Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress

Zong, Yue; Zhang, Chen-Song; Li, Mengqi; Wang, Wen; Wang, Zhichao; Hawley, Simon A.; Ma, Teng; Feng, Jin-Wei; Tian, Xiao; Qu, Qi; Wu, Yuqing; Zhang, Cixiong; Ye, Zhiyun; Lin, Shu-Yong; Piao, Hulin; Hardie, D. Grahame; Lin, Sheng-Cai

doi:10.1038/s41422-019-0163-6

Cited by 125 publications

(167 citation statements)

References 77 publications

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“…This effect could be mediated by direct activation of AMPK within the α-cell as pharmacological and genetic activation of α-cell AMPK stimulates glucagon secretion (7,8). Importantly, this indicates that the likely net effect of AMPK activation throughout the whole body is to increase glucose delivery to the brain, as previously suggested (22), indicating that at the level of the whole organism, central AMPK activation may supersede peripheral activation in a hierarchical manner, akin to that suggested for subcellular pools of AMPK (26).…”

Section: Resultssupporting

confidence: 64%

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

Am¹,

Malekizadeh²,

Walker³

et al. 2019

Preprint

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AMP-activated protein kinase (AMPK) is a critical cellular and whole body energy sensor activated by energy stress, including hypoglycemia, which is frequently experienced by people with diabetes. Previous studies using direct delivery of an AMPK activator to the ventromedial hypothalamus (VMH) in rodents increased hepatic glucose production.Moreover, recurrent glucoprivation in the hypothalamus leads to blunted AMPK activation and defective hormonal responses to subsequent hypoglycemia. These data suggest that amplifying AMPK activation may prevent or reduce frequency hypoglycemia in diabetes. We used a novel brain-permeable AMPK activator, R481, which potently increased AMPK phosphorylation in vitro. R481 significantly increased peak glucose levels during glucose tolerance tests in rats, which were attenuated by treatment with AMPK inhibitor SBI-0206965 and completely abolished by blockade of the autonomic nervous system. This occurred without altering insulin sensitivity measured by hyperinsulinemic-euglycemic clamps.Endogenous insulin secretion was not altered by R481 treatment. During hyperinsulinemichypoglycemic clamp studies, R481 treatment reduced exogenous glucose requirements and amplified peak glucagon levels during hypoglycemia. These data demonstrate that peripheral administration of the brain permeable AMPK activator R481 amplifies the counterregulatory response to hypoglycemia in rats, which could have clinical relevance for prevention of hypoglycemia.

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Section: Resultssupporting

confidence: 64%

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

Am¹,

Malekizadeh²,

Walker³

et al. 2019

Preprint

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“…Recently, it was demonstrated that different intensities of AMPK stimulation trigger activation of specific subcellular pools, resulting in phosphorylation of distinct downstream targets. Under conditions of glucose starvation that do not elevate cellular adenosine monophosphate: ADP or adenosine diphosphate:ATP ratios, only lysosomal AMPK is activated and exclusively through the lysosomal pathway …”

Section: Resultsmentioning

confidence: 99%

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Yordanov

Hipolito

Liebscher

et al. 2019

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Mechanisms that control lysosomal function are essential for cellular homeostasis. Lysosomes adapt in size and number to cellular needs but little is known about the underlying molecular mechanism. We demonstrate that the late endosomal/lysosomal multimeric BLOC‐1‐related complex (BORC) regulates the size of these organelles via PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate [PI(3,5)P2] production. Deletion of the core BORC component Diaskedin led to increased levels of PI(3,5)P2, suggesting activation of PIKfyve, and resulted in enhanced lysosomal reformation and subsequent reduction in lysosomal size. This process required AMP‐activated protein kinase (AMPK), a known PIKfyve activator, and was additionally dependent on the late endosomal/lysosomal adaptor, mitogen‐activated protein kinases and mechanistic target of rapamycin activator (LAMTOR/Ragulator) complex. Consistently, in response to glucose limitation, AMPK activated PIKfyve, which induced lysosomal reformation with increased baseline autophagy and was coupled to a decrease in lysosomal size. These adaptations of the late endosomal/lysosomal system reversed under glucose replete growth conditions. In summary, our results demonstrate that BORC regulates lysosomal reformation and size in response to glucose availability.

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“…Palmitate interacts with CD36 and can palmitoylate it (Tao et al, 1996;Thorne et al, 2010;Zhao et al, 2018). This increases CD36 translocation to the plasma membrane and favors the formation of a complex with Fyn, Lyn and LKB1, preventing AMPK activation under chronic palmitate treatment conditions (Li et al, 2019;Zhao et al, 2018). Acute binding to palmitate, on the other hand, may alleviate LKB1 inhibition, activating AMPK and lipophagy (Li et al, 2019;Samovski and Abumrad, 2019;Samovski et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…This increases CD36 translocation to the plasma membrane and favors the formation of a complex with Fyn, Lyn and LKB1, preventing AMPK activation under chronic palmitate treatment conditions (Li et al, 2019;Zhao et al, 2018). Acute binding to palmitate, on the other hand, may alleviate LKB1 inhibition, activating AMPK and lipophagy (Li et al, 2019;Samovski and Abumrad, 2019;Samovski et al, 2015). Zhang and co-workers elegantly described the mild and early activation of AMPK upon glucose starvation before any changes in ATP levels, in a manner regulated by aldolase activity (a glycolytic enzyme).…”

Section: Discussionmentioning

confidence: 99%

“…Curiously, cells deprived of glucose do not activate glycolysis upon palmitate after 6 hours, indicating that PLC cells may be unable to provide carbons to form glycolytic intermediates, even when total ATP production is not compromised (Fig 3). Interestingly, in more recent work, the group observed that AMPK is activated in a stratified manner in compartments, proportionally to the severity of nutrient stress (Zong et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

Kakimoto

Zorzano

Kowaltowski

2020

Preprint

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Palmitic acid is the most abundant saturated fatty acid in human serum. In cell culture systems, palmitate overload is considered a toxic stimulus, and promotes lipid accumulation, insulin resistance, endoplasmic reticulum stress, oxidative stress, as well as cell death. An increased supply of fatty acids has also been shown to change the predominant form of the mitochondrial network, although the metabolic effects of this change are still unclear. Here, we aimed to uncover the early bioenergetic outcomes of lipotoxicity. We incubated hepatic PLC/PRF/5 cells with palmitate conjugated to BSA and followed real-time oxygen consumption and extracellular acidification for 6 hours. Palmitate increased glycolysis as soon as 1 hour after the stimulus, while oxygen consumption was not disturbed, despite overt mitochondrial fragmentation and cellular reductive imbalance.Palmitate only induced mitochondrial fragmentation if glucose and glutamine were available, while glycolytic enhancement did not require glutamine, showing it is not dependent on morphological changes. NAD(P)H levels were significantly abrogated in palmitate-treated cells. Knockdown of the mitochondrial NAD(P) transhydrogenase or addition of the mitochondrial oxidant-generator menadione in control cells modulated ATP production from glycolysis. Indeed, using selective inhibitors, we found that the production of superoxide/hydrogen peroxide at the IQ site of electron transport chain complex I is associated with the metabolic rewiring promoted by palmitate, while not changing mitochondrial oxygen consumption. In conclusion, we demonstrate that increased glycolytic flux linked to mitochondrially-generated redox imbalance is an early bioenergetic result of palmitate overload and lipotoxicity.

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Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress

Cited by 125 publications

References 77 publications

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

Brain permeable AMPK activator R481 raises glycemia by autonomic nervous system activation and amplifies the counterregulatory response to hypoglycemia in rats

Biogenesis of lysosome‐related organelles complex‐1 (BORC) regulates late endosomal/lysosomal size through PIKfyve‐dependent phosphatidylinositol‐3,5‐bisphosphate

Increased glycolysis is an early outcome of palmitate-mediated lipotoxicity

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