Domeless receptor loss in fat body tissue reverts insulin resistance induced by a high-sugar diet in Drosophila melanogaster

Abstract

Insulin resistance is a hallmark of type 2 diabetes resulting from the confluence of several factors, including genetic susceptibility, inflammation, and diet. Under this pathophysiological condition, the dysfunction of the adipose tissue triggered by the excess caloric supply promotes the loss of sensitivity to insulin at the local and peripheral level, a process in which different signaling pathways are involved that are part of the metabolic response to the diet. Besides, the dysregulation of insulin signaling is strongly associated with inflammatory processes in which the JAK/STAT pathway plays a central role. To better understand the role of JAK/STAT signaling in the development of insulin resistance, we used a simple organism, Drosophila melanogaster, as a type 2 diabetes model generated by the consumption of a high-sugar diet. In this model, we studied the effects of inhibiting the expression of the JAK/STAT pathway receptor Domeless, in fat body, on adipose metabolism and glycemic control. Our results show that the Domeless receptor loss in fat body cells reverses both hyperglycemia and the increase in the expression of the insulin resistance marker Nlaz, observed in larvae fed a high sugar diet. This effect is consistent with a significant reduction in Dilp2 mRNA expression and an increase in body weight compared to wild-type flies fed high sugar diets. Additionally, the loss of Domeless reduced the accumulation of triglycerides in the fat body cells of larvae fed HSD and also significantly increased the lifespan of adult flies. Taken together, our results show that the loss of Domeless in the fat body reverses at least in part the dysmetabolism induced by a high sugar diet in a Drosophila type 2 diabetes model.

Insulin-Like Peptides and Cross-Talk With Other Factors in the Regulation of Insect Metabolism

“…This results in inhibition of glucose consumption by muscles and the redirection of available energy to haemocytes, which is required during defence against pathogen infection ( Gallant, 2013 ; Zhao and Karpac, 2017 ). The results obtained by Lourido et al (2021) also support supposition about the close relationships between JAK/STAT and ILPs in the regulation of insect metabolism. These authors showed that loss of the Domless receptor (part of JAK/STAT pathway) in the fat body of D. melanogaster reverses hyperglycaemia and increases the expression level of the insulin resistance marker nlaz in larvae on a high sugar diet.…”

The Genetics of Diabetes: What We Can Learn from Drosophila

“…For example, HSD-fed flies contributed to confirmation of the involvement of the JAK/STAT pathway in the development of obesity and diabetes [ 133 ]. It was recently found that the loss of the JAK/STAT pathway receptor domeless in the fat body was able to reverse, at least in part, the dysmetabolism induced by a high sugar diet [ 134 ].…”

Crème de la Créature: Dietary Influences on Behavior in Animal Models

“…Adult flies fed a high fat or high sugar diet for 7–14 days have higher lipid levels and altered insulin and glucose homeostasis (Birse et al, 2010 ; Musselman et al, 2011 ; May et al, 2019 ; Wilinski et al, 2019 ; Lourido et al, 2021 ), as well as changes in the levels of hundreds of metabolites, including amino acids, 1-Carbon metabolism, and nucleotides, organic acids, and overall carbon-nitrogen balance, depending on the type and length of diet exposure (Heinrichsen et al, 2014 ; Wilinski et al, 2019 ; Figures 1 , 2 ). These metabolic phenotypes reflect hallmarks of metabolic syndrome, and despite differences in anatomy compared to vertebrates, they contribute to defects in heart contractility and structure (Birse et al, 2010 ; Na et al, 2013 ) and in the function of the malpighian tubules; they also shorten lifespan (Na et al, 2013 ; Jung et al, 2018 ) and lower the resistance to other metabolic stresses (Heinrichsen and Haddad, 2012 ).…”

“…These metabolic phenotypes reflect hallmarks of metabolic syndrome, and despite differences in anatomy compared to vertebrates, they contribute to defects in heart contractility and structure (Birse et al, 2010 ; Na et al, 2013 ) and in the function of the malpighian tubules; they also shorten lifespan (Na et al, 2013 ; Jung et al, 2018 ) and lower the resistance to other metabolic stresses (Heinrichsen and Haddad, 2012 ). The similarities in metabolic and physiological outcomes are perhaps not surprising considering that they are the result of the activation of conserved nutrient-sensing pathways, such as insulin-Target of Rapamycin (TOR; Birse et al, 2010 ; Li et al, 2010 ), hexosamine biosynthesis (Na et al, 2013 ; May et al, 2019 ), and Janus Kinases-Signal Transducer and Activator of Transcription proteins (JAK-STAT; Yu et al, 2018 ; Lourido et al, 2021 ). As in mammals, flies fed with these diets also show alterations in genes involved in immune response, inflammation, metabolism, neural signaling, synaptic function, and sensory perception in the brain and specific populations of neurons (Hemphill et al, 2018 ; Jung et al, 2018 ; May et al, 2019 ; Stobdan et al, 2019 ; Vaziri et al, 2020 ); some of these variations in gene expression have been causally linked to neural and behavioral changes, while others only remain correlated.…”