A number of human genes linked to obesity in multiple genome-wide association studies (GWAS) have orthologous genes in Drosophila that can be more easily studied. In one specific model, Dsk (postulated to be orthologous to human CCK), TfAP-2 (orthologous to human TFAP2B), and twz (orthologous to human KCTD15) have been investigated in the context of regulation of feeding behavior. These 3 Drosophila genes had been shown previously to interact in the regulation of inter-male aggressive behavior and that this function requires octopamine, the invertebrate analog of noradrenaline. The identified receptors for human CCK are CCKAR and CCKBR, which are orthologous to Drosophila CCKLR-17D1 and CCKLR-17D3, receptors for Dsk.
Results using this system support the following model: TfAP-2 and twz regulate octopamine signaling to initiate feeding; then octopamine, in a negative feedback loop, induces expression of Dsk to inhibit consummatory behavior. Independent modification of two behaviors was observed, both meal size and frequency of feeding. It has been found that hyperactivation of octopaminergic neurons is sufficient to induce hyperphagia in adult males.
[updated Jan. 2020 by FlyBase; FBrf0222196]
KCTD15 is associated with BMI in multiple GWAS studies (see GWAS Catalog, below in 'External links').
CCK is associated with BMI in multiple GWAS studies (see GWAS Catalog, below in 'External links').
TFAP2B is associated with childhood obesity, BMI, or waist-hip ratio in multiple GWAS studies (see GWAS Catalog, below in 'External links').
TFAP2B encodes a member of the AP-2 family of transcription factors; the TFAP2B protein functions as both a transcriptional activator and repressor. [Gene Cards, TFAP2B; 2020.01.23]
KCTD15 is known to inhibit AP-2 transcriptional activity by interaction with its activation domain. [Gene Cards, KCTD15; 2020.01.23]
CCK encodes a member of the gastrin/cholecystokinin family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products; the encoded peptides have been shown to regulate gastric acid secretion and food intake. [Gene Cards, CCK; 2020.01.23]
Postulated to be orthologous to Dmel\Dsk.
Many to one: 2 human to 1 fly.
Many to one: 5 human to 1 fly.
High-scoring ortholog of human KCTD15; moderate-scoring ortholog of KCTD1 (1 Drosophila to 2 human).
Postulated to be orthologous to human neuropeptide progenitor CCK.
Moderate-scoring ortholog of human TFAP2A, TFAP2C, TFAP2D, TFAP2E, and TFAP2B (1 Drosophila to 5 human).
