Our lab explores the pathophysiology resulting from overnutrition, asking: why does a high-calorie diet make us so sick? We model changes in the diet using Drosophila melanogaster. High-sugar-fed flies develop hyperglycemia, hyperlipidemia, insulin resistance, obesity, cardiovascular disease, reduced lifespan, and increased susceptibility to infection – much like type 2 diabetes patients. Likewise, fly starvation requires highly conserved pathways to determine whether starved flies live or die. We are exploiting the fly’s genetic tools along with genomics and metabolomics to better understand the molecular events that go wrong in the face of overnutrition and other adverse dietary conditions.
1. Lipotoxicity
Overloading biochemical pathways typically leads to feedback inhibition, with reduced flux through catalysis when the products are plentiful. During overnutrition, fat storage eventually slows and shifts some lipid pools into organs not well-suited to accommodate them. Lipids of various types accumulate in the hemolymph, fat body, and other tissues, leading to increased “lipotoxicity”: the accumulation of toxic lipid species such as free fatty acids and their derivatives. These “lipotoxins” have a number of detrimental effects depending on their chain length, double bond content, and location. Our research entails assessing tissue-specific lipid pools and their dynamics during high-sugar feeding. Two proteins that control these lipid pools are dChREBP and Desat1. We are currently trying to correlate changes in lipid metabolism with changes in physiology by using mass spectrometry and genomics along with functional assays including sugar tolerance, longevity, infection susceptibility, and cardiac function.
2. Insulin signaling
Insulin signaling is essential for growth, development, and metabolic homeostasis in all animals. Peripheral insulin resistance in type 2 diabetics is associated with a broad range of organ-specific symptoms. These include retinopathy, neuropathy, cardiomyopathy, hepatic steatosis, and nephropathy – a complex web of different cellular processes that have some things in common. One of these things is insulin signaling, typically measured by Akt phosphorylation or FOXO activity. We do not yet know the mechanisms of insulin’s downstream targets that contribute to type 2 diabetes and its complications. A better understanding of these pathways could help treat metabolic disease in insulin-resistant, obese individuals.
Our lab is taking a tissue-specific approach to try to identify autonomous modulators of insulin signaling. RNA-seq studies examined differential expression downstream of the insulin receptor (InR) in the larval fat body using RNAi and a constitutively active InR. In doing this, we devised a list of potential targets that are likely to play previously undescribed roles in the downstream regulation of insulin signaling.
We dubbed one of these genes (CG32335) meep. Targeting meep via RNAi in the fat body makes larvae insulin resistant and hypersensitive to sugar overload. Meep also regulates lifespan and hyperglycemia in high-sugar-fed flies. Additional InR targets included immune regulators, which led us to characterize infection susceptibility during high-sugar-induced insulin resistance. Future studies will test the roles of other conserved InR target genes in immunity and tissue-specific pathophysiology.
3. Gut function
To further investigate the effects of high-sugar feeding on physiology, we are looking at gut permeability in HS-fed flies. In collaboration with Gretchen Mahler’s lab at Binghamton, we are also using a human gut cell co-culture model to analyze the effects of high sugar on the gut epithelium.
4. Transcriptional network inference
In collaboration with Tom Baranski and Michael Brent’s lab at Washington University, we developed a gene regulatory network for the larval fat body under different diets and in different genotypes. Follow-up studies will probe the roles of predicted regulatory nodes from this network.
