Obesity-Linked Homologues TfAP-2 and Twz Establish Meal Frequency in Drosophila melanogaster

Abstract

In all animals managing the size of individual meals and frequency of feeding is crucial for metabolic homeostasis. In the current study we demonstrate that the noradrenalin analogue octopamine and the cholecystokinin (CCK) homologue Drosulfakinin (Dsk) function downstream of TfAP-2 and Tiwaz (Twz) to control the number of meals in adult flies. Loss of TfAP-2 or Twz in octopaminergic neurons increased the size of individual meals, while overexpression of TfAP-2 significantly decreased meal size and increased feeding frequency. Of note, our study reveals that 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. Intriguingly, we found that the mouse TfAP-2 and Twz homologues, AP-2β and Kctd15, co-localize in areas of the brain known to regulate feeding behavior and reward, and a proximity ligation assay (PLA) demonstrated that AP-2β and Kctd15 interact directly in a mouse hypothalamus-derived cell line. Finally, we show that in this mouse hypothalamic cell line AP-2β and Kctd15 directly interact with Ube2i, a mouse sumoylation enzyme, and that AP-2β may itself be sumoylated. Our study reveals how two obesity-linked homologues regulate metabolic homeostasis by modulating consummatory behavior.

TfAP-2 is required for night sleep in Drosophila

“…Ubiquitous early knockdown of this gene is lethal at the larval or pupal stage, and hypomorphic loss-of-function mutation affects limb and brain development [19]. To test for sleep phenotypes, we generated viable mutants using RNAi to knock down TfAP - 2 specifically in the nervous system [26, 27]. We followed the sleep behavior of the flies using established sleep monitor systems.…”

“…As GABAergic neurons play a role in sleep control, we also tested the gad - Gal4 driver [35]. A recent study reported that TfAP-2 regulates Drosophila aggression behavior by acting in octopaminergic neurons [26, 27, 36]. In addition, it has been previously shown that octopamine regulates sleep in Drosophila and we hence also tested tdc - Gal4 [37].…”

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

“…Indeed, psychopathological symptoms have been shown to alter eating behavior which in turn leads to obesity (Lee, 2007). Two genes recently associated with obesity have been TFAP2B and KCTD15 , for which a combined function that affects eating behavior has been described (Williams et al., 2014; Zarelli & Dawid, 2013). Following the rationale that argues for a connection between ED and obesity, we could expect that genetic alterations in central pathways involved in the modulation of eating behavior and food intake that may lead to obesity, could also be linked to ED.…”

“…These results support previous reports suggesting a combined function of this two genes (Zarelli & Dawid, 2013), and their alleged implication in the regulation of feeding behavior (Williams et al., 2014). It is of note that, overall, the impact of these obesity‐related genes was more evident in BN patients than in the AN group, which makes sense if we bear in mind that alterations in the CNS resulting in behaviors leading to obesity (e.g., anxiety, binge‐eating, etc.)…”

“…A number of GWAS have identified SNPs in or near de KCTD15 gene as putative regulators of body mass index (BMI) (Mei et al., 2012; Paternoster et al., 2011; Thorleifsson et al., 2009; Willer et al., 2009). Interestingly, there is recent evidence in animal models that TFAP2B and KCTD15 homologues co‐localize in areas of the brain where they interact to regulate feeding behavior and reward (Williams et al., 2014) (Figure 1). …”