Peroxisomal ERK mediates Akh/glucagon action and glycemic control

Li, Jiaying; Dang, Peixuan; Li, Zhen; Zhao, Tujing; Cheng, Daojun; Pan, Dingyu; Yuan, Yufeng; Song, Wei

doi:10.1016/j.celrep.2023.113200

Cited by 3 publications

(2 citation statements)

References 52 publications

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“…However, it is conceivable that the activation of AkhR has a more extensive role than facilitating neutral lipid mobilization. Recently, AKH has been found to activate extracellular signal-regulated kinase (ERK), which in turn increases amino acid catabolism and gluconeogenesis in the fly fat body 52 . Together with our observations, it seems plausible that amino acid-induced AKH secretion serves as a mechanism for flies to process excessive amino acids ingested from the diet.…”

Section: Discussionmentioning

confidence: 99%

Sensing of dietary amino acids and regulation of calcium dynamics in adipose tissues through Adipokinetic hormone inDrosophila

Ahmad,

Wu,

Guo

et al. 2024

Preprint

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Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various obesity-related diseases.Drosophila melanogasterhas emerged as an excellent model for investigating metabolism and its associated disorders. In this study, we used live-cell imaging to demonstrate that the fly functional homolog of mammalian glucagon, Adipokinetic hormone (AKH), secreted from AKH hormone-producing cells (APCs) in the corpora cardiaca, stimulates intracellular Ca2+waves in the larval fat body/adipose tissue to promote lipid metabolism. Further, we show that specific dietary amino acids activate the APCs, leading to increased intracellular Ca2+and subsequent AKH secretion. Finally, a comparison of Ca2+dynamics in larval and adult fat bodies revealed different mechanisms of regulation, highlighting the interplay of pulses of AKH secretion, extracellular diffusion of the hormone, and intercellular communication through gap junctions. Our study underscores the suitability ofDrosophilaas a powerful model for exploring real-time nutrient sensing and inter-organ communication dynamics.

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Section: Discussionmentioning

confidence: 99%

Sensing of dietary amino acids and regulation of calcium dynamics in adipose tissues through Adipokinetic hormone inDrosophila

Ahmad,

Wu,

Guo

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…However, it is conceivable that the activation of AkhR has a more extensive role than facilitating neutral lipid mobilization. Recently, AKH has been found to activate extracellular signal-regulated kinase (ERK), which in turn increases amino acid catabolism and gluconeogenesis in the y fat body 49 . Together with our observations, it seems plausible that amino acid-induced AKH secretion serves as a mechanism for ies to process excessive amino acids ingested from the diet.…”

Section: Dietary Amino Acid-mediated Activation Of Apcsmentioning

confidence: 99%

Dietary Amino Acids Promote Glucagon-like Hormone Release to Generate Novel Calcium Waves in Adipose Tissues

He,

Ahmad,

et al. 2024

Preprint

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Nutrient sensing and the subsequent metabolic responses are fundamental functions of animals, closely linked to diseases such as type 2 diabetes and various obesity-related morbidities. Among different metabolic regulatory signals, cytosolic Ca2+ plays pivotal roles in metabolic regulation, including glycolysis, gluconeogenesis, and lipolysis. Recently, intercellular calcium waves (ICWs), the propagation of Ca2+ signaling through tissues, have been found in different systems to coordinate multicellular responses. Nevertheless, our understanding of how ICWs are modulated and operate within living organisms remains limited. In this study, we explore the real-time dynamics, both in organ culture and free-behaving animals, of ICWs in Drosophila larval and adult adipose tissues. We identified Adipokinetic hormone (AKH), the fly functional homolog of mammalian glucagon, as the key factor driving Ca2+ activities in adipose tissue. Interestingly, we found that AKH, which is released in a pulsatile manner into the circulating hemolymph from the AKH-producing neurosecretory cells (APCs) in the brain, stimulates ICWs in the larval fat by a previously unrecognized gap-junction-independent mechanism to promote lipolysis. In the adult fat body, however, gap-junction-dependent random ICWs are triggered by a presumably uniformly diffused AKH. This highlights the stage-specific interplay of hormone secretion, extracellular diffusion, and intercellular communication in the regulation of Ca2+ dynamics. Additionally, we discovered that specific dietary amino acids activate the APCs, leading to increased intracellular Ca2+ and subsequent AKH secretion. Altogether, our findings identify that dietary amino acids regulate the release of AKH peptides from the APCs, which subsequently stimulates novel gap-junction-independent ICWs in adipose tissues, thereby enhancing lipid metabolism.

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A tumor-secreted protein utilizes glucagon release to cause host wasting

Ding,

Li,

Cheng

et al. 2024

Preprint

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Tumor-host interaction plays a critical role in malignant tumor-induced organ wasting across multiple species. Despite known regulation of regional wasting of individual peripheral organs by tumors, whether and how tumors utilize critical host catabolic hormone(s) to simultaneously induce systemic host wasting, however, is largely unknown. Using the conserved yki3SA-tumor model in Drosophila, we discovered that tumors increase the production of adipokinetic hormone (Akh), a glucagon-like catabolic hormone, to cause systemic host wasting, including muscle dysfunction, lipid loss, hyperglycemia, and ovary atrophy. We next integrated RNAi screening and Gal4-LexA dual expression system to identify that yki3SA-gut tumors secrete Pvf1 to remotely activate its receptor Pvr in Akh-producing cells (APCs), ultimately promoting Akh production. The underlying molecular mechanisms involved the Pvf1-Pvr axis that triggers Mmp2-dependent ECM remodeling of APCs and enhances innervation from the excitatory cholinergic neurons. Interestingly, we also confirmed the similar mechanisms governing tumor-induced glucagon release and organ wasting in mammals. Blockade of either glucagon or PDGFR (homolog of Pvr) action efficiently ameliorated organ wasting in the presence of malignant tumors. Therefore, our results demonstrate that tumors remotely promote neural-associated Akh/glucagon production via Pvf1-Pvr axis to cause systemic host wasting.

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Peroxisomal ERK mediates Akh/glucagon action and glycemic control

Cited by 3 publications

References 52 publications

Sensing of dietary amino acids and regulation of calcium dynamics in adipose tissues through Adipokinetic hormone inDrosophila

Sensing of dietary amino acids and regulation of calcium dynamics in adipose tissues through Adipokinetic hormone inDrosophila

Dietary Amino Acids Promote Glucagon-like Hormone Release to Generate Novel Calcium Waves in Adipose Tissues

A tumor-secreted protein utilizes glucagon release to cause host wasting

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