Research Article: High fat diet induces sex-specific differential gene expression in Drosophila melanogaster

Date Published: March 12, 2019

Publisher: Public Library of Science

Author(s): Tsering Stobdan, Debashis Sahoo, Priti Azad, Iain Hartley, Erilynn Heinrichsen, Dan Zhou, Gabriel G. Haddad, Efthimios M. C. Skoulakis.

http://doi.org/10.1371/journal.pone.0213474

Abstract

Currently about 2 billion adults globally are estimated to be overweight and ~13% of them are obese. High fat diet (HFD) is one of the major contributing factor to obesity, heart disease, diabetes and cancer. Recent findings on the role of HFD in inducing abnormalities in neurocognition and susceptibility to Alzheimer’s disease are highly intriguing. Since fundamental molecular pathways are often conserved across species, studies involving Drosophila melanogaster as a model organism can provide insight into the molecular mechanisms involving human disease. In order to study some of such mechanisms in the central nervous system as well in the rest of the body, we investigated the effect of HFD on the transcriptome in the heads and bodies of male and female flies kept on either HFD or regular diet (RD). Using comprehensive genomic analyses which include high-throughput transcriptome sequencing, pathway enrichment and gene network analyses, we found that HFD induces a number of responses that are sexually dimorphic in nature. There was a robust transcriptional response consisting of a downregulation of stress-related genes in the heads and glycoside hydrolase activity genes in the bodies of males. In the females, the HFD led to an increased transcriptional change in lipid metabolism. A strong correlation also existed between the takeout gene and hyperphagic behavior in both males and females. We conclude that a) HFD induces a differential transcriptional response between males and females, in heads and bodies and b) the non-dimorphic transcriptional response that we identified was associated with hyperphagia. Therefore, our data on the transcriptional responses in flies to HFD provides potentially relevant information to human conditions including obesity.

Partial Text

Diet consisting of high saturated fat (HFD) is a risk factor associated with cardiovascular disease (CVD) [1–3]. HFD is the most lethal habit after smoking [4] and a main contributing factor for obesity pandemic [5, 6]. A recent WHO report suggests that ~1.9 billion (39%) adults are overweight (http://www.who.int). These data suggest that obesity worldwide has tripled from 3·2% in 1975 to 11% in 2016 in men, and from 6·4% to 15% in women. Alarmingly, during the same period, childhood and adolescent obesity has increased tenfold in both girls (5 million to 50 million) and boys (6 million to 74 million) [7]. Globally, the United States is positioned at the top with an adult obesity prevalence rate between 38.3%-40.4% (+26.5% overweight) in women, 34.3%-37.7% (+38.7% overweight) in men [8, 9] and age-standardized childhood obesity at 12.7% [10]. At this rate, obesity will not only have a severe impact on associated chronic diseases like diabetes [11], cardiovascular disease [12], cancer [13], and osteoarthritis, but it is also expected to influence the basic socioeconomic development of entire countries [10].

In the current study, we demonstrate that consumption of a HFD leads to diverse gene expression patterns in the heads and bodies of D. melanogaster. To our knowledge, this is the first comprehensive study that identified transcriptome changes in the heads and bodies of both males and females under normal condition and after the consumption of a HFD. Male and female comparisons of the body’s transcriptome are consistent with previous studies where a large number of genes (74.4%) are differentially expressed [38]. Since the comparisons of differentially expressed genes in the heads of male and female flies at the basal level itself depicts a large number of genes (e.g., 3240 genes, p<0.05), our focus here is to decipher the effect of HFD on the head and on the body of males and females respectively. In the current study we used a comprehensive transcriptome analysis to explore both pervasive and sexually dimorphic alterations in the heads and in the bodies of flies with high dietary fat intake. There were distinct genes in the males and females that were activated by HFD but both converged to influence similar biological processes. Among the sexually dimorphic features, we show that the consumption of HFD leads to i) a female-centric enhancement of lipid metabolism and ii) a male-centric robust downregulation of genes related to stress response in the heads and downregulation of genes related to glycosidase activity in the bodies. It is also interesting to note that certain metabolic activities are sexually dimorphic even in the heads. However, the revelation that only males had stress response genes differentially expressed in their heads due to HFD is quite intriguing. The non-dimorphic observations include fat body specific genes differentially expressed, plausibly to regulate lipid homeostasis, and also a strong correlation between the takeout gene and hyperphagic behavior. Overall, our findings on transcriptional changes in flies to HFD can facilitate human studies investigating HFD-induced phenotype including obesity.   Source: http://doi.org/10.1371/journal.pone.0213474

 

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