Targets For Development Of Anti-obesity Drugs Research Articles

Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat

The endocannabinoidome encompasses several fatty acid (FA)-derived mediators, including the endocannabinoid anandamide (AEA) and 2-arachidonoyl-glycerol (2-AG), which served as targets for anti-obesity drug development, and their congener N-acyl-ethanolamines (NAEs) and 2-monoacyl-glycerols (2‑MAGs), which are involved in food intake and energy metabolism. Body weight and fat distribution have been suggested as determinants of peripheral endocannabinoid levels. We aimed at investigating factors, beyond body fat composition, that are associated with circulating NAE and 2-MAG levels in a heterogeneous human population. Plasma NAEs and 2-MAGs were measured using LC–MS/MS in a cross-sectional sample of healthy men and women (n = 195) covering a wide range of BMI and individuals before and after a 2-day Mediterranean diet (n = 21). Circulating levels of all 2-MAGs and NAEs, other than N-oleoyl-ethanolamine (OEA), correlated with body fat mass and visceral adipose tissue (0.26 < r < 0.54). NAE levels were elevated in individuals with elevated fat mass, while 2-MAGs were increased in individuals with predominantly visceral body fat distribution. Dietary intakes of specific FAs were associated with 2-AG and omega-3-FA-derived NAEs or 2-MAGs, irrespective of the body fat distribution. Some gut bacterial families (e.g. Veillonellaceae, Peptostreptococcaceae and Akkermansiaceae) were associated with variations in most NAEs or omega-3-FA-derived 2‑MAGs, independently of fat mass and dietary FA intake. Finally, a 2-day Mediterranean diet intervention increased circulating levels of NAEs and 2-MAGs in agreement with changes in FA intake (p < 0.01). Self-reported intake and short-term dietary intervention increased in oleic acid and EPA and DHA intake as well as certain gut microbiota taxa are associated to circulating NAEs and 2‑MAGs independently of adiposity measures, thus highlighting the potential importance of these variables in determining endocannabinoidome signaling in humans.

PyRod Enables Rational Homology Model-based Virtual Screening Against MCHR1.

Several encouraging pre‐clinical results highlight the melanin‐concentrating hormone receptor 1 (MCHR1) as promising target for anti‐obesity drug development. Currently however, experimentally resolved structures of MCHR1 are not available, which complicates rational drug design campaigns. In this study, we aimed at developing accurate, homologymodel‐based 3D pharmacophores against MCHR1. We show that traditional approaches involving docking of known active small molecules are hindered by the flexibility of binding pocket residues. Instead, we derived three‐dimensional pharmacophores from molecular dynamics simulations by employing our novel open‐source software PyRod. In a retrospective evaluation, the generated 3D pharmacophores were highly predictive returning up to 35 % of active molecules and showing an early enrichment (EF1) of up to 27.6. Furthermore, PyRod pharmacophores demonstrate higher sensitivity than ligand‐based pharmacophores and deliver structural insights, which are key to rational lead optimization.

Adenylate cyclase 3: a new target for anti-obesity drug development.

Obesity has become epidemic worldwide, and abdominal obesity has a negative impact on health. Current treatment options on obesity, however, still remain limited. It is then of importance to find a new target for anti-obesity drug development based upon recent molecular studies in obesity. Adenylate cyclase 3 (ADCY3) is the third member of adenylyl cyclase family and catalyses the synthesis of cAMP from ATP. Genetic studies with candidate gene and genome-wide association study approaches have demonstrated that ADCY3 genetic polymorphisms are associated with obesity in European and Chinese populations. Epigenetic studies have indicated that increased DNA methylation levels in the ADCY3 gene are involved in the pathogenesis of obesity. Furthermore, biological analyses with animal models have implicated that ADCY3 dysfunction resulted in increased body weight and fat mass, while reduction of body weight is partially explained by ADCY3 activation. In this review, we describe genomic and biological features of ADCY3, summarize genetic and epigenetic association studies of the ADCY3 gene with obesity and discuss dysfunction and activation of ADCY3. Based upon all data, we suggest that ADCY3 is a new target for anti-obesity drug development. Further investigation on the effectiveness of ADCY3 activator and its delivery approach to treat abdominal obesity has been taken into our consideration.

A neural basis for melanocortin-4 receptor-regulated appetite.

Pro-opiomelanocortin (POMC)- and agouti-related peptide (AgRP)-expressing neurons are oppositely regulated by caloric depletion and co-ordinately stimulate and inhibit homeostatic satiety, respectively. This bimodality is principally underscored by the antagonistic actions of these ligands at downstream melanocortin-4 receptors (MC4R) within the paraventricular nucleus of the hypothalamus. Although this population is critical to energy balance the underlying neural circuitry remains unknown. Enabled by mice expressing Cre-recombinase in MC4R neurons, we demonstrate bidirectional control of feeding following real-time activation and inhibition of PVHMC4R neurons and further identify these cells as a functional exponent of ARCAgRP neuron-driven hunger. Moreover, we reveal this function to be mediated by a PVHMC4R→lateral parabrachial nucleus (LPBN) pathway. Activation of this circuit encodes positive valence, but only in calorically depleted mice. Thus, the satiating and appetitive nature of PVHMC4R→LPBN neurons supports the principles of drive reduction and highlights this circuit as a promising target for anti-obesity drug development.

Gut Peptides: Targets for Antiobesity Drug Development?

Gut peptides play multiple roles in the controls of gastrointestinal function and in the initiation and termination of meals. Plasma levels of these peptides are differentially affected by the presence of nutrients in the digestive tract, and the patterns of peptide release are consistent with both their feeding stimulatory and inhibitory actions. A number of these peptide systems have been investigated as potential targets for antiobesity drug development. Progress has been made in developing long-acting peptide analogs and, in some cases, nonpeptide agonists and antagonists. Whether any individual approach will have significant long-term efficacy remains to be demonstrated. Approaches that target multiple systems may hold the most promise.

The Current Status and Future Perspectives of Studies of Cannabinoid Receptor 1 Antagonists as Anti-Obesity Agents

Since the discovery of rimonabant (Acomplia: 1), a large effort has been directed at the discovery of new, potent and selective CB(1)R antagonists that serve as anti obesity drugs. As a result, a number of compounds reached various stages of clinical trials by late 2008. However, the announcement by Sanofi-Aventis that they were discontinuing all ongoing trials with rimonabant, as a result of the finding that risks associated with depression and anxiety outweighed its benefits, had a major impact on this area. A wave of terminations of programs targeting the development of CB(1)R blockers for treatment of obesity ensued. However, abandoning this CB(1)R therapeutic target for anti-obesity drug development seems to be premature, since there are a number of potential approaches have been uncovered to circumvent the problems of the current agents. In this review, we summarize advances that have been made and the status of studies of a diverse array of CB(1)R antagonists that have been identified mainly based on modifications of the first-in-class CB(1)R antagonist, rimonabant. Various approaches have been employed to design these analogs, such as bioisosteric replacement, introduction of conformational constraints, scaffold hopping and ligand-based molecular modeling. In addition, current approaches that have been uncovered to avoid psychiatric side effects of CB(1)R antagonists are summarized. Finally, the design of non-brain penetrating and peripherally acting CB(1)R antagonists, allosteric modulators of CB(1)R, and neutral antagonists for CB(1)R is also discussed in this review.

Neuropeptide Y receptors as targets for anti-obesity drug development: perspective and current status

Neuropeptide Y is a widely distributed neuropeptide that elicits a plethora of physiological effects via interaction with six different receptors (Y 1–y 6). Recent attention has focused on the role of neuropeptide Y in the regulation of energy homeostasis. Neuropeptide Y stimulates food intake, inhibits energy expenditure, increases body weight and increases anabolic hormone levels by activating the neuropeptide Y Y 1 and Y 5 receptors in the hypothalamus. Based on these findings, several neuropeptide Y Y 1 and Y 5 receptor antagonists have been developed recently as potential anti-obesity agents. In addition, mice lacking neuropeptide Y, the neuropeptide Y Y 1 receptor or the neuropeptide Y Y 5 receptor have been generated. The data obtained to date with these newly developed tools suggests that neuropeptide Y receptor antagonists, particularly neuropeptide Y Y 1 receptor antagonists, may be useful anti-obesity agents. However, the redundancy of the neurochemical systems regulating energy homeostasis may limit the effect of ablating a single pathway. In addition, patients in whom the starvation response is activated, such as formerly obese patients who have lost weight or patients with complete or partial leptin deficiency, may be the best candidates for treatment with a neuropeptide Y receptor antagonist.

UCP3: An Uncoupling Protein Homologue Expressed Preferentially and Abundantly in Skeletal Muscle and Brown Adipose Tissue

Uncoupling proteins (UCPs) are inner mitochondrial membrane transporters which dissipate the proton gradient, releasing stored energy as heat. UCP1 is expressed exclusively in brown adipocytes while UCP2 is expressed widely. We now report the molecular cloning of a third uncoupling protein homologue, designated UCP3. At the amino acid level, hUCP3 is 71% identical to hUCP2 and 57% identical to hUCP1. UCP3 is distinguished from UCP1 and UCP2 by its abundant and preferential expression in skeletal muscle in humans, and brown adipose tissue and skeletal muscle in rodents. Since skeletal muscle and brown adipose tissue are believed to be important sites for regulated energy expenditure in humans and rodents, respectively, UCP3 may be an important mediator of adaptive thermogenesis. Since UCP3 is minimally expressed in human heart and other critical organs, it is a promising target for anti-obesity drug development aimed at increasing thermogenesis.

Antisense to NPY-Y1 demonstrates that Y1 receptors in the hypothalamus underlie NPY hypothermia and feeding in rats.

Neuropeptide Y (NPY) is a highly potent endogenous peptide which when injected into the medial hypothalamus causes spontaneous eating behaviour and an intense fall in body temperature (Tb). This study used antisense oligodeoxynucleotides (ODNs) to determine whether the Y1 subtype of NPY receptor could underlie these remarkable physiological responses. In the unrestrained rat, the ventromedial hypothalamus (VMH) which is highly reactive to NPY was injected with antisense for NPY (aNPY), Y1 receptors (aNPY-Y1) and mismatched controls (mNPY; mNPY-Y1). After cannulae were implanted bilaterally in the brain of 19 rats, 0.4 or 0.8 microgram per 0.8 microliter of the phosphorothioate synthesised ODNs were delivered to the VMH of the rats at 12 h intervals over 2 d. Only the lower dose of aNPY-Y1, but not aNPY, evoked an intense phasic rise in the Tb following each micro-injection. Simultaneously, 0.4 microgram per 0.8 microliter of aNPY-Y1, but not aNPY, suppressed feeding behaviour after a sequence of micro-injections and on the following day. Body weights and locomotor activity of the rats likewise declined concomitantly with the hyperthermia and hypophagia caused by the Y1 receptor antisense. Neither of the control ODNs for NPY or Y1 receptors injected similarly in the VMH of the rats exerted any effects on these measures. These results clearly provide convincing evidence that in the VMH the Y1 subtype of NPY receptor mediates, in part, the neuronal mechanisms responsible for spontaneous feeding and hypothermia produced by native NPY when applied directly to this structure. The concurrent decline in body weight and activity caused by aNPY-Y1 could be caused by the episodes of hyperthermia.