Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice

Ashraf, Sadia; Ashraf, Nadia; Yılmaz, Gizem; Harmancey, Romain

doi:10.14814/phy2.14958

Cited by 4 publications

(2 citation statements)

References 91 publications

(98 reference statements)

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“…Similarly, an autonomic imbalance due to increased sympathetic activation is a cause of liver dysfunction [25,32]. Chronic activation of sympathetic nerves reaching the liver leads to increased gluconeogenesis and lipogenesis, thus increasing lipid accumulation and liver steatosis [33,34]. This evidence is supported by the fact that liver denervation reduces liver steatosis and improves NAFLD [33].…”

Section: Discussionmentioning

confidence: 95%

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

Fernandois,

Vázquez,

Barroso

et al. 2023

IJMS

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Autonomic innervation is important to regulate homeostasis in every organ of the body. The sympathetic nervous system controls several organs associated with metabolism and reproduction, including adipose tissue, the liver, and the ovaries. The sympathetic nervous system is controlled within the central nervous system by neurons located in the hypothalamus, which in turn are regulated by hormones like leptin. Leptin action in the hypothalamus leads to increased sympathetic activity in the adipose tissue. In this short report, we propose that leptin action in the brain also controls the sympathetic innervation of other organs like the liver and the ovary. We performed two experiments: We performed an intracerebroventricular (ICV) injection of leptin and measured norepinephrine levels in several organs, and we used a validated model of overnutrition and obesity to evaluate whether an increase in leptin levels coexists with high levels of norepinephrine in the liver and ovaries. Norepinephrine was measured by ELISA in adipose tissue and by HPLC-EC in other tissues. Leptin was measured by ELISA. We found that the ICV injection of leptin increases norepinephrine levels in several organs, including the liver and ovaries. Also, we found that diet-induced obesity leads to an increase in leptin levels while inducing an increase in norepinephrine levels in the liver and ovaries. Finally, since hyperactivity of the sympathetic nervous system is observed both in non-alcoholic fatty liver disease and polycystic ovary syndrome, we think that an increase in norepinephrine levels induced by hyperleptinemia could be involved in the pathogenesis of both diseases.

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Section: Discussionmentioning

confidence: 95%

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

Fernandois,

Vázquez,

Barroso

et al. 2023

IJMS

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“…In addition, β-AR showed regulation of glucose uptake and glycogen synthesis (7). β1-AR agonists reduced insulin-induced glucose uptake and glycogen synthesis (8). Glycogen storage in cardiomyocytes has been shown to be related with myocardial hypertrophy.…”

Section: Introductionmentioning

confidence: 99%

AKT-mTOR signaling-mediated rescue of PRKAG2 R302Q mutant-induced familial hypertrophic cardiomyopathy by treatment with β-adrenergic receptor (β-AR) blocker metoprolol

Jiang¹,

Geng²,

Wu³

et al. 2022

Cardiovasc Diagn Ther

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Background: Protein kinase AMP-activated non-catalytic subunit gamma 2 gene (PRKAG2) cardiac syndrome, caused by mutations in PRKAG2, often shows myocardial hypertrophy and abnormal glycogen deposition in cardiomyocytes. However, it remains incurable due to a lack of a management guideline for treatment.Methods: We constructed a fluorescently labeled adenovirus carrying the wild-type or R302Q mutant of the PRKAG2 gene, infected neonatal rat cardiomyocytes (NRCMs) and H9C2 cell lines, and then analyzed changes in AMP-activated protein kinase (AMPK) activity, cell hypertrophy, glycogen storage, and cell proliferation when presence or absence of metoprolol or protein kinase A (PKA) inhibition H89, and then analyzed the changes in AKT-mTOR signal transduction activity.Results: Overexpression of PRKAG2 R302Q in primary cardiomyocytes increased the activity of AMPK, induced cellular hypertrophy and glycogen storage, and promoted the phosphorylation levels of AKT-mTOR signaling pathway. Application of either β1-adrenergic receptor (β1-AR) blocker metoprolol or PKA inhibitor H89 to the cardiomyocytes rescued the hypertrophic cardiomyopathy (HCM)-like phenotypes induced by PRKAG2 R302Q, including suppression of both AKT-mTOR phosphorylation and AMPK activity.Conclusions: The current study not only determined the mechanism regulating HCM induced by PRKAG2 R302Q mutant, but also demonstrated a therapeutic strategy using β1-AR blocker to treat the patients with PRKAG2 cardiac syndrome.

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Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression

Xu,

Zhao,

Zhu

et al. 2024

Journal of Hepatology

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Crosstalk between beta‐adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high‐fat diet‐fed male mice

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Cited by 4 publications

References 91 publications

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

Multi-Organ Increase in Norepinephrine Levels after Central Leptin Administration and Diet-Induced Obesity

AKT-mTOR signaling-mediated rescue of PRKAG2 R302Q mutant-induced familial hypertrophic cardiomyopathy by treatment with β-adrenergic receptor (β-AR) blocker metoprolol

Targeting PYK2 with heterobifunctional T6BP helps mitigate MASLD and MASH-HCC progression

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