2002, Neuropeptides.

[17]  B. O'dowd,et al.  Oligomerization of opioid receptors: generation of novel signaling units. , 2002, Current opinion in pharmacology.

[18]  C. Bailey,et al.  Delta opioid receptors mediate glucose uptake in skeletal muscles of lean and obese-diabetic (ob/ob) mice. , 2001, Metabolism: clinical and experimental.

[19]  Juei-Tang Cheng,et al.  Plasma glucose-lowering effect of tramadol in streptozotocin-induced diabetic rats. , 2001, Diabetes.

[20]  D. Coscina,et al.  Whole-body metabolism varies across the estrous cycle in Sprague–Dawley rats , 2001, Physiology & Behavior.

[21]  J. Flier,et al.  Obesity and insulin resistance. , 2000, The Journal of clinical investigation.

[22]  T. Nagy,et al.  Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. , 2000, Obesity research.

[23]  D. Coscina,et al.  Paraventricular nucleus injections of naloxone methiodide inhibit NPY's effects on energy substrate utilization , 2000, Neuroreport.

[24]  M. J. Glass,et al.  Opioids and food intake: distributed functional neural pathways? , 1999, Neuropeptides.

[25]  P S Kalra,et al.  Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. , 1999, Endocrine reviews.

[26]  J. Vonesch,et al.  Activity of the δ-Opioid Receptor Is Partially Reduced, Whereas Activity of the κ-Receptor Is Maintained in Mice Lacking the μ-Receptor , 1998, The Journal of Neuroscience.

[27]  R. Surwit,et al.  Diet-induced changes in uncoupling proteins in obesity-prone and obesity-resistant strains of mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Y. Mizunoe,et al.  Preventive Effect of Dapsone on Renal Scarring following Mannose-Sensitive Piliated Bacterial Infection , 1997, Chemotherapy.

[29]  Brigitte L. Kieffer,et al.  Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the µ-opioid-receptor gene , 1996, Nature.

[30]  Z. Vogel,et al.  Expression of opioid receptors during heart ontogeny in normotensive and hypertensive rats. , 1996, Circulation.

[31]  A. Levine,et al.  Effects of opioid antagonists naloxone and naltrexone on neuropeptide Y-induced feeding and brown fat thermogenesis in the rat. Neural site of action. , 1995, The Journal of clinical investigation.

[32]  G. Pasternak,et al.  Reductions in body weight following chronic central opioid receptor subtype antagonists during development of dietary obesity in rats , 1995, Brain Research.

[33]  Stanley J. Watson,et al.  Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications , 1995, Trends in Neurosciences.

[34]  A. Levine,et al.  The effect of norbinaltorphimine, β-funaltrexamine and naltrindole on NPY-induced feeding , 1993, Brain Research.

[35]  J. Buckingham,et al.  Pharmacological characterization of opioid receptors influencing the secretion of corticotrophin releasing factor in the rat. , 1986, Neuroendocrinology.

[36]  R. Marks-Kaufman,et al.  Modifications in food intake and energy metabolism in rats as a function of chronic naltrexone infusions , 1984, Pharmacology Biochemistry and Behavior.

[37]  M. Dubois,et al.  An immunological study of the uncoupling protein of brown adipose tissue mitochondria. , 1983, The Biochemical journal.

[38]  M. Apfelbaum,et al.  Endogenous opiates and energy balance. , 1982, Science.

[39]  B. Ludwig,et al.  Cytochrome c oxidase--structure, function, and physiology of a redox-driven molecular machine. , 2003, Reviews of physiology, biochemistry and pharmacology.

[40]  Juan I. Young,et al.  A Role for the Endogenous Opioid -Endorphin in Energy Homeostasis , 2003 .

[41]  J. McGarry,et al.  Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. , 2001, Diabetes.

[42]  L. Christin,et al.  Energy expenditure in obese women before and during weight loss, after refeeding, and in the weight-relapse period. , 1993, The American journal of clinical nutrition.