Ingenuity pathway analysis of clozapine-induced obesity

Abstract

Background: Lipid accretion is one of the major side effects of clozapine pharmacotherapy of schizophrenia that made clozapine into an interesting obesity drug model.

Method: Ingenuity Pathway Analysis (IPA) engine was used for core analysis and building the networks of weight regulation.

Results: The examination of molecules that were selected into 'clozapine neighborhood' identified them as multifunctional signals that appear to orchestrate vascular and tissue functions plausibly implicated in adiposity side effect.

Conclusions: It is hypothesized that clozapine unmasks the functional and morphological phenotype of microvascular deficit that facilitates shunting nutrients from utilization toward storage.

Fig. 1

Data flow for clozapine obesity analysis. The algorithm consists of two phases. Initial step derives data from ‘neighborhood molecules’ when clozapine neighborhood database was used for comparison with ingestion-control network. In the following stage, the list of molecules algorithm for both networks was submitted to the Ingenuity Pathways Analysis (IPA) [15]. At each stage, the networks could be edited at will.

Fig. 2

A subcellular layout of the reprogrammed clozapine neighborhood (CN) generated using the Ingenuity Pathways Analysis. The IPA has an in-built facility representing diverse molecules and connections between them. Nodes’ shapes represent the functional class of the molecule (node symbols based on IRA glossary are shown on the left). The relationships between the interacting nodes are indicated by continuous edges pointing from one node to another thereby signifying a direct influence (e.g., activation or inhibition) whereas interrupted edges label the presence of indirect relations. All symbols describing the nature of the relationship between the nodes are omitted to reduce the clutter. For the same reason, not all receptors for the classical neurotransmitter systems are included and ‘self-referential’ edges that arise from the ability of a gene product to act upon itself are deleted. In order to increase visibility of ‘CN outsiders’ their nodes are enlarged and edges made bold. Note that classical neurotransmitter systems represent distinct separate hubs (highlighted in black on the right). For abbreviations see text, Table 1 and figure 3.

Fig. 3

Classical neurotransmitters of clozapine neighborhood in A auto-layout format and B a gamut of multifunctional molecules identified by IPA core and functional analyses (see table 2). Both graphs are connected via a clozapine bridging hub to emphasize that they are related to the same ‘neighborhood’. Therefore, clozapine ‘outsiders’ were transferred to the B-section of the web. As in figure 2, some ties are not represented in the graph, and all ‘self-referential’ edges, as well as the labels that describe the nature of the relationship between the nodes were omitted to reduce the clutter. Clozapine hub, as well as the size of nodes is overemphasized for visual clarity (their symbols are shown in figure 2). They do not communicate differences of functional hierarchy. ADRA1A-1D, ADRA2A, ADRA2B, ADRA2C = Adrenergic receptor α 1a-1d; α 2a, 2b, 2c; AVP (AVPR1A, AVPR1B, AVPR2) = arginine vasopressin (and its receptors); cAMP = cyclic AMP; CCK = cholecystokinin receptor; CHRM1-M4 = muscarinic receptor, M₁-M₄; CRH = corticotropin releasing hormone; DRD1-D5 = dopamine D₁–D₅ receptor; EGR1 = early growth response 1; FOS = viral oncogene homolog; GABA = γ-aminobutyric acid; GH = growth hormone; GRIA1 = glutamate receptor, AMPA 1; GRIN = glutamate receptor, NMDA; HIF1 = hypoxia-inducible factor 1; HRH1–4 = histamine receptor H₁-H₄; HTR4–7 = 5-hydroxytryptamine receptors 4–7; HTR1A, 1B, 1D, 1F, 2A, 2B, 2C, 3A, 3B, 5A = 5-hydroxytryptamine receptors 1A through 5A; KCNH2 = potassium voltage-gated channel; NE = norepinephrine; NR4A1 = nuclear receptor subfamily 4; NTS = neurotensin; POMC = pro-opiomelanocortin; PRKACB, PRKAR2A, PRKAR2B = protein kinase; PRL = prolactin; SST = somatostatin; TAC1 = tachykinin; substance P; TRH = thyrotropin; VIP = vasoactive intestinal peptide (see also abbreviations in the text and table 1).