Re: AMPK - 일주기 리듬 2013 nature

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세포에 에너지가 부족하면

세포질(리보솜)에서 AMPK 합성 --> 에너지 센싱. 포도당 세포내 유입촉진 --> 미토콘드리아 ATP 합성 촉진

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AMP-activated protein kinase as a key molecular link between metabolism and clockwork

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• Published: 26 July 2013

AMP-activated protein kinase as a key molecular link between metabolism and clockwork

• Yongjin Lee & 
• Eun-Kyoung Kim 

Experimental & Molecular Medicine volume 45, pagee33 (2013)Cite this article

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Abstract

Circadian clocks regulate behavioral, physiological and biochemical processes in a day/night cycle. Circadian oscillators have an essential role in the coordination of physiological processes with the cyclic changes in the physical environment. Such mammalian circadian clocks composed of the positive components (BMAL1 and CLOCK) and the negative components (CRY and PERIOD (PER)) are regulated by a negative transcriptional feedback loop in which PER is rate-limiting for feedback inhibition. In addition, posttranslational modification of these components is critical for setting or resetting the circadian oscillation. Circadian regulation of metabolism is mediated through reciprocal signaling between the clock and metabolic regulatory networks. AMP-activated protein kinase (AMPK) in the brain and peripheral tissue is a crucial cellular energy sensor that has a role in metabolic control. AMPK-mediated phosphorylation of CRY and Casein kinases I regulates the negative feedback control of circadian clock by proteolytic degradation. AMPK can also modulate the circadian rhythms through nicotinamide adenine dinucleotide-dependent regulation of silent information regulator 1. Growing evidence elucidates the AMPK-mediated controls of circadian clock in metabolic diseases such as obesity and diabetes. In this review, we summarize the current comprehension of AMPK-mediated regulation of the circadian rhythms. This will provide insight into understanding how their components regulate the metabolism.

일주기 리듬은 

일/밤 주기로 행동, 생리 및 생화학 과정을 조절합니다. 

일주기 발진기는 

물리적 환경의 주기적 변화에 따라 생리 과정을 협응하는 데 필수적인 역할을 합니다. 

이러한 포유류의 일주기 리듬은 

양성 성분(BMAL1 및 CLOCK)과 음성 성분(CRY 및 PERIOD (PER))으로 구성되어 있으며, 

PER이 피드백 억제를 제한하는 음성 전사 피드백 루프에 의해 조절됩니다. 

또한, 이러한 구성 요소의 번역 후 변형은 생체시계 진동의 설정 또는 재설정에 필수적입니다. 

생체시계는 시계와 대사 조절 네트워크 간의 상호작용을 통해 대사 조절을 매개합니다. 

뇌와 주변 조직에 존재하는 AMP 활성화 단백질 키나제(AMPK)는 

대사 조절에 역할을 하는 중요한 세포 에너지 센서입니다. 

AMPK에 의한 CRY 및 케이신 키나제 I의 인산화는 

단백질 분해에 의한 생체시계 진동의 음성 피드백 조절을 조절합니다. 

AMPK는 

니코틴아미드 아데닌 디뉴클레오티드(NAD) 의존적 조절을 통해 

침묵 정보 조절자 1(SIR1)을 조절함으로써 생체시계 리듬을 조절할 수 있습니다. 

최근 연구들은 

비만과 당뇨병과 같은 대사 질환에서 

AMPK에 의한 생체시계 조절 메커니즘을 밝히고 있습니다. 

본 리뷰에서는 AMPK에 의한 생체시계 리듬 조절에 대한 현재의 이해를 요약합니다. 

이는 생체시계 구성 요소가 대사 조절에 어떻게 작용하는지 이해하는 데 기여할 것입니다.

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Introduction

Circadian rhythms are under the direct influence of environmental cues, most notably the day–night cycles and controlled a genetically determined endogenous clock.1 Circadian (derived from the Latin circa diem; about a day) clock could adapt organisms to the natural environment and then enable them to anticipate the environmental changes that the behavior and physiology of organisms can be adjusted to proper time a day.

Circadian rhythms are widely distributed in plants, animals, fungi and cyanobacteria, and are regulated by endogenous molecular oscillators called circadian clocks.2, 3 In mammals, important daily activities such as sleep/wake cycles and metabolic homeostasis are governed by the endogenous circadian clock.4, 5, 6

Available data suggest that the major mechanism of the molecular clock is a transcriptional negative feedback loop containing CLOCK (or NPAS2), BMAL1, PERIOD (PER), and CRYPTOCHROME (CRY). The CLOCK (or NPAS2)-BMAL1 heterodimer activates transcription of the negative elements, PER and CRY, as well as circadian output genes, through E-box enhancer elements.3, 4, 5, 6, 7, 8 As PER levels increase in the cytoplasm, PER associates with CRY, the complex enters the nucleus to shut down transcription driven by CLOCK-BMAL1 complex. Thus, temporal accumulation and degradation rates of PER predominate in determining the timing of the negative feedback loop. There is one more regulatory feedback loop, in which RORs activate the transcription of BMAL1 and CLOCK, whereas Rev-Erbs repress BMAL1, CLOCK and NPAS2 through retinoic acid-related orphan receptor response element (RORE; Figure 1).9, 10, 11

소개

생체 리듬은 환경적 신호, 특히 낮과 밤의 주기 및 유전적으로 결정된 내인성 시계에 의해 직접적으로 영향을 받습니다.1 생체 리듬(라틴어 circa diem에서 유래, 약 하루) 시계는 유기체가 자연 환경에 적응하도록 돕고, 환경 변화에 대비해 유기체의 행동과 생리적 기능을 하루 중 적절한 시간에 조정할 수 있도록 합니다.

생체리듬은 식물, 동물, 곰팡이, 청색조류 등에 널리 분포되어 있으며, 내인성 분자 진동기인 생체리듬 시계에 의해 조절됩니다.2, 3 포유류에서는 수면/각성 주기 및 대사 균형과 같은 중요한 일일 활동이 내인성 생체리듬 시계에 의해 조절됩니다.4, 5, 6

현재까지의 데이터는 분자 시계의 주요 메커니즘이 CLOCK (또는 NPAS2), BMAL1, PERIOD (PER), 및 CRYPTOCHROME (CRY)를 포함하는 전사적 음성 피드백 루프임을 제시합니다. CLOCK(또는 NPAS2)-BMAL1 이량체는 E-박스 증강 요소를 통해 PER 및 CRY와 같은 음성 요소 및 생체 리듬 출력 유전자의 전사를 활성화합니다.3, 4, 5, 6, 7, 8 세포질에서 PER 수준이 증가하면 PER은 CRY와 결합하여 복합체가 핵으로 이동해 CLOCK-BMAL1 복합체에 의해 유도된 전사를 차단합니다. 따라서 PER의 시간적 축적 및 분해 속도가 음성 피드백 루프의 타이밍을 결정하는 주요 요인입니다. 추가적인 조절 피드백 루프가 존재하며, 이 루프에서 RORs는 BMAL1과 CLOCK의 전사를 활성화시키며, Rev-Erbs는 레티노산 관련 고아 수용체 반응 요소(RORE; 그림 1)를 통해 BMAL1, CLOCK 및 NPAS2를 억제합니다.9, 10, 11

Figure 1

Feedback loops control the mammalian circadian clock. Mechanism of the molecular clock is a transcriptional negative feedback loop containing CLOCK, BMAL1, (PERIOD) PER and CRY. The CLOCK-BMAL1 heterodimer binds to enhancer E-box located in the promoter region of Per and Cry genes to activate their transcriptions. After translation, PERs and CRYs perform nuclear translocation and inhibit CLOCK-BMAL1, resulting in decreased transcription of their genes. There is other regulatory feedback loop. CLOCK-BMAL1 also induces the expression‎ of Rev-Erbs and RORs, and in turn RORs activate the transcription of BMAL1 and CLOCK, whereas Rev-Erbs repress BMAL1 and CLOCK through retinoic acid-related orphan receptor response element (RORE) binding.

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In MEFs, CLOCK, BMAL1 and CRY1 are similarly abundant, which is different from liver where BMAL1 is far less abundant than the other two. CRY2, PER1 and PER2 are less abundant than the other core clock proteins. The levels of PER1/2 (the limiting component in the negative complex) to BMAL1 (the limiting component in the positive complex) are almost 1:1. The combined levels of PER1 and PER2 are only about half of those of CLOCK and BMAL1, implying that CLOCK-BMAL1 would be twice as abundant as PER-CRY, a negative complex.12 This finding suggests that the ratio between the negative and positive complexes must be important for the molecular oscillator and rhythm generation, and PER seems to be rate-limiting for the rhythms.7, 12, 13

Some clock-controlled genes are transcription factors such as albumin D-box-binding protein, RORα and REV-Erbα, which regulate cyclic expression‎ of other genes.14 D-box-binding protein binds to D-boxes (TTA (T/C) GTAA), whereas RORα and Rev-Erbα bind to the Rev-Erb/ROR binding element, or RRE [(A/T) A (A/T) NT (A/G) GGTCA]. Approximately 10% of the transcriptome displays robust circadian rhythmicity.15, 16

The adenosine monophosphate (AMP)–activated protein kinase (AMPK) is a serine/threonine protein kinase that works as a central sensor of metabolic signals.17 AMPK is activated by adenosine triphosphate (ATP) exhaustion, which causes an increase in the AMT/ATP ratio.18 Once activated, AMPK switches on catabolic pathways to produce ATP while simultaneously shutting down energy-consuming anabolic processes.

AMPK is a heterotrimeric protein kinase consisting of a catalytic (α) subunit and two regulatory (β, γ) subunits. The N-terminus of the subunit contains a typical serine/threonine protein kinase catalytic domain. The C-terminal half of the α subunit contains a region of approximately 150 amino-acid residues at the extreme C-terminus required for association with the β and γ subunits, whereas a region immediately downstream of the catalytic domain appears to have an inhibitory function.19 The β subunit has two conserved domains located in central and C-terminal region. C-terminal region is required to form a functional α β γ complex that is regulated by AMP, whereas the central domain is recognized for a glycogen-binding domain.20, 21 The γ subunits (γ1, γ2 and γ3) contain variable N-terminal regions followed by four tandem repeats of a 60-aa sequence termed as a CBS motif.22 The γ subunit contains four CBS domains, which bind AMP or ATP.23, 24

AMPK activated by increases in adenosine diphosphate (ADP) and AMP signals that the energy state of the cell is compromised. It is active when phosphorylated at T172 on the catalytic (α) subunit. Activation of AMPK by liver kinase B1–mediated25 or calcium–calmodulin-dependent protein kinase, kinase β-mediated26 phosphorylation is increased in the presence of high ratios of AMP/ATP or elevated intracellular calcium, respectively. Binding of ADP and AMP to the γ subunit cause conformational changes that inhibit T172 dephosphorylation and cause further allosteric activation.17

AMPK has been recognized as a key regulator of mammalian metabolic function. Nutrient-regulated diurnal phosphorylation of AMPK substrates in rat livers27 makes AMPK an attractive candidate contributor to peripheral clock entrainment. Biochemical and bioinformatics studies have established the optimal amino-acid sequence context in which phosphorylation by AMPK is likely,28, 29 which has facilitated prediction of novel substrates.

In this review, we will discuss the comprehensive studies on the catalytic activity of AMPK regulating circadian rhythms that affect behavior, energy metabolism and gene expression‎. We seek to further explore the connection among circadian rhythms, AMPK and metabolism.

A connection between circadian rhythms and AMPK

AMPK activation has recently been linked to regulation of the circadian clock, which couples daily light and dark cycles to the control of physiology in a wide variety of tissues and the hypothalamus through tightly coordinated transcriptional programs.30 Several master transcription factors are involved in orchestrating this oscillating network.

The role of AMPK in the phosphorylation and degradation of cryptochrome

In mammals, the maintenance of circadian clock function depends on clock genes and their protein products in autoregulatory transcriptional feedback loops. In an autoregulatory feedback, the cyclic translation of Per and Cry messenger RNA leads to cyclic levels of PER and CRY proteins. These proteins form complexes and accumulate in the nucleus where they inhibit expression‎ of their genes by acting on CLOCK-BMAL1 heterodimers.4

AMPK was shown to regulate the stability of the core clock component CRY1, which acts as energy sensors and can convert nutrient signal to circadian clocks. This process is performed by phosphorylation of CRY1-Ser 71, which stimulates the direct binding of the F-box and leucine-rich repeat protein 3 (FBXL3) to CRY1, targeting it for ubiquitin-mediated degradation.31

The importance of CRY stability for determining the speed of mammalian clocks became apparent when the most prominent mutants identified in each of two forward genetic screens for circadian rhythm perturbation in mice where alleles of the E3 ligase component FBXL332 that catalyzes the polyubiquitination of CRY1 and CRY2 and thus stimulates their proteasomal degradation.33

Previous studies showed that FBXL3 interacts with CRY1 and CRY2, promoting the degradation of both proteins by the ubiquitin/proteasome system, thus contributing to period length determination. Mutation of FBXL3 (C358S or I364T), a component of a SKP1–CUL1–F-box (SCF) E3 ubiquitin ligase complex, results in∼26-h period phenotypes in mice, indicating that FBXL3 has an important role in circadian period determination.34, 35, 36 However, overexpression‎ of CRY1 protein does not lead to period alteration,37 suggesting that the FBXL3 mutation might affect additional clock components.

Thus, loss of AMPK signaling in vivo stabilizes CRYs and disrupts circadian rhythms, consistent with the hypothesis that this pathway contributes to the metabolic control of light-independent peripheral circadian clocks. Given that AMPK is a central regulator of metabolic processes, the rhythmic regulation of AMPK has implications for the circadian regulation of metabolism. Genetic alteration of circadian clocks either ubiquitously38 or in a tissue-specific manner39 elicits dramatic changes in feeding behavior, body weight, running endurance and glucose homeostasis, each of which is also altered by manipulation of AMPK.40, 41, 42, 43, 44, 45 The abilities of AMPK to mediate circadian regulation and of CRY1 to function as a chemical energy sensor suggest a close correlation between metabolic and circadian rhythms (Figure 2).

Figure 2

The regulation of AMP-activated protein kinase (AMPK) on CRY1 and CKIδ/ɛ in circadian clock. AMPK phosphorylates CRY1, leading to its interaction with FBXL3. This process promotes the degradation of both proteins by the ubiquitin/proteasome system, thus contributing to period length determination. AMPK also phosphorylates Ser389 of CKIɛ, resulting in increased CKIɛ activity and degradation of PER2, which lead to shortened period length.

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The role of AMPK in the phosphorylation of Casein kinase I

CKI represents a unique group within the superfamily of serine/threonine-specific protein kinases that is ubiquitously expressed in eukaryotic organisms.46 The molecular weight of mammalian CKI isoforms (α, β, γ1, γ2, γ3, δ and ɛ) varies from 37 kDa (CKI α) to 51 kDa (CKI γ 3). There are highly conserved sequences within their kinase domains in all CKI isoforms, but differ significantly in the length and primary structure of their N-terminal (9–76 aa) and C-terminal non-catalytic domains (24 aa up to more than 200 aa).47, 48

Casein kinases are important modulators of circadian clock function in mammals. A naturally occurring mutation in hamsters (Tau) that causes a long circadian period was determined to be a hypomorphic allele of casein kinase I epsilon (CKIɛ).49 In addition, genetic disruption or pharmacological inhibition of CKIɛ and/or casein kinase I delta (CKIδ) alters both cellular and behavioral circadian rhythms in mice. Casein kinases, preferentially phosphorylate serines located within negatively charged amino-acid sequence motifs and several serines in PER2 (which are conserved in PER1) have been identified as targets of CKI phosphorylation.50 CKI-mediated phosphorylation of PER proteins is a primary determinant of their stability and circadian period.51

AMPK induces a phase advance of circadian expression‎ of clock genes by degrading PER2 through phosphorylating CKIɛ Ser389. AMPK phosphorylates Ser389 of CKIɛ, resulting in increased CKIɛ activity and degradation of PER2, leading to shortened period length (Figure 2).52

PER proteins are progressively phosphorylated and disappear over a circadian day. Numerous studies using biochemical and genetic approaches showed that CKIδ/ɛ phosphorylates PER in vitro and in cultured cells.41, 42, 43 Phosphorylation of PER affects its cellular location and stability.9, 43, 44, 45 In Drosophila, genetic studies have demonstrated that double-time, an ortholog of CKIδ/ɛ, is required for normal phosphorylation and turnover of dPER, and for behavioral circadian rhythms.46, 53 However, in mammals, the known mutations in CKIɛ or CKIδ, including null mutations,51 do not substantially disrupt the molecular oscillator and circadian rhythms to the extent seen in Drosophila mutants carrying the dbtP or dbtAR allele.51, 53, 54 This suggests that the two mammalian enzymes are at least partially redundant, or there are other kinases that can compensate for the loss of CKIδ/ɛ. In mutant mammals carrying mutations in CKIɛ or CKIδ, PER still oscillates in abundance and phosphorylation. Interestingly, a CKIδ null mutation produced more severe phenotypes than did a CKIɛ null mutation, suggesting that they may not be equally redundant.51 In mammalian cells, as in Drosophila, the dominant-negative form of CKI shows that general reduction of CKIδ/ɛ activities results in slower oscillating of circadian rhythms.

Like in Drosophila, the phosphorylation of mammalian PER by CK1δ/ɛ stimulates its degradation. In mammals, the CK1δ/ɛ binding domain and phosphorylation sites of PER proteins have been identified.19 Phosphorylation of PER by CK1δ/ɛ leads to conformational changes and masking of a nuclear localization signal.23 However, CRY proteins form a complex with PER and CK1δ/ɛ and protect PER from degradation that leads to nuclear accumulation of the CRY–PER–CK1δ/ɛ complex.19, 23 This complex inhibits the transcriptional activity of the DNA-bound BMAL1–CLOCK complex, thus the transcription of CRY and PER. It is thought that phosphorylation of different PER proteins by CK1δ/ɛ has additional effects on the regulation of each PER protein. Furthermore, CK1δ/ɛ is able to phosphorylate BMAL1 and CRY proteins thereby modulating the functions of these clock proteins.20

The role of AMPK on SIRT1-mediated regulation in circadian clock

The regulation of gene expression‎ that characterizes circadian physiology is involved in dynamic changes in chromatin transition.55 Activation of clock-controlled genes by CLOCK:BMAL1 is associated with circadian changes in histone modifications at their promoters. CLOCK itself has a role as an enzyme with histone acetyltransferase activity, specifically targeting H3 K9/K14 in the chromatin and also non-histone targets, such as its own partner BMAL1.56 The histone acetyltransferase activity of CLOCK is counterbalanced by silent information regulator 1 (SIRT1), a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent histone deacetylases.57, 58 SIRT1 is a nuclear protein implicated in critical metabolic and physiological processes.

SIRT1 is also involved in the suppression of many age-related diseases such as cancer, Alzheimer’s disease and type 2 diabetes.59 At the cellular level, SIRT1 controls DNA repair and apoptosis, circadian clocks, inflammatory pathways, insulin secretion and mitochondrial biogenesis.60

The reciprocal play between AMPK and SIRT1 is implicated in circadian clock and metabolic state through interacting with each other. AMPK enhances SIRT1 activity through increasing cellular NAMPT expression‎ and nicotinamide adenine dinucleotide levels, leading to inhibition of CLOCK-BMAL1 complex. AMPK-mediated SIRT1 action also activates the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-γ coactivator 1α, PGC-1α and the forkhead box O1, −O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism (Figure 3).61, 62

AMPK가 SIRT1 매개 조절을 통한 생체시계 조절에서의 역할

생체시계 생리학을 특징짓는 유전자 발현 조절은 염색질 전환의 동적 변화와 관련되어 있습니다.55 CLOCK:BMAL1에 의해 조절되는 생체시계 유전자의 활성화는 그 프로모터에서의 히스톤 변형의 생체시계 변화와 연관되어 있습니다. CLOCK 자체는 히스톤 아세틸전달효소 활성을 가진 효소로서, 염색질 내 H3 K9/K14를 특이적으로 표적화하며, 자신의 파트너 BMAL1과 같은 비히스톤 표적도 표적화합니다. 56

CLOCK의 히스톤 아세틸전달효소 활성은 니코틴아미드 아데닌 디뉴클레오티드 의존성 히스톤 탈아세틸화 효소인 시르투인 가족의 일원인 침묵 정보 조절자 1(SIRT1)에 의해 균형을 이룹니다.57, 58 SIRT1은 중요한 대사 및 생리적 과정에 관여하는 핵 단백질입니다.

SIRT1은 암, 알츠하이머 병, 제2형 당뇨병 등 많은 노화 관련 질환의 억제에 관여합니다.59 세포 수준에서 SIRT1은 DNA 복구 및 아포토시스, 생체 시계, 염증 경로, 인슐린 분비, 미토콘드리아 생성에 관여합니다.60

AMPK와 SIRT1 간의 상호작용은

서로 상호작용을 통해 생체 리듬 시계와 대사 상태에 관여합니다.

AMPK는

세포 내 NAMPT 발현과 니코틴아미드 아데닌 디뉴클레오티드 수준을 증가시켜

SIRT1 활성을 증강시키며, 이는 CLOCK-BMAL1 복합체의 억제를 초래합니다.

AMPK에 의한 SIRT1 작용은 과산화체 증식 활성화 수용체-γ 공활성인자 1α(PGC-1α) 및 포크헤드 박스 O1, −O3(FOXO3a) 전사 인자 등 하류 SIRT1 표적의 탈아세틸화 및 활성 조절을 활성화합니다. AMPK에 의해 유도된 SIRT1 매개 탈아세틸화는 AMPK와 SIRT1이 에너지 대사(그림 3)에 미치는 많은 수렴적 생물학적 효과를 설명합니다.61, 62

Figure 3

The mechanism of silent information regulator 1 (SIRT1) on circadian regulation. The reciprocal play between AMP-activated protein kinase and SIRT1 is implicated in circadian clock and metabolic state. AMPK enhances SIRT1 activity through increasing cellular NAMPT expression‎ and nicotinamide adenine dinucleotide (NAD+) levels, leading to inhibition of CLOCK-BMAL1 complex. AMPK-mediated SIRT1 action also activates the deacetylation and modulation of the activity of downstream SIRT1 targets that include the PGC-1α.

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SIRT1 functions as an enzymatic controller of CLOCK function, transducing signals originated by cellular metabolites to the circadian machinery. Targeting SIRT1 with small molecule modulators has been a significant area of interest for several years. The study on the regulation of AMPK for SIRT1 is of importance primarily based on the promise that this approach holds for the discovery of new therapeutic agents for multiple diseases of aging.63, 64

The influence of AMPK on circadian rhythms in metabolisms

The role of AMPK on the effects of energy balance by modulating the palmitate in the hypothalamus

Energy homeostasis of our bodies is under the regulated control of homeostatic hormones, nutrients and the expression‎ of neuropeptides that alter feeding behavior in the hypothalamus.

AMPK has an important role in food intake and energy metabolism because it affects both the central nervous system and peripheral tissues. Many studies show that the activation of the hypothalamic AMPK is involved in the stimulation of food intake and the hypothalamic AMPK activity is increased during fasting and decreased during refeeding.65, 66, 67

Constitutively, active AMPK led to increases in neuropeptide Y (NPY) and agouti-related peptide (AgRP) messenger RNA levels and subsequently caused an increase in the body weight of mice, whereas AMPK inhibition with dominant-negative forms of AMPK prevented increased weight gain and decreased the messenger RNA levels of orexigenic neuropeptides.66 NPY gene expression‎ is controlled by numerous signaling cascades. Phosphatidylinositol 3-kinase (PI3K), MAPK, mammalian target of rapamycin (mTOR) and AMPK have all been implicated in the control of NPY gene expression‎.

It was found that there is a link between excess palmitate concentrations and changes in clock genes and orexigenic neuropeptide messenger RNA levels at the level of a hypothalamic neuron.21 A high-fat diet leads to changes in the expression‎ of circadian behavior and transcripts such as CLOCK, BMAL1 and PER2 in the hypothalamus, liver and fat cells.68 Elevated levels of palmitate, a predominant saturated fatty acid in diet and fatty acid biosynthesis, alter cellular function. It is likely that palmitate-induced signal transduction cascades lead to changes in circadian transcript expression‎ such as an increase in BMAL1 and CLOCK and a decrease in PER2 and Rev-Erbα through AMPK-mediated regulation.

Taken together, AMPK might have a role in the palmitate-mediated regulation of clock genes in addition to regulation of orexigenic neuropeptide NPY in the hypothalamus.

AMPK가 대사 과정의 생체 리듬에 미치는 영향

AMPK가 시상하부에서 팔미테이트 조절을 통해 에너지 균형에 미치는 영향

우리 몸의 에너지 균형은 시상하부에서 식이 행동을 조절하는 호르몬, 영양소 및 신경펩티드의 발현에 의해 조절됩니다.

AMPK는

중추 신경계와 말초 조직 모두에 영향을 미치기 때문에

식이 섭취와 에너지 대사에서 중요한 역할을 합니다.

많은 연구에서 시상하부 AMPK의 활성화가 식이 섭취 자극에 관여하며,

시상하부 AMPK 활성은 금식 시 증가하고

재급식 시 감소한다는 것이 밝혀졌습니다.65, 66, 67

항상 활성화된 AMPK는 신경펩티드 Y (NPY) 및 아구티 관련 펩티드 (AgRP) 메신저 RNA 수준을 증가시켜 쥐의 체중 증가를 유발했으며, 반면 AMPK를 억제하는 우성 음성 형태의 AMPK는 체중 증가를 방지하고 식욕 자극 신경펩티드의 메신저 RNA 수준을 감소시켰습니다.66 NPY 유전자 발현은 다양한 신호 전달 경로에 의해 조절됩니다. 포스파티딜인오실 3-키나제(PI3K), MAPK, 포유류 라파마이신 표적(mTOR) 및 AMPK는 모두 NPY 유전자 발현 조절에 관여하는 것으로 알려져 있습니다.

과도한 팔미테이트 농도와 시상하부 신경세포 수준에서 시계 유전자 및 식욕 자극 신경펩티드 메신저 RNA 수준의 변화 사이에 연관성이 발견되었습니다.21 고지방 식단은 시상하부, 간 및 지방 세포에서 CLOCK, BMAL1 및 PER2와 같은 생체 리듬 행동 및 전사체 발현 변화를 유발합니다. 68 식이 및 지방산 생합성에서 주요 포화 지방산인 팔미테이트의 농도 상승은 세포 기능을 변화시킵니다. 팔미테이트에 의한 신호 전달 경로는 AMPK 매개 조절을 통해 BMAL1 및 CLOCK 발현 증가와 PER2 및 Rev-Erbα 발현 감소와 같은 생체 리듬 전사체 발현 변화를 초래할 가능성이 있습니다.

종합적으로, AMPK는 시상하부에서 식욕 조절 신경펩티드 NPY의 조절 외에도 팔미테이트 매개 시계 유전자 조절에 역할을 할 수 있습니다.

Interplay between AMPK and metformin

Metformin is an important feedback to the circadian clock in the peripheral tissues, synchronizing it to the environmental cues such as food availability.69 Metformin is a commonly-used treatment for type 2 diabetes whose mechanism of action has been linked, in part, to activation of AMPK. However, little is known regarding metformin effect on circadian rhythms.

Metformin leads to increased leptin and decreased glucagon levels.70, 71 The effect of metformin on liver and muscle metabolism similarly leads to AMPK activation either by liver kinase B1 and/or other kinases in the muscle.72 Metformin blocks mitochondria complex I leading to increased NADH levels. An increase of NADH leads to enhanced activity of CLOCK-BMAL1-mediated expression‎. Metformin activates liver CKIα and muscle CKIɛ, leading to CKI-mediated phosphorylation of PER2.73 Growing results show the differential effects of metformin in the liver and muscle and the critical role that the circadian clock has in orchestrating metabolic processes. Those processes might be mediated by AMPK activation through metformin.

Circadian clock and metabolic diseases

Circadian rhythms are integral to the normal functioning of numerous physiological processes. The center of the biological clock exists in the suprachiasmatic nuclei. In addition to this central clock, each organ has its own biological clock system, termed the peripheral clock.

Each cardiovascular tissue or cell, including heart and aortic tissue, cardiomyocyte, vascular smooth muscle cell and vascular endothelial cell also has intrinsic biological rhythm.74, 75 The peripheral clock system within each cardiovascular organ seems to have significant roles during the progression of cardiovascular disorders.76 Loss of synchronization between the internal clock and external stimuli can induce cardiovascular organ damage. Discrepancy in the phases between the central and peripheral clocks also seems to contribute to progression of the disorders.

The important role of CK1δ/ɛ as one of the clock proteins is underlined by the fact that mutations of CK1 or mutations of phosphorylation sites of their substrates are correlated with various diseases.

In mammals, similar defects have been described for a CK1ɛ mutant. Syrian hamsters homozygous for the Tau mutation in the CK1ɛ gene resulting in an exchange of the conserved amino-acid residue 178 (R178C) have a shortened circadian period.10 The reason for this effect could be explained by the dominant-negative features of this CK1ɛ mutant. CK1ɛR178C still associates with PER but its kinase activity is much lower compared to that of wild-type CK1ɛ. As a consequence, PER is hypophosphorylated and more stable. Although CK1δ partly compensates the mutant CK1ɛ, the preserved ratio of CK1ɛ and CK1δ binding to PER proteins still leads to hypophosphorylation of PER, resulting in shortening of the circadian rhythm in hamsters with Tau mutation.77

In humans, a polymorphism of CK1ɛ at the autophosphorylation site serine 408 in which serine is substituted by asparagine (S408N) seems to have a protective role in the development of familiar advanced sleep phase syndrome (FASPS).77 The lack of this autophosphorylation site results in an increased kinase activity of CK1ɛ and an elongation of the circadian rhythm. In addition, substitution of serine with glycine at amino-acid residue 662 within the CK1ɛ binding domain of mPER2, which reduces CK1ɛ-mediated phosphorylation of mPER, is found in FASPS patients.18 Furthermore, the polymorphism V647G of the hPER3 gene affects the CK1δ/ɛ binding site and correlates with delayed sleep phase syndrome (DSPS).77

Conclusion and future perspective

The master circadian oscillators in suprachiasmatic nuclei are principally entrained by the light/dark cycle through the retina stimulation, while pacemakers in peripheral organs, such as liver, are reset by food availability, hormone, metabolic and neuronal signals.

We expect that the communication of nutritional status to clocks is complex and that additional pathways contribute in vivo. The ability of AMPK to respond to metabolic cues and to directly modify circadian clock components suggests that it may be an important mediator of metabolic entrainment in peripheral clocks. AMPK-mediated phosphorylation of CRYs contributes to metabolic entrainment of peripheral clocks. Pharmacological activation of AMPK by intraperitoneal injection of either AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside)31 or metformin52 also caused a phase shift of the liver clock in mice, which suggests a possible ability to entrain the liver clock. These data suggest that AMPK activation may also have a role in circadian entrainment of muscle clocks.78

Genetic alteration of circadian clocks either ubiquitously9, 79 or in a tissue-specific manner39 elicits dramatic changes in feeding behavior, body weight, running endurance and glucose homeostasis, each of which is also altered by manipulation of AMPK.40, 41, 42, 44, 45

There have been many studies of the link between circadian rhythms and metabolism in brain and peripheral organs. The role of AMPK between the circadian clock and metabolism is essential for maintaining metabolic homeostasis and preventing metabolic disorders. The orchestration of circadian rhythms and metabolic regulation is tightly interlocked at both physiological and molecular levels.

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