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Methylnaltrexone potentiates body weight and fat reduction with leptin

Chun-Su Yuan, MD, PhD, Shi Sun, PhD, Anoja Attele, MD, Chong-Zhi Wang, PhD, Robin Tong, BS, Robert J. Israel, MD


Objective: Leptin increases energy expenditure by enhancing systemic and brown adipose metabolism. In a neonatal rat model, retroperitoneal fat pad weight decreased significantly in leptin-treated animals, which reduced body weight. As opioids increase feeding, opioid antagonists may decrease food intake and body weight. However, interactions between leptin and the activity of peripheral opioids on body weight and fat accumulation have not been investigated. In this study, the authors evaluated the effects of naloxone (a nonselective opioid antagonist) and methylnaltrexone (a peripherally acting opioid antagonist) on the action of leptin in neonatal rats.
Results: Compared with control, the weight gain of pups given a single daily intraperitoneal injection of leptin 0.5 mg/kg, leptin 0.5 mg/kg plus naloxone 0.3 mg/kg, or leptin 0.5 mg/kg plus methylnaltrexone 3.0 mg/kg for 8 consecutive days was significantly reduced (all p < 0.01). Naloxone or methylnaltrexone significantly potentiated leptin’s effect on body weight (p < 0.05 or p < 0.01, respectively). After coadministration of leptin plus naloxone or leptin plus methylnaltrexone, weight reduction in the right retroperitoneal fat pads was also significant compared with the reduction after leptin alone (p < 0.05 or p < 0.01, respectively).
Conclusions: The data suggest the existence of a peripheral opioid-related mechanism in leptinactive modulation of body weight.


leptin, opioids, naloxone, methylnaltrexone, body weight, adipose tissue, neonatal rat

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Jequier E: Leptin signaling, adiposity, and energy balance. Ann N Y Acad Sci. 2002; 967: 379-388.

Arora S, Anubhuti: Role of neuropeptides in appetite regulation and obesity–A review. Neuropeptides. 2006; 40: 375-401.

Zhang Y, Proenca R, Maffei M, et al.: Positional cloning of the mouse obese gene and its human homologue. Nature. 1994; 372: 425-432.

Campfield LA, Smith FJ, Guisez Y, et al.: Recombinant mouse OB protein: Evidence for a peripheral signal linking adiposity and central neural networks. Science. 1995; 269: 546-549.

Attele AS, Shi ZQ, Yuan CS: Leptin, gut, and food intake. Biochem Pharmacol. 2002; 63: 1579-1583.

Wiwanitkit V: Interaction between leptin and leptin receptor in gastric carcinoma: gene ontology analysis. Rev Esp Enferm Dig. 2007; 99: 201-205.

Yuan CS, Attele AS, Dey L, et al.: Gastric effects of cholecystokinin and its interaction with leptin on brainstem neuronal activity in neonatal rats. J Pharmacol Exp Ther. 2000; 295: 177-182.

Yuan CS, Dey L, Xie JT, et al.: Gastric effects of galanin and its interaction with leptin on brainstem neuronal activity. J Pharmacol Exp Ther. 2002; 301: 488-493.

Shi ZQ, Nelson A, Whitcomb L, et al.: Intracerebroventricular administration of leptin markedly enhances insulin sensitivity and systemic glucose utilization in conscious rats. Metabolism. 1998; 47: 1274-1280.

Wang JL, Chinookoswong N, Scully S, et al.: Differential effects of leptin in regulation of tissue glucose utilization in vivo. Endocrinology. 1999; 140: 2117-2124.

Halaas JL, Gajiwala KS, Maffei M, et al.: Weight-reducing effects of the plasma protein encoded by the obese gene. Science. 1995; 269: 543-546.

Yuan CS, Attele AS, Zhang L, et al.: Leptin reduces body weight gain in neonatal rats. Pediatr Res. 2000; 48: 380-383.

Ahima RS, Antwi DA: Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am. 2008; 37: 811-823.

Kotz CM, Grace MK, Briggs J, 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. J Clin Invest. 1995; 96: 163-170.

Appleyard SM, Hayward M, Young JI, et al.: A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology. 2003; 144: 1753-1760.

Cao WH, Morrison SF: Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia. Am J Physiol Regul Integr Comp Physiol. 2005; 288: R723-R732.

Yuan CS: Methylnaltrexone mechanisms of action and effects on opioid bowel dysfunction and other opioid adverse effects. Ann Pharmacother. 2007; 41: 984-993.

Ravishankar Ram M, Beena G, Ragunathan P, et al.: Analysis of structure, function, and evolutionary origin of the ob gene product—leptin. J Biomol Struct Dyn. 2007; 25: 183-188.

Bado A, Levasseur S, Attoub S, et al.: The stomach is a source of leptin. Nature. 1998; 394: 790-793.

Mix H, Manns MP, Wagner S, et al.: Expression of leptin and its receptor in the human stomach. Gastroenterology. 1999; 117: 509.

Hukshorn CJ, Saris WH: Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care. 2004; 7: 629-633.

Dhillo WS: Appetite regulation: An overview. Thyroid. 2007; 17: 433-445.

Cramer CP, Blass EM: Mechanisms of control of milk intake in suckling rats. Am J Physiol. 1983; 245: R154-R159.

Bernardis LL, Bellinger LL: The dorsomedial hypothalamic nucleus revisited: 1998 update. Proc Soc Exp Biol Med. 1998; 218: 284-306.

Himms-Hagen J, Ricquier D: Brown adipose tissue. In Bray GA, James WPT (ed.): Hand-book of Obesity, New York: Marcel Decker, 1997: 415-432.

Cozzolino D, Sessa G, Salvatore T, et al.: The involvement of the opioid system in human obesity: A study in normal weight relatives of obese people. J Clin Endocrinol Metab. 1996; 81: 713-718.

Shalev U, Yap J, Shaham Y: Leptin attenuates acute food deprivation-induced relapse to heroin seeking. J Neurosci. 2001; 21: RC129.

Baile CA, McLaughlin CL, Della-Fera MA: Role of cholecystokinin and opioid peptides in control of food intake. Physiol Rev. 1986; 66: 172-234.

Yuan CS, Israel RJ: Methylnaltrexone: A peripherally acting opioid antagonist. In Dean R, Bilsky EJ, Negus SS (eds.): Opiate Receptors and Antagonists. New York, NY: Humana Press, 2009: 175-198.



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