Su558 INSULIN AND GLUCOSE ALTERED AMPK-TET2-5HMC AXIS TOWARD ON THE OBESITY-RELATED COLORECTAL CANCER DEVELOPMENT
Takashi KonYu SasakiYasuhiko AbeYusuke OnozatoMakoto YagiNaoko MizumotoTakayuki SakaiMatsuki UmeharaMinami ItoAyumi KosekiYoshiyuki Ueno
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Many cell processes that are disrupted in aging skeletal muscle are also regulated by AMP‐activated protein kinase (AMPK). However, the effect of aging on skeletal muscle AMPK activation is controversial and unclear. Our purpose was to determine the effect of old‐age on endurance‐type contraction‐induced AMPK activation in skeletal muscle. Gastrocnemius muscles from YA (8 mo old) and O (30 mo old) male Fischer344 x Brown Norway F1 hybrid rats were removed after 10 minutes of electrically stimulated in situ contractions (STIM). Muscles from the resting legs served as controls (REST). AMPK phosphorylation and AMPKα2 activity were 63% and 19% lower, respectively, in O vs. YA muscles after STIM. AMPKα1 activity was unaffected by STIM in YA, but increased by 30% in O muscles. AMPK α1 protein concentration was 45% greater, while α2 content was 18% lower in O vs. YA muscles. AMPK β1, β2, and γ1 proteins were unaffected by age, but AMPK γ2 and γ3 concentrations were 75% and 85% lower in O vs. YA muscles, respectively. In conclusion, AMPKα2 activation is impaired while AMPKα1 activation is enhanced after endurance‐type in situ contractions in aged skeletal muscle. This work was funded by NIAMSD Grant AR‐51928.
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5'-Adenosine monophosphate-activated protein kinase (AMPK) is a potential therapeutic target for various medical conditions. We here identify a small-molecule compound (RX-375) that activates AMPK and inhibits fatty acid synthesis in cultured human hepatocytes. RX-375 does not bind to AMPK but interacts with prohibitins (PHB1 and PHB2), which were found to form a complex with AMPK. RX-375 induced dissociation of this complex, and PHBs knockdown resulted in AMPK activation, in the cultured cells. Administration of RX-375 to obese mice activated AMPK and ameliorated steatosis in the liver. High-throughput screening based on disruption of the AMPK-PHB interaction identified a second small-molecule compound that activates AMPK, confirming the importance of this interaction in the regulation of AMPK. Our results thus indicate that PHBs are previously unrecognized negative regulators of AMPK, and that compounds that prevent the AMPK-PHB interaction constitute a class of AMPK activator.
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The AMP-activated protein kinase (AMPK) is a principal nutrient sensor and a master regulator of cellular energy homeostasis. Once activated, AMPK induces glucose uptake, which leads to a transient decrease in blood glucose level and can be used as an indicator of AMPK activity. Here, we present a protocol accessing AMPK activity in mice by measuring glucose uptake induced by AMPK activators, MK8722 and A769662. This protocol can be used to evaluate AMPK signaling in vivo under various pathophysiological conditions. For complete details on the use and execution of this protocol, please refer to Jiang et al. (2021).
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Adenosine 5'-monophosphate-activated protein activated protein kinase (AMPK), a heterotrimeric complex, is an important kinase to regulate glycolipid metabolism and energy balance involved in a variety physiological processes in human body. Many research indicated that the function and activity of AMPK were closely related to inflammation, diabetes and cancers. Recent reports show that inhibition of metformin (a first-line drug) on hepatic glucose in patients with hyperglycemia is associated with AMPK pathway, suggesting that targeting AMPK may be one of the effective strategies for the prevention and treatment of a variety of chronic diseases. Here, we review research progress on the structure, activation and regulation of AMPK in glycolipid metabolism to provide an insight into the basic and clinical research of diabetes therapy.AMP 激活的蛋白激酶 (AMP-activated protein kinase，AMPK) 是一种异源三聚体复合物，作为机体能量平衡和糖脂代谢的重要激酶参与多种生理过程的调节。研究表明，炎症、糖尿病和癌症等多种慢性疾病也与AMPK功能和活性调节有密切关系。新近发现，糖尿病一线用药二甲双胍抑制肝糖产生改善病人高血糖的作用与AMPK激活有关，提示靶向AMPK 可能是预防和治疗多种慢性疾病的有效策略之一。文中从AMPK 的结构与活性、AMPK在糖代谢调控中的作用和AMPK 在血脂代谢调控中的作用3 个方面综述了AMPK 研究的进展，旨在为糖脂代谢调控的基础和临床研究提供依据。.
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AMP activated protein kinase (AMPK) is a heterotrimeric αβγ complex. Selective pharmacological activation of specific AMPK‐complexes through targeting of its regulatory subunits is an attractive strategy to confine AMPK activation to select tissues to combat diseases such as type 2 Diabetes. Furthermore, it is a useful tool to study specific AMPK complexes in vivo. Here, a putative direct α‐AMPK specific activator, PT‐1, was found to selectively increase γ1, but not γ3 AMPK‐associated activity in incubated mouse muscles. In contrast, the AMP‐mimetic AMPK activator, AICAR stimulated both γ1 and γ3 AMPK activities. Both PT‐1 and AICAR augmented AMPK Thr172 phosphorylation when measured in whole muscle lysates. However, unlike AICAR, PT‐1 did not increase TBC1D1 Ser237 or ACCbeta Ser221 phosphorylation, suggesting that these phosphorylations are catalyzed by γ3 but not γ1‐AMPK complexes. Unlike AICAR, known to require α2,β2 and γ3 AMPK to increase glucose transport, PT‐1 failed to stimulate this process. In summary, this study demonstrates for the first time γ1‐ but not γ3‐AMPK activation by PT‐1. TBC1D1 Ser237, ACCbeta Ser221 and glucose transport‐stimulation reflect α2β2γ3‐ but not γ1‐AMPK activity in mouse muscle. Funded by Danish Research Council and Novo Nordisk Foundation.
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AMP-activated protein kinase (AMPK) has been suggested as a molecular hub for cellular metabolic control and accumulating evidence supports a disturbance in AMPK activity and its regulatory pathways in many different types of diseases including neurological diseases. In fact, AMPK is highly expressed in the brain with a predominant neuronal localization and shown to be activated by resveratrol as well as metablic stress. Since metabolic stress is one of the key pathological alterations in Alzheimer disease (AD) and the pathogenic mechanism is unclear, we hypothesizes that decreased activity of AMPK is keen to the mechanism of metabolic defects found in AD. To this end, in this study, we analyzed the expression of AMPK in AD brains and investigated the pathophysiological role of AMPK in AD. The expression pattern of AMPK in AD was analyzed by a series of molecular techniques and included the AD model systems that were investigated for the role of AMPK in the pathogenesis of AD. Counter to our hypothesis, the level of active AMPK was dramatically increased in AD brains and mainly localized in the vulnerable neurons containing neurofibrillary tangles (NFT). The pathological implications of this finding will be discussed based on the results from the AD model systems. Our results clearly demonstrate that AMPK is significantly activated in the vulnerable neurons in AD. While the pathological consequence(s) of such AMPK activation is yet to be determined, it is likely that the activation of AMPK in AD might not be neuroprotective as shown in previous studies. Indeed, the activation of AMPK has been linked to neurodegeneration and aberrant processing of amyloid-β precursor proteins, suggesting that the higher activity of AMPK might be harmful to neurons and this potential mechanism will be discussed.
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AMP-activated protein kinase (AMPK) is a central regulator of energy homeostasis, which coordinates metabolic pathways and thus balances nutrient supply with energy demand. Because of the favorable physiological outcomes of AMPK activation on metabolism, AMPK has been considered to be an important therapeutic target for controlling human diseases including metabolic syndrome and cancer. Thus, activators of AMPK may have potential as novel therapeutics for these diseases. In this review, we provide a comprehensive summary of both indirect and direct AMPK activators and their modes of action in relation to the structure of AMPK. We discuss the functional differences among isoform-specific AMPK complexes and their significance regarding the development of novel AMPK activators and the potential for combining different AMPK activators in the treatment of human disease. An enzyme with a key role in metabolism could offer a target for drugs to treat obesity, type 2 diabetes and cancer. The enzyme AMPK (AMP-activated protein kinase) is crucial for regulating energy and metabolism in cells, and is thought to be important in protecting against several diseases. Joohun Ha and colleagues at Kyung Hee University, Seoul, have reviewed the research into agents designed to activate AMPK to assess their feasibility as drugs. The researchers suggest that AMPK activators are potentially useful for the treatment of conditions such as obesity, type 2 diabetes and cancer. Combining different AMPK activators in different clinical contexts might provide optimal treatment. They conclude that more research is needed to determine the precise mechanisms of action of AMPK activators and thereby optimize treatment strategies.
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AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic α-subunit (α1 and α2) and regulatory β (β1 and β2)- and γ (γ1, γ2, γ3)-subunits, which are uniquely distributed across different cell types. There has been keen interest in developing specific and isoform-selective AMPK-activating drugs for therapeutic use and also as research tools. Moreover, establishing ways of enhancing cellular AMPK activity would be beneficial for both purposes. Here, we investigated if a recently described potent AMPK activator called 991, in combination with the commonly used activator 5-aminoimidazole-4-carboxamide riboside or contraction, further enhances AMPK activity and glucose transport in mouse skeletal muscle ex vivo. Given that the γ3-subunit is exclusively expressed in skeletal muscle and has been implicated in contraction-induced glucose transport, we measured the activity of AMPKγ3 as well as ubiquitously expressed γ1-containing complexes. We initially validated the specificity of the antibodies for the assessment of isoform-specific AMPK activity using AMPK-deficient mouse models. We observed that a low dose of 991 (5 μM) stimulated a modest or negligible activity of both γ1- and γ3-containing AMPK complexes. Strikingly, dual treatment with 991 and 5-aminoimidazole-4-carboxamide riboside or 991 and contraction profoundly enhanced AMPKγ1/γ3 complex activation and glucose transport compared with any of the single treatments. The study demonstrates the utility of a dual activator approach to achieve a greater activation of AMPK and downstream physiological responses in various cell types, including skeletal muscle.
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