Glucagon changes substrate preference in gluconeogenesis

Xu, Huiting; Wang, Yujue; Kwon, Hyokjoon; Shah, Ankit; Kalemba, Katarzyna M.; Su, Xiaoyang; He, Liang; Wondisford, Fredric E.

doi:10.1016/j.jbc.2022.102708

Cited by 6 publications

(5 citation statements)

References 46 publications

(77 reference statements)

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“…Thereafter, DHAP can enter the gluconeogenic pathway directly (the direct cytosolic pathway), or indirectly by glycolytic conversion to pyruvate and subsequent activities of mitochondrial transport, PC and PEPCK1 (the indirect mitochondrial pathway). While there is evidence that glycerol utilizes the direct cytosolic pathway, 20 whether impaired pyruvate transport and subsequent metabolism impacts glycerol-mediated gluconeogenesis has not been established.…”

Section: Introductionmentioning

confidence: 99%

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Yiew,

Deja,

Ferguson

et al. 2023

iScience

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Section: Introductionmentioning

confidence: 99%

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Yiew,

Deja,

Ferguson

et al. 2023

iScience

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“…Our data demonstrate that during early physiologic fasting, glycerol represents a key gluconeogenic substrate for the maintenance of adequate blood glucose. Indeed, other recent studies have demonstrated the importance of glycerol for hepatic gluconeogenesis under physiologic conditions 27–29 .…”

Section: Discussionmentioning

confidence: 95%

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

Hashsham,

Kodur,

et al. 2024

Preprint

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The brain augments glucose production during fasting, but the mechanisms are poorly understood. Here, we show thatCckbr-expressing neurons in the ventromedial hypothalamic nucleus (VMNCckbrcells) prevent low blood glucose during fasting through sympathetic nervous system (SNS)-mediated augmentation of adipose tissue lipolysis and substrate release. Activating VMNCckbrneurons mobilized gluconeogenic substrates without altering glycogenolysis or gluconeogenic enzyme expression. Silencing these cells (CckbrTetToxanimals) reduced fasting blood glucose, impaired lipolysis, and decreased circulating glycerol (but not other gluconeogenic substrates) despite normal insulin, counterregulatory hormones, liver glycogen, and liver gluconeogenic gene expression. Furthermore, β3-adrenergic adipose tissue stimulation in CckbrTetToxanimals restored lipolysis and blood glucose. Hence, VMNCckbrneurons impact blood glucose not by controlling islet or liver physiology, but rather by mobilizing gluconeogenic substrates. These findings establish a central role for hypothalamic and SNS signaling during normal glucose homeostasis and highlight the importance of gluconeogenic substrate mobilization during physiologic fasting.

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“…The net effect would be to enhance the conversion of glutamine to glutamate and subsequently increase the formation of oxalacetate in the mitochondria pericentral hepatocytes. In turn, oxalacetate exit from the mitochondria by the glutamate-aspartate translocase and the cytoplasmic oxalacetate can then serve as substrate for PEPCK to further drive gluconeogenesis 62,63 . This mechanism accounts for, at least in part, the basis for increased pericentral gluconeogenesis that occurs in the starved state.…”

Section: Discussionmentioning

confidence: 99%

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

Okada,

Landgraf,

Xiaoli

et al. 2024

Preprint

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The liver acts as a master regulator of metabolic homeostasis in part by performing gluconeogenesis. This process is dysregulated in type 2 diabetes, leading to elevated hepatic glucose output. The parenchymal cells of the liver (hepatocytes) are heterogeneous, existing on an axis between the portal triad and the central vein, and perform distinct functions depending on location in the lobule. Here, using single cell analysis of hepatocytes across the liver lobule, we demonstrate that gluconeogenic gene expression (Pck1 and G6pc) is relatively low in the fed state and gradually increases first in the periportal hepatocytes during the initial fasting period. As the time of fasting progresses, pericentral hepatocyte gluconeogenic gene expression increases, and following entry into the starvation state, the pericentral hepatocytes show similar gluconeogenic gene expression to the periportal hepatocytes. Similarly, pyruvate-dependent gluconeogenic activity is approximately 10-fold higher in the periportal hepatocytes during the initial fasting state but only 1.5-fold higher in the starvation state. In parallel, starvation suppresses canonical beta-catenin signaling and modulates expression of pericentral and periportal glutamine synthetase and glutaminase, resulting in an enhanced pericentral glutamine-dependent gluconeogenesis. These findings demonstrate that hepatocyte gluconeogenic gene expression and gluconeogenic activity are highly spatially and temporally plastic across the liver lobule, underscoring the critical importance of using well-defined feeding and fasting conditions to define the basis of hepatic insulin resistance and glucose production.

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Glucagon changes substrate preference in gluconeogenesis

Cited by 6 publications

References 46 publications

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Effects of hepatic mitochondrial pyruvate carrier deficiency on de novo lipogenesis and gluconeogenesis in mice

Control of Physiologic Glucose Homeostasis via the Hypothalamic Modulation of Gluconeogenic Substrate Availability

Spatial hepatocyte plasticity of gluconeogenesis during the metabolic transitions between fed, fasted and starvation states

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