The 'Tyranny of choices' in the ingestion-controlling network

Abstract

Background: Currently used antiobesity remedies offer only a modest weight reduction, and have untoward effects that can complicate treatment efforts. Motivated by the needs of the pharmacotherapy of obesity, the study explored the role of neuropeptide Y, leptin, and corticotrophin-releasing hormone.

Method: The study used Ingenuity Pathway Analysis which is a tool for automated discovery and visualization of molecular interactions.

Results: In ingestion-controlling networks, neuropeptide Y, leptin, and corticotrophin-releasing hormone molecules are commonly combined into the units designated as 'maximal motifs'. The analysis of this triad allowed suggesting that maximal motifs are not more than a compendium of admission rules and transmission alternatives of their nodes catalogued in the dataset. Nonetheless, these options seem to endow them with the flexibility needed to respond dynamically as a functional unit to changing internal (metabolic) conditions or environmental challenges.

Conclusion: Thus far, each peptide represents a separate target for pharmaceutical interventions (as judged by US patents scanned). The study concludes with predictions regarding designs of 'multitargeted' antiobesity agents since only by hitting a combination of targets can an appropriate therapeutic effect be achieved.

Fig. 1

Maximal motif along with the procedure of its disarticulation and reconnections of nodes. A Ancestral maximal motif, LEP-CRH-NPY with edge labels. B The sequence of generating a family of novel triads derived from the ancestral one. It opens with a removal of all arcs between the nodes. In the next step, they were submitted for reconnection by using path explorer or a ‘connect’ macro. When one or two nodes were submitted for connection sequentially (e.g., CRH, NPY + LEP; LEP + CRH, NPY + LEP, and so on), the ensuing motif was not identical to the primary one. By comparison, when all nodes were process at once by a ‘connect’ macro, the ancestral (initial) topography (such as in A) was readily regained. C A set of de novo (‘hardwired’) motifs based on the same nodes (1–12) that differ merely in arcs and edges. For clarity, their molecule names are communicated by shading and shape conforming to that in (A). Motif becomes ‘maximal’ when the filter was set to include all compartments, brain sites, and all experimental animals for node interactions available in Ingenuity data bases. Their enumeration does not follow the standard [5] patterns. Note differences in edge labels for the maximal (A) as compared to derived motifs (B). Edge labels: E – expression (includes metabolism); I – inhibition; LO – localization; PP – protein-protein binding; T – transcription (© 2002–2009 Ingenuity Systems, Inc.; all rights reserved).

Fig. 2

Maximal motif (LEP-NPY-CRH) with functional interactions predicted by IPA functional analysis. Graph A is ordered to show motif molecules as hubs revealed by ‘growth’ macro connected to 49 molecules with 157 direct and indirect relationships (shading of the triad as in figure 1). Superimposed functional labels the triad molecules may be recruited for dissimilar functions. Statistical significance values computed using a Fisher's exact test based on IPA knowledge bases. Graphs B and C are predicted by IPA functional analysis. Their molecules are involved in diverse tasks (as marked in the legends). These functions exceed the random expectation of their probability as shown in p values based on Fisher's exact test. Arrowheads signify directions of interaction between nodes (e.g., binding, phosphorylation, dephosphorylation, ligand-receptor activation, or a destination of metabolic outcome for metabolic pathways). Lines with a terminal bar indicate negative regulation. In the interest of reading ease, the labels of arcs and edges, as well as self-connections were removed.

Fig. 3

Outcome of ‘rehabilitation’ of percolated graphs. A Original and percolated (Aa) graphs after deletion of LEP-NPY-CRH nodes. B Percolated graph reconnected by IPA macro with triads #1, 3, and 6 (consult fig. 1 C). Note that some edges may change following reconnection (#1, 3), or remain unaltered (#6). Nonetheless, the bidirectional connections of the ancestral motif (as in A) were never restored. For clarity, only bold connections supposed to be activated are shown. Nodes engaged in the hypothetical changes of traffic are gradient-shaded. Abbreviations of labels and symbols as in figures 1 and 2 (© 2002–2009 Ingenuity Systems, Inc.; all rights reserved).