A study through which the effects of rare genetic variants carried by severely obese people were studied in fruit flies has implicated a neuronal signaling pathway in weight gain, and identified genes not previously linked with human obesity in the regulation of adiposity. The study, headed by Sadaf Farooqi, PhD, and Andrea Brand, PhD, at the University of Cambridge, also demonstrated that fruit flies can be harnessed as an effective screening platform for new obesity genes that could provide new insights with therapeutic potential.

“Our study serves as a proof of principle that Drosophila functional screens are an efficient and effective way to assess the likely pathogenicity of rare variants associated with human obesity,” Brand said. “This has allowed us to identify new and potentially important targets for development of therapies, and gives us new insights for finding further obesity genes.” The team reported on their studies in PLOS Biology, in a paper titled, “Predicting novel candidate human obesity genes and their site of action by systematic functional screening in Drosophila,” in which they concluded, “This work provides a template for identifying genes carrying pathogenic variants relatively rapidly and for investigating the signalling pathways within which these proteins act. In this way, the identification of candidate obesity causing genes from severely obese people has the potential to uncover entire signalling pathways linked to obesity.”

“Obesity is a systems-level disorder arising from complex interactions between multiple organ systems,” the authors wrote. Obesity represents a major risk factor for type 2 diabetes, cardiovascular disease, cancers, and also COVID-19. And while there are obvious environmental drivers to weight gain, multiple genetic studies have demonstrated that perhaps 40–70% of variation in body weight is attributable to genetic variation. “The discovery of genes that contribute to the regulation of human body weight can provide insights into the mechanisms involved in energy homeostasis and identify potential targets for weight loss therapy,” they continued. “Moreover, drug targets supported by human genetic evidence are more likely to transit successfully through the drug discovery pipeline.”

However, identifying genes that contribute to obesity has been challenging for several reasons, including the fact that as an organism-level characteristic, weight is not well modeled in cell culture. “The situation is more complex when studying homozygous mutations in new candidate genes,” the researchers further noted. “Some of these genes may play a direct causal role in the development of obesity, others may increase susceptibility to obesity only in certain contexts, and some genes will play no role at all.”

A classical approach to the discovery of pathogenic gene variants is to investigate consanguineous populations that demonstrate a high degrees of parental relatedness— parents who are first or second cousins. In these populations large portions of the genome are identical by descent as a result of family structure in preceding generations.

Animal models also provide a useful platform for exploring the effects of genes on weight; for example, the role of the leptin signaling system in obesity was first established using mice. But genetic research in mice takes time and is expensive. In contrast, Experiments in fruit flies are fast and relatively less costly, meaning that many genes can be screened simultaneously for their effects. Like humans, flies gain weight and develop heart problems when raised on high-fat or high-sugar diets. And many genes known to affect fat levels in flies have evolutionary counterparts—orthologues—in humans, increasing the likelihood that the results of studies in flies would be meaningful for understanding human obesity. “As in humans, Drosophila accumulate lipids and become obese when raised on a high-fat or high-sugar diet, developing cardiomyopathy and diabetic phenotypes,” the investigators continued.

To search for obesity genes, the authors turned to a large dataset of gene sequences from people with early-onset severe obesity, including many consanguineous families, whose highly similar genomes made searching for potential obesity genes easier. The researchers focused on rare homozygous variants identified in affected individuals. They then used RNA interference (RNAi) to reduce the activity of each gene, in turn in fruit flies, and studied the effects on levels of triacylglyceride, the major fat storage molecule in flies.

Their experiments showed that triacylglyceride levels increased significantly after reducing the activity of four genes, including one called dachsous, which had not been previously linked to human obesity, and is involved in the Hippo signaling pathway. “By assessing the function of these genes in vivo in Drosophila, we identified 4 genes, not previously linked to human obesity, that regulate adiposity (itpr, dachsous, calpA, and sdk),” the authors commented. “Dachsous is a transmembrane protein upstream of the Hippo signaling pathway.”

The authors then found that knocking down different links in the Hippo pathway also dramatically altered triacylglyceride levels. And when that reduced gene activity was confined to neurons, triacylglycerides increased significantly, indicating that the central nervous system was controlling adiposity.“We found that 3 further members of the Hippo pathway, fat, four-jointed, and hippo, also regulate adiposity and that they act in neurons, rather than in adipose tissue (fat body).”

In humans, the authors found that rare variants in genes encoding two members of the Hippo pathway, called FAT4 and TAOK2, were also associated with obesity, albeit not in every database. “We then searched for variants in the novel obesity genes we identified in Drosophila, and their associated signaling pathways, in larger cohorts of unrelated obese people and healthy controls,” the team noted. “Screening Hippo pathway genes in larger human cohorts revealed rare variants in TAOK2 associated with human obesity.”

“Studies of obese individuals have the potential to identify genes that, when mutated, might lead to human obesity,” Brand noted. “Establishing a functional relationship between these candidate genes and obesity is challenging, however. We were able to assess the function of candidate genes in the humble fruit fly and not only identified four novel obesity genes, but also predicted a fifth, in which rare variants were subsequently found in obese individuals.”

The authors concluded, “The use of Drosophila as a model system enables the investigation of genetic pathways underlying obesity at a whole organism level … Here, we demonstrate the success of functional screens in Drosophila in assessing the likely pathogenicity of rare variants in human genes associated with severe obesity and in predicting novel candidate human obesity genes and signaling pathways … Future work to generate precision obesity models incorporating patient-specific genetic mutations using CRISPR/Cas9 technology will elucidate further the role of the variants and their associated genes in the regulation of obesity.”

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