Study On The Pathogenesis Of Akh/Glucagon In Wasting Diseases

Adipokinetic hormone（Akh）is a neuropeptide produced by the corpora cardiaca cells of insects.In drosophila,Akh plays a crucial role in the mobilization and breakdown of fat energy and acts in coordination with insulin to regulate energy storage and utilization.Moreover,Akh possesses the capacity to stimulate trehalose elevation,which serves as an analog of mammalian blood glucose in drosophila.In mammals,glucagon,which shares a high degree of functional homology with Akh,is accountable for similar functions.Glucagon is a peptide produced by alpha cells in the pancreas,which primarily acts on the liver to increase glucose levels by promoting liver gluconeogenesis,glycogenolysis,and inhibiting glycogen synthesis.In rodents,glucagon can directly act on adipose tissue through its receptor,promoting fat breakdown and thermogenesis,thereby maintaining body temperature and energy expenditure.Wasting syndrome is a debilitating condition characterized by prolonged weight loss,muscle wasting,fatigue,and malnutrition,affecting various systems and organs in the body.This condition leading to complications such as compromised immune function,metabolic derangements,and cardiovascular disease,thereby substantially reducing their quality of life and lifespan.Sleep deprivation（SD）is a pervasive public health issue that portends adverse health outcomes and disease risks in contemporary society.Studies have indicated that severe sleep deprivation can lead to metabolic disorders and the development of energy wasting.However,the role of the metabolic hormone Akh/Glucagon in modulating these processes,and its underlying mechanisms remain ambiguous.Thus,this study aims to elucidate the pathogenic mechanism of Akh/Glucagon in energy wasting following SD.Cancer cachexia,also known as tumor-induced wasting syndrome,is a type of wasting disease that often occurs with hyperglycemia and insulin resistance.Its molecular mechanism is still unclear,and there are currently no effective treatment options.Several studies have shown that tumor can secrete a large number of factors that act on different target organs,remotely regulating the metabolism of the host.Previous studies have found that intestinal tumors in drosophila secrete Imp L2,which acts on muscle and fat,impairing insulin signaling pathways and hijacking the energy utilization.It is unknown whether Akh,as a counter-regulatory hormone of insulin,is also hijacked by tumors and their secreted factors,leading to energy wasting.Therefore,the second objective of this study is to investigate the role of Akh/Glucagon in tumor-induced energy wasting and how it is regulated.In the sleep deprivation model,the LexA-LexAop and UAS-GAL4 genetic manipulation system was used to overexpress the ion channel protein（Trp A1）in specific neurons of drosophila through heat activation to induce sleep deprivation.Multiple sleep deprivation-related mutants in drosophila were also employed,and these severely sleep-deprived flies showed varying degrees of energy wasting,including a decrease in glycogen and lipid storage.Further studies found that Akh secretion increased,and the signaling pathway was activated in sleep-deprived drosophila.The energy wasting caused by sleep deprivation could be effectively restored by the lack of Akh resulting from gene mutation.Sleep deprivation also led to an increase in Ast A secretion in the gut,and specific knockdown of gut Ast A using Ats A³³-GAL4 and pros-GAL4 could alleviate the energy wasting caused by sleep deprivation.Mechanistically,Ast A-R2,the receptor expressed by Akh-producing cells,could respond to gut Ast A,activate intracellular calcium signaling,and promote Akh secretion,resulting in energy wasting.In mammals,continuous sleep deprivation for 48 hours in mice resulted in weight loss,loss of muscle and fat mass,and a decrease in liver glycogen.Blocking glucagon signaling by either knocking out the Gcg gene or using the glucagon receptor antagonist GRA effectively restored the energy wasting caused by sleep deprivation.Moreover,the study discovered that galanin,the mammalian homolog of Ast A,was upregulated under sleep deprivation and could stimulate the secretion of glucagon in mice.Blocking the galanin signaling pathway with M35 inhibitors also restored the energy wasting caused by sleep deprivation.For the tumor model,intestinal tumors were induced by using the LexA-LexAop and UAS-GAL4 gene manipulation systems to express the activated form of the oncogene yki^3SA in drosophila intestinal stem cells,in mice,including Apc^Min/+mice and LLC tumor-bearing mice,the main wasting phenotype of cachexia was simulated.The results showed that,in both drosophila and mice,Akh/Glucagon was over-secreted during tumor-induced wasting,leading to the activation of the signaling pathway.Depletion of Akh/Glucagon significantly alleviated the wasting phenotype of cachexia and improved abnormal glucose metabolism in mice.Further investigation revealed that the receptor Pvr on APCs mediated Akh secretion.Knocking down Pvr in APCs restored the energy wasting caused by drosophila intestinal tumors.These results suggest that in drosophila,Pvf1 secreted by tumor cells remotely activates the Pvr receptor on APCs,promoting Akh synthesis and release,resulting in cachexia and energy wasting.