Naltrexone/bupropion for obesity: an investigational combination pharmacotherapy for weight loss

AbstractThe mechanism of action of the combination therapy, naltrexone/bupropion (NB), for obesity has not been fully described to date. Weight loss attempts rarely result in long-term success. This is likely a result of complex interactions among multiple peripheral and CNS systems that defend against weight loss, and may explain the overwhelming lack of effective obesity treatments. NB is an investigational combination therapy for obesity that was developed based on evidence that obesity involves alterations in the hypothalamic melanocortin system as well as brain reward systems that influence food craving and mood. Naltrexone and bupropion both have actions in these brain regions that may cause them to influence food intake, food craving, and other aspects of eating behavior that affect body weight. We review the individual actions of naltrexone and bupropion in brain hypothalamic and reward systems, and describe the current in vitro, in vivo, and clinical evidence for how NB influences food intake and produces weight loss

Early improvement in food cravings are associated with long-term weight loss success in a large clinical sample

Correction to: International Journal of Obesity (2017) 41,1232–1236; doi:10.1038/ijo.2017.89 Since publication the authors of this paper have requested that it be made open access under the CC BY licence

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Tesofensine, a Novel Triple Monoamine Reuptake Inhibitor, Induces Appetite Suppression by Indirect Stimulation of α1 Adrenoceptor and Dopamine D1 Receptor Pathways in the Diet-Induced Obese Rat

Tesofensine is a novel monoamine reuptake inhibitor that inhibits both norepinephrine, 5-HT, and dopamine (DA) reuptake function. Tesofensine is currently in clinical development for the treatment of obesity, however, the pharmacological basis for its strong effect in obesity management is not clarified. Using a rat model of diet-induced obesity (DIO), we characterized the pharmacological mechanisms underlying the appetite suppressive effect of tesofensine. DIO rats treated with tesofensine (2.0 mg/kg, s.c.) for 16 days showed significantly lower body weights than vehicle-treated DIO rats, being reflected by a marked hypophagic response. Using an automatized food intake monitoring system during a 12 h nocturnal test period, tesofensine-induced hypophagia was investigated further by studying the acute interaction of a variety of monoamine receptor antagonists with tesofensine-induced hypophagia in the DIO rat. Tesofensine (0.5–3.0 mg/kg, s.c.) induced a dose-dependent and marked decline in food intake with an ED50 of 1.3 mg/kg. The hypophagic response of tesofensine (1.5 mg/kg, s.c.) was almost completely reversed by co-administration of prazosin (1.0 mg/kg, α1 adrenoceptor antagonist) and partially antagonized by co-administration of SCH23390 (0.03 mg/kg, DA D1 receptor antagonist). In contrast, tesofensine-induced hypophagia was not affected by RX821002 (0.3 mg/kg, α2 adrenoceptor antagonist), haloperidol (0.03 mg/kg, D2 receptor antagonist), NGB2904 (0.1 mg/kg, D3 receptor antagonist), or ritanserin (0.03 mg/kg, 5-HT2A/C receptor antagonist). Hence, the mechanism underlying the suppression of feeding by tesofensine in the obese rat is dependent on the drug's ability to indirectly stimulate α1 adrenoceptor and DA D1 receptor function