근육 - myokine, 지방 - adipokine - 장내세균과의 관계

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Gut microbiota and regulation of myokine-adipokine function

Author links open overlay panelFrancesco Suriano 1, Matthias Van Hul 1, Patrice D Cani

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Both skeletal muscle and adipose tissue are considered as endocrine organs due to their ability to produce and secrete several bioactive peptides (e.g. myokines and adipokines). Those bioactive molecules are well known for their capacity to influence whole-body homeostasis and alterations in their production/secretion are contributing to the development of various metabolic disorders. While it is well accepted that changes in the composition and functionality of the gut microbiota are associated with the onset of several pathological disorders (e.g. obesity, diabetes, and cancer), its contribution to the regulation of the myokine-adipokine profile and function remains largely unknown. This review will focus on myokines and adipokines with a special interest on their interaction with the gut microbiota.

골격근과 지방 조직은 

모두 여러 생리활성 펩타이드(예: 마이오카인 및 아디포카인)를 생산하고 분비하는 능력으로 인해 

내분비 기관으로 간주됩니다. 

이러한 생리 활성 분자는 

전신 항상성에 영향을 미치는 것으로 잘 알려져 있으며, 

생산/분비의 변화는 

다양한 대사 장애의 발병에 기여하고 있습니다. 

장내 미생물총의 구성과 기능의 변화가 

여러 병적 장애(예: 비만, 당뇨병, 암)의 발병과 관련이 있다는 사실은 잘 알려져 있지만, 

미오카인-아디포카인 프로파일과 기능 조절에 대한 기여도는 

아직 많이 알려지지 않았습니다. 

이 리뷰에서는 

장내 미생물과의 상호작용에 특별한 관심을 가지고 

마이오카인과 아디포카인에 초점을 맞출 것입니다.

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Current Opinion in Pharmacology 2020, 52:9–17

This review comes from a themed issue on Musculoskeletal

Edited by David M Mutch and David J Dyck

For a complete overview see the Issue and the Editorial

Available online 7th May 2020

https://doi.org/10.1016/j.coph.2020.03.006

1471-4892/© 2020 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

It is now well established that the gut microbiota can influence an individual’s health status. Various underlying mechanisms have been proposed and both direct and indirect mechanisms of action have been described for specific bacterial metabolites, such as short-chain fatty acids (SCFAs), bile acids, branched chain amino acids, indole propionic acid, and endocannabinoids [1]. In addition to bacterial components, many endogenous factors can be influenced by the gut microbiota. Myokines and adipokines, produced and secreted by the skeletal muscles and adipose tissues respectively, may be considered as potential mediators. In this review, we start by introducing myokines and adipokines and then focus on the crosstalk between these molecules and the gut microbiota, taking a particular interest on how they affect metabolic homeostasis of the whole body.

장내 미생물이 

개인의 건강 상태에 영향을 미칠 수 있다는 것은 

이제 잘 알려진 사실입니다. 

다양한 기본 메커니즘이 제안되었으며 

단쇄 지방산(SCFA), 

담즙산, 

분지 사슬 아미노산, 

인돌 

프로피온산, 

엔도카나비노이드와 같은 특정 박테리아 대사 산물에 대한 

직접 및 간접 작용 메커니즘이 

모두 설명되었습니다 [1]. 

박테리아 성분 외에도 

많은 내인성 요인이 장내 미생물에 의해 영향을 받을 수 있습니다. 

골격근과 지방 조직에서 각각 생성 및 분비되는 

마이오카인과 아디포카인이 

잠재적인 매개체로 고려될 수 있습니다. 

이 리뷰에서는 마이오카인과 아디포카인을 소개하는 것으로 시작하여 이러한 분자와 장내 미생물총 사이의 상호 작용에 초점을 맞추고, 특히 전신의 대사 항상성에 어떤 영향을 미치는지에 대해 살펴봅니다.

Myokines

In the body, there are different type of muscles (skeletal, cardiac, smooth), which perform different functions based on their location. They are mainly responsible for maintaining and changing body posture, producing force and motion, generating heat (both through shivering and non-shivering), as well as facilitating movement of internal organs, such as the heart, digestive organs, and blood vessels [2,3]. Skeletal muscle is the largest organ in the human body, accounting for about 30% of body mass in women and 40% in men, though muscle mass is affected by several conditions such as fasting, physical inactivity, cancer, obesity, untreated diabetes, hormonal changes, heart failure, AIDS, chronic obstructive pulmonary disease (COPD), or aging [4]. Skeletal muscle acts as an endocrine organ, as muscle cells, called myocytes, are able to synthesize and release several cytokines and bioactive molecules in response to muscular contraction (major physiological stimulus) and other stimuli (e.g. nutrients, stress, environmental factors, metabolic dysfunction) [2,5]. Interleukin (IL)-6 was the first muscle-secreted protein to be identified in the bloodstream [6]. In contrast to the deleterious effects (e.g. insulin resistance, impaired glucose metabolism) associated with elevated plasma concentration of IL-6 during obesity and diabetes [7], the release of IL-6 after muscle contraction was associated locally (within the muscle) with an increase in glucose uptake and fat oxidation via an activation of AMP-activated protein kinase (AMPK) and/or phosphatidylinositol 3-kinase (PI3-K) [6].These effects are mediated by the binding of IL-6 to its specific transmembrane alpha receptor (ILRα) which form a complex that induces the homodimerization of the glycoprotein (gp)-130 (also known as IL6Rβ) leading to downstream signaling pathways [6]. IL-6 may also act distally. In the liver, it stimulates hepatic glucose production during exercise. In the adipose tissue, it acts as a lipolytic hormone, accelerating free-fatty acids release [6,8]. These beneficial effects of IL-6 highlight the cross talk between skeletal muscle and liver/adipose tissue. IL-6 secreted in response to exercise was also associated to enhance insulin secretion by increasing glucagon-like peptide (GLP)-1 secretion from the intestinal L-cells and the pancreatic alpha-cells [9]. However, the different discrepancies observed for the role of IL-6 on metabolism are still debated. It was also proposed that IL-6 may arbitrate the anti-inflammatory effects of exercise via the inhibition of pro-inflammatory cytokines, like the endotoxin-induced tumor-necrosis factor alpha (TNF-α), and the stimulation of anti-inflammatory cytokines production such as the IL-1 receptor antagonist, IL-10, and the soluble TNF receptor [6,8,10]. More than ten years ago Pedersen et al. suggested that cytokines like IL-6, but also other proteins, that are produced, expressed and secreted by muscle fibers and act as autocrine/paracrine as well as endocrine mediators to perform biological functions should be classified as myokines [6]. Most exert their effects via specific receptors (both transmembrane and nuclear), that are expressed in various tissues and organs (e.g. liver, adipose tissue, brain), thus influencing different metabolic pathways [11, 12, 13]. Several secretome studies performed in vivo (mouse and human), in vitro (mouse and human muscle cell lines) and ex vivo (culturing exercised rats muscle) have let to the characterization and the identification of several myokines secreted by the skeletal muscle [14, 15, 16, 17, 18, 19, 20, 21]. Although the definition is clear, caution is warranted when searching the current literature, as the term ‘myokine’ is often erroneously used to designate all proteins that originate from the skeletal muscle. A recent review has described in detail the proposed myokines and the different methods used for their identification and validation [22]. These include myostatin, IL-8, IL-15, irisin, fibroblast growth factor (FGF) 21, myonectin (also known as CTRP15), brain-derived neutrophic factor (BDNF), decorin, meteorin-like (Metrnl)-1, musculin, secreted protein acidic and rich in cysteine (SPARC) [23,24]. IL-8 and BDNF primarily exert their effects in autocrine and/or paracrine manner, and are involved in angiogenesis and AMPK-mediated fatty acid oxidation respectively. Others act either locally (autocrine and paracrine) or distally (endocrine), thereby being involved in the regulation of several metabolic pathways (e.g. regulation of the skeletal muscle growth, body weight regulation, energy homeostasis, glucose homeostasis, brown-fat-like development, systemic lipid homeostasis, hypertrophy and myogenesis) [23,24]. As the field is still relatively new, the myokine family is expected to grow as research continues.

신체에는 다양한 유형의 근육(골격근, 심장근, 평활근)이 있으며, 위치에 따라 다른 기능을 수행합니다. 골격근은 주로 몸의 자세를 유지 및 변화시키고, 힘과 움직임을 생성하며, 열을 발생(떨림과 비 떨림 모두)하고, 심장, 소화기관, 혈관과 같은 내부 장기의 움직임을 촉진하는 역할을 담당합니다[2,3]. 골격근은 인체에서 가장 큰 기관으로 여성의 경우 체중의 약 30%, 남성의 경우 40%를 차지하지만 근육량은 금식, 신체 활동 부족, 암, 비만, 치료되지 않은 당뇨병, 호르몬 변화, 심부전, 에이즈, 만성 폐쇄성 폐질환(COPD) 또는 노화와 같은 여러 조건에 의해 영향을 받습니다[4]. 

골격근은 

근세포라고 하는 근육 세포가 

근육 수축(주요 생리적 자극) 및 

기타 자극(예: 영양소, 스트레스, 환경 요인, 대사 기능 장애)에 반응하여 

여러 사이토카인과 생리 활성 분자를 합성 및 방출할 수 있으므로 

내분비 기관으로 작용합니다[2,5]. 

인터루킨(IL)-6은 

혈류에서 최초로 확인된 근육 분비 단백질입니다[6]. 

비만과 당뇨병에서 

IL-6의 혈장 농도 상승과 관련된 해로운 영향(예: 인슐린 저항성, 포도당 대사 장애)과 달리[7], 

근육 수축 후 IL-6의 방출은 

국소적으로(근육 내) AMP 활성화 단백질 키나제(AMPK) 및/또는 

포스파티딜이노시톨 3-kinase(PI3-K)의 활성화를 통한 

포도당 흡수 및 지방 산화의 증가와 관련이 있었습니다[6]. 

이러한 효과는

 IL-6가 특정 막 통과 알파 수용체(ILRα)와 결합하여 

복합체를 형성함으로써 매개되며, 

이는 당단백질(gp)-130(IL6Rβ라고도 함)의 동이합체화를 유도하여 

하류 신호 경로로 이어집니다[6]. 

IL-6는 

원위적으로도 작용할 수 있습니다. 

간에서는 

운동 중 간 포도당 생성을 자극합니다. 

지방 조직에서는 

지방 분해 호르몬으로 작용하여 

유리 지방산 방출을 촉진합니다[6,8]. 

이러한 

IL-6의 유익한 효과는 

골격근과 간/지방 조직 간의 상호 작용을 강조합니다. 

운동에 반응하여 분비되는 IL-6는 

장 L세포와 췌장 알파세포에서 글루카곤 유사 펩타이드(GLP)-1 분비를 증가시켜 

인슐린 분비를 촉진하는 것과도 관련이 있습니다 [9]. 그러나 신진대사에 대한 IL-6의 역할에 대해서는 여전히 여러 가지 의견이 분분합니다. 

또한 IL-6는 

내독소 유발 종양괴사인자 알파(TNF-α)와 같은 

전 염증성 사이토카인의 억제와 

IL-1 수용체 길항제, IL-10 및 수용성 TNF 수용체와 같은 항염증성 사이토카인 생성의 자극을 통해 

운동의 항염증 효과를 중재할 수 있다고 제안되었습니다 [6,8,10]. 

10여 년 전 Pedersen 등은 

근육 섬유에서 생성, 발현 및 분비되고 

내분비 매개체뿐만 아니라 자율신경/파라크린으로 작용하여 

생물학적 기능을 수행하는 IL-6와 같은 사이토카인과 

다른 단백질도 마이오카인으로 분류해야 한다고 제안했습니다[6]. 

대부분은 다양한 조직과 기관(예: 간, 지방 조직, 뇌)에서 발현되는 특정 수용체(막 통과 및 핵 모두)를 통해 효과를 발휘하여 다양한 대사 경로에 영향을 미칩니다[11, 12, 13]. 생체 내(마우스 및 인간), 시험관 내(마우스 및 인간 근육 세포주), 생체 외(운동한 쥐 근육 배양)에서 수행된 여러 세크레톰 연구를 통해 골격근에서 분비되는 여러 마이오카인의 특성 및 동정을 확인할 수 있었습니다[14, 15, 16, 17, 18, 19, 20, 21]. 

정의는 명확하지만 '마이오카인'이라는 용어가 골격근에서 유래하는 모든 단백질을 지칭하는 데 잘못 사용되는 경우가 많으므로 현재 문헌을 검색할 때는 주의가 필요합니다. 최근 리뷰에서 제안된 마이오카인과 그 식별 및 검증에 사용되는 다양한 방법에 대해 자세히 설명했습니다 [22]. 

여기에는 

미오스타틴, 

IL-8, IL-15, 

이리신, 

섬유아세포 성장인자(FGF) 21, 

미오넥틴(CTRP15라고도 함), 

뇌 유래 호중구 인자(BDNF), 

데코린, 

메테오린 유사(Metrnl)-1, 

무스뮤린, 분

비 단백질 산성 및 시스테인 풍부(SPARC) [23,24] 등이 포함됩니다. 

IL-8과 BDNF는 

주로 자율신경 및/또는 파라크린 방식으로 그 효과를 발휘하며, 

각각 혈관 신생과 AMPK 매개 지방산 산화에 관여합니다. 

다른 물질들은 국소적으로(자율신경 및 파라크린) 또는 

원위적으로(내분비) 작용하여 

여러 대사 경로(예: 골격근 성장 조절, 체중 조절, 에너지 항상성, 포도당 항상성, 갈색 지방 유사체 발달, 전신 지질 항상성, 비대 및 근생성)의 조절에 관여합니다[23,24].

이 분야는 아직 비교적 새로운 분야이므로 연구가 계속 진행됨에 따라 마이오카인 계열은 더욱 확대될 것으로 예상됩니다.

Although, a link between immune changes and skeletal muscle contractile activity (exercise) has been proposed almost 20 years ago [25], possible mechanisms are not yet fully deciphered. Recent data suggest that exercise and its variables (volume, intensity, density) influence the myokine profile production [26], and that certain myokines (e.g. IL-6) lie at the basis of the reduction in the production of pro-inflammatory cytokines (e.g. TNF-α and IL-1β), thereby contributing to reduced systemic inflammation, eventually leading to a decreased risk of developing insulin resistance and type 2 diabetes [27]. Additionally, myokines, such as BDNF, IL-6, IL-13, IL-15, Irisin, and FGF21, are known to exert an important role in mediating the health-promoting effects of regular physical activity through their ability to affect lipid and glucose metabolism [27]. Of note, many myokines (e.g. IL-6, TNF-α and myostatin) are also produced by the adipose tissue and are therefore referred to as adipo-myokines. They are thought to be involved in the interplay between adipose tissue and skeletal muscle [28]. In 2013, Raschke and Eckel [29], described the interplay between adipo-myokines as two sides of the same coin. This description refers to their ability to exert beneficial or adverse effect on the target tissue depending on their circulating concentrations. A more recent study in mice revealed that Metrnl, another adipo-myokine, is a critical regulator of muscle regeneration that acts directly on immune cells (e.g. macrophages) to promote an anti-inflammatory/pro-regenerative environment and myogenesis. These effects were explained by the ability of Metrnl to signals directly to macrophages via a signal transducer and activator of transcription (Stat)-3-dependent mechanism, while activating muscle cells (e.g. satellite cells) proliferation indirectly through macrophages-induced insulin-like growth factor (IGF)-1 secretion [30••,31]. Although, both myokines and adipokines have autocrine, paracrine, and endocrine effects within their corresponding tissues and their target tissues, two different classification standards are needed. Given that skeletal muscle tissue is the largest tissue present in our body in a physiological healthy status, an alteration in the lean muscle mass/fat mass ratio can be considered an important element in the alteration of the adipokine-myokine profile in addition to being a predictor of insulin resistance and metabolic syndrome. We assume that this is the main reason for which myokines and adipokines cannot be classified under the same standard.

면역 변화와 골격근 수축 활동(운동) 사이의 연관성은 

거의 20년 전에 제안되었지만[25], 

가능한 메커니즘은 아직 완전히 해독되지 않았습니다. 

최근 데이터에 따르면 

운동과 그 변수(운동량, 강도, 밀도)가 

마이오카인 프로파일 생성에 영향을 미치며[26], 

특정 마이오카인(예: IL-6)이 전 염증성 사이토카인(예: TNF-α 및 IL-1β)의 생산을 감소시켜 

전신 염증 감소에 기여하여 

결국 인슐린 저항성과 

제2형 당뇨병 발병 위험을 낮추는 것으로 나타났습니다[27]. 

또한 

BDNF, IL-6, IL-13, IL-15, 이리신, FGF21과 같은 마이오카인은 

지질 및 포도당 대사에 영향을 미치는 능력을 통해 

규칙적인 신체 활동의 건강 증진 효과를 매개하는 데 

중요한 역할을 하는 것으로 알려져 있습니다 [27]. 

특히 

많은 마이오카인(예: IL-6, TNF-α, 미오스타틴)은 

지방 조직에서도 생성되므로 

아디포-마이오카인이라고 불립니다. 

이들은 지방 조직과 골격근 사이의 상호 작용에 관여하는 것으로 생각됩니다 [28]. 

2013년에 라쉬케와 에켈[29]은 

아디포-마이오카인의 상호 작용을 

동전의 양면과 같다고 설명했습니다. 

이 설명은 

순환하는 농도에 따라 

표적 조직에 유익하거나 악영향을 미칠 수 있는 능력을 말합니다. 

최근 생쥐를 대상으로 한 연구에서는 또 다른 아디포마이오카인인 Metrnl이 근육 재생의 중요한 조절자로서 면역 세포(대식세포 등)에 직접 작용하여 항염증/친재생 환경과 근육 생성을 촉진한다는 사실이 밝혀졌습니다. 

이러한 효과는 신호 변환기 및 전사 활성화제(Stat)-3 의존적 메커니즘을 통해 대식세포에 직접 신호를 보내는 Metrnl의 능력과 대식세포 유도 인슐린 유사 성장 인자(IGF)-1 분비를 통해 간접적으로 근육 세포(예: 위성 세포) 증식을 활성화하는 것으로 설명됩니다[30--,31]. 

마이오카인과 아디포카인은 

모두 해당 조직과 표적 조직 내에서 

자율신경, 

파라크린 및 

내분비 효과를 나타내지만, 

두 가지 다른 분류 기준이 필요합니다. 

골격근 조직이 생리적으로 건강한 상태에서 우리 몸에 존재하는 가장 큰 조직이라는 점을 고려할 때, 제지방량/지방량 비율의 변화는 인슐린 저항성과 대사 증후군의 예측 인자 외에도 아디포카인-마이오카인 프로파일의 변화에서 중요한 요소로 간주될 수 있습니다. 이것이 바로 마이오카인과 아디포카인을 동일한 기준으로 분류할 수 없는 주된 이유라고 생각합니다.

Adipokines

The adipose tissue has long been regarded as an inert tissue that stores and releases energy under the form of lipids. This view has changed dramatically following new insights into the dynamics of this metabolically active organ. It is now well accepted that the adipose tissue also serves as an important endocrine organ capable of synthesizing a wide variety of biologically active compounds that regulate whole body homeostasis [32]. These bioactive peptides, referred to as adipokines, can act either locally as autocrine and paracrine factors or systemically as endocrine factors, and they have been implicated in the regulation of several metabolic pathways [32]. Already in 1987, Siiteri suggested that adipose tissue had an endocrine function, based on its capacity to interconvert steroid hormones [33]. Later in 1994, the discovery that the adipokine leptin was able to signal the energy status of the periphery to the central nervous system was the major breakthrough confirm‎ing the adipose tissue as a crucial endocrine organ [34]. In the years that followed, the adipose tissue secretome was characterized in depth by several proteomic profiling approaches [35,36]. To date, more than 600 secretory proteins have been identified within the adipose tissue, but it is expected that this number could still increase as the adipose tissue secretome is further characterized [35]. Not all these proteins are adipokines secreted by adipocytes, as many factors originate from the non-adipocyte matrix of adipose tissue composed of connective tissue matrix, nerve tissue, stromovascular cells, and immune cells [37,38]. Leptin, adiponectin, resistin, chemerin, visfatin, vaspin, apelin, omentin, and hundreds more adipokines have been studied and characterized for their main actions [32]. Local (autocrine and paracrine) actions of adipokines (e.g. adiponectin, chemerin, IL-6, TNF-α) include regulation of adipogenesis, adipocyte metabolism, immune cells migration, and insulin sensitivity. Systemic (endocrine) effects of adipokines such as leptin, adiponectin, resistin, chemerin, and apelin involve the modulation and regulation of different biological processes such as glucose metabolism, insulin secretion, inflammation, blood pressure, cardiomyocyte contraction, lipid metabolism, appetite, and satiety [32]. Like myokines, adipokines exert their effects through the activation of specific receptors that can be both transmembrane or nuclear proteins [32].

지방 조직은 

오랫동안 지질 형태로 에너지를 저장하고 방출하는 

불활성 조직으로 여겨져 왔습니다. 

이러한 관점은 이 신진대사 활동 기관의 역학에 대한 새로운 통찰력을 얻으면서 극적으로 바뀌었습니다. 

이제 

지방 조직은 

전신 항상성을 조절하는 

다양한 생물학적 활성 화합물을 합성할 수 있는 중요한 

내분비 기관으로도 작용한다는 사실이 잘 알려져 있습니다[32]. 

아디포카인이라고 하는 이러한 생리활성 펩타이드는 

국소적으로 자율신경 및 부신피질 호르몬으로 작용하거나 

전신적으로 내분비 호르몬으로 작용할 수 있으며, 

여러 대사 경로의 조절에 관여하는 것으로 알려져 있습니다 [32]. 

이미 1987년에 Siiteri는 지방 조직이 스테로이드 호르몬을 상호 전환하는 능력을 바탕으로 내분비 기능을 가지고 있다고 제안했습니다[33]. 

이후 1994년, 

아디포카인 렙틴이 

말초의 에너지 상태를 

중추신경계에 전달할 수 있다는 사실이 밝혀지면서 

지방 조직이 중요한 내분비 기관임을 확인하는 

획기적인 발견이 이루어졌습니다[34]. 

그 후 몇 년 동안 지방 조직 분비물은 

여러 가지 단백질체 프로파일링 접근법을 통해 

심층적으로 특성화되었습니다 [35,36]. 

현재까지 지방 조직 내에서 

600개 이상의 분비 단백질이 확인되었지만, 

지방 조직 분비체가 추가로 특성화됨에 따라 

이 수는 계속 늘어날 것으로 예상됩니다 [35]. 

많은 인자가 

결합 조직 기질, 

신경 조직, 

기질 혈관 세포 및 면역 세포로 구성된 

지방 조직의 비지방 세포 기질에서 유래하기 때문에 

이러한 단백질이 모두 지방 세포에서 분비되는 아디포카인은 아닙니다 [37,38]. 

렙틴, 

아디포넥틴, 

레지스틴, 

체메린, 

비스파틴, 

바스핀, 

아펠린, 

오멘틴 및 

수백 가지 이상의 아디포카인이 연구되고 

주요 작용에 대한 특징이 밝혀졌습니다[32]. 

아디포카인(예: 아디포넥틴, 체메린, IL-6, TNF-α)의 국소(자율신경 및 파라크린) 작용에는 

지방 형성, 지방 세포 대사, 면역 세포 이동 및 인슐린 감수성 조절이 포함됩니다. 

렙틴, 아디포넥틴, 레지스틴, 체메린, 아펠린과 같은 

아디포카인의 전신(내분비) 효과는 

포도당 대사, 인슐린 분비, 염증, 혈압, 심근세포 수축, 지질 대사, 식욕 및 포만감과 같은 

다양한 생물학적 과정의 조절과 조절에 관여합니다[32]. 

마이오카인과 마찬가지로 

아디포카인은 막 통과 단백질 또는 

핵 단백질일 수 있는 특정 수용체의 활성화를 통해 

그 효과를 발휘합니다[32].

In accordance with anatomical location, the adipose tissues can generally be divided into two main depots: visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT). Taking into account phenotype, functional role, and gene expression‎ profile, they can be further classified as either white, brown or beige [39]. The adipose tissue secretome is not ubiquitous, but is depot-specific and it is strongly influenced by systemic and local components associated with inflammation, insulin resistance, obesity and more [40]. Further adding to the complexity, the different adipose tissues expresse a plethora of receptors (both transmembrane and nuclear) to integrate and respond to the afferent signals from the periphery and the central nervous system [37,41]. It is this complex intrinsic network of receptors and ligands that enable the different adipose tissues to be implicated in the regulation of many biological processes such as energy metabolism, neuroendocrine function, and immune function [37,41]. It is therefore not surprising that a dysregulation of this signaling balance between periphery and adipose tissue is associated with the onset of several pathologies. For example, the adverse metabolic consequences of adipose tissue excess which occur during obesity can disrupt the normal production/function of several adipokines, and the altered adipokines profile maybe partially explain the link between obesity and inflammation, metabolic and cardiovascular comorbidities [42]. However, the underlying mechanisms that connect adipokines and obesity-related inflammation and metabolism are still not clearly understood [43]. Interestingly, several studies (in vivo and in vitro) have highlighted the role of certain adipokines (leptin, resistin, adiponectin, visfatin) in mediating the cross talk between skeletal muscle and adipose tissue in the context of insulin sensitivity through their ability to affect insulin signaling pathways, glucose transporter 4 (GLUT-4) translocation and modulate insulin-mediated skeletal muscle glucose uptake [44]. An important limitation of those type of studies is the use of cells derived from rodent skeletal muscle, which are characterized by a different fiber type composition and metabolic characteristics as compared to human skeletal muscle [44]. Of note, the negative effects of certain pro-inflammatory adipokines [e.g. TNF-α, monocyte chemoattractant protein-1 (MCP-1) also known as CCl2] secreted abundantly during metabolic disorders can to some extent be counterbalanced by the protective properties of skeletal muscle-secreted peptides [8]. As described for the myokines, growing evidence highlight that physical activity may partly exerts its beneficial effects via alterations in the adipokine profile through an increase in the secretion of anti-inflammatory adipokines and reduction in pro-inflammatory adipokines [45].

해부학적 위치에 따라 지방 조직은 

일반적으로 내장 지방 조직(VAT)과 

피하 지방 조직(SAT)의 두 가지 주요 저장소로 나눌 수 있습니다. 

표현형, 기능적 역할 및 유전자 발현 프로필을 고려하여 

백색, 갈색 또는 베이지색으로 더 분류할 수 있습니다 [39]. 

지방 조직 분비물은 어디에나 존재하는 것이 아니라

 저장소 특이적이며 

염증, 인슐린 저항성, 비만 등과 관련된 전

신 및 국소 구성 요소의 영향을 많이 받습니다 [40]. 

복잡성을 더욱 가중시키는 것은 

다양한 지방 조직이 

수많은 수용체(막 통과 및 핵 모두)를 발현하여 

말초 및 중추 신경계의 구심성 신호를 통합하고 

이에 반응한다는 점입니다[37,41]. 

다양한 지방 조직이 

에너지 대사, 신경 내분비 기능 및 면역 기능과 같은 

많은 생물학적 과정의 조절에 관여할 수 있는 것은 

이러한 복잡한 수용체와 리간드의 내재적 네트워크입니다 [37,41]. 

따라서 

말초와 지방 조직 사이의 이러한 신호 균형의 조절 장애가 

여러 병리의 발병과 관련이 있다는 것은 놀라운 일이 아닙니다. 

예를 들어, 

비만 중에 발생하는 지방 조직 과잉의 불리한 대사 결과는 

여러 아디포카인의 정상적인 생산/기능을 방해할 수 있으며,

 변화된 아디포카인 프로필은 

비만과 염증, 대사 및 심혈관 동반 질환 사이의 연관성을 부분적으로 설명할 수 있습니다 [42]. 

그러나 아디포카인과 비만 관련 염증 및 대사를 연결하는 

근본적인 메커니즘은 

아직 명확하게 이해되지 않았습니다 [43]. 

흥미롭게도 

여러 연구(생체 내 및 시험관 내)에서는 

인슐린 신호 전달 경로, 포도당 수송체 4(GLUT-4) 전위에 영향을 미치고 

인슐린 매개 골격근 포도당 흡수를 조절하는 능력을 통해 

인슐린 감수성의 맥락에서 골격근과 지방 조직 간의 교차 대화를 중재하는

 특정 아디포카인(렙틴, 레지스틴, 아디포넥틴, 비스파틴)의 역할을 강조하고 있습니다[44]. 

이러한 유형의 연구에서 중요한 한계는 설치류 골격근에서 유래한 세포를 사용한다는 점인데, 이는 인간 골격근과 다른 섬유 유형 구성과 대사 특성이 특징입니다 [44]. 특히, 대사 장애 중에 많이 분비되는 특정 염증성 아디포카인[예: TNF-α, CCl2라고도 알려진 단핵구 화학 유인 단백질-1(MCP-1)]의 부정적인 영향은 골격근 분비 펩타이드의 보호 특성으로 어느 정도 상쇄될 수 있습니다[8]. 마이오카인에 대해 설명한 것처럼, 신체 활동이 항염증성 아디포카인의 분비 증가와 전염증성 아디포카인의 감소를 통해 아디포카인 프로필의 변화를 통해 부분적으로 유익한 효과를 발휘할 수 있다는 증거가 점점 더 많아지고 있습니다 [45].

Gut microbiota: link to the myokine-adipokine function?

Besides the well described effects of exercise and nutrients on the development of the adipose tissue and muscles, the role of gut bacteria is becoming more and more described in the literature. Indeed, the tremendous number of bacteria that are living in our gastrointestinal tract are dialoguing not only directly with our intestinal epithelial cells but also indirectly with different organs at distance from the gut [1]. Therefore, we propose that the gut microbiota could be one of the neglected environmental factors implicated in the regulation of the myokine-adipokine profile. How the gut microbiota affects myokine-adipokine production and/or function is still poorly understood. However, a connection between microbes and myokines-adipokines may be found in the well-known ability of the gut microbiota and their resulting metabolites to affect different host metabolic pathways [46,47].

A growing body of evidence suggests that alterations in the composition and/or function of the gut microbiota during pathological conditions, sometimes referred to as ‘dysbiosis’, play a key role in the onset of several metabolic disorders that include obesity, type 2 diabetes, liver disease, but also cancer and even neurological disorders [48]. Changes in the gut microbiota composition have been linked to gut barrier dysfunction (e.g. reduced mucus layer thickness, disruption of the tight junction proteins, decreased secretion of antimicrobial peptides) (Figure 1), leading to the translocation of pathogen associated molecular patterns (PAMPs) able to induce an abnormal host immune response and low-grade inflammation [48] (Figure 1). Modifications in bile acids profiles, decreased secretion of gut peptides, and lower production of short chain fatty acids (SCFAs) and higher levels of branched-chain amino acids have also been observed during dysbiosis [49]. Given the important contribution of the gut microbiota in maintaining a good state of health and well-being, its modulation is considered an important tool to prevent or treat dysbiosis associated-metabolic disorders [1].

운동과 영양소가 

지방 조직과 근육 발달에 미치는 영향은 잘 알려져 있지만, 

장내 박테리아의 역할은 

문헌에 점점 더 많이 기술되고 있습니다. 

실제로 

위장관에 서식하는 엄청난 수의 박테리아는 

장 상피 세포와 직접적으로 소통할 뿐만 아니라 

장에서 멀리 떨어진 다른 기관과도 간접적으로 소통하고 있습니다[1]. 

따라서 

장내 미생물이 

마이오카인-아디포카인 프로파일의 조절에 관여하는 

무시된 환경 요인 중 하나가 될 수 있다고 제안합니다. 

장내 미생물이 

마이오카인-아디포카인 생산 및/또는 기능에 어떻게 영향을 미치는지는 

아직 잘 알려져 있지 않습니다. 

그러나 

미생물과 미오카인-아디포카인 사이의 연관성은 

장내 미생물과 그 결과 대사 산물이 다양한 숙주 대사 경로에 영향을 미치는 잘 알려진 능력에서 찾을 수 있습니다 [46,47].

병리학적인 상태에서 

장내 미생물총의 구성 및/또는 기능의 변화(때때로 'dysbiosis'라고도 함)가 

비만, 제2형 당뇨병, 간 질환뿐만 아니라 

암, 심지어 신경 장애를 포함한 

여러 대사 장애의 발병에 중요한 역할을 한다는 증거가 점점 더 많이 제시되고 있습니다 [48]. 

장내 미생물 구성의 변화는 

장 장벽 기능 장애(예: 점액층 두께 감소, 

긴밀한 접합 단백질의 파괴, 항균 펩타이드 분비 감소)와 관련이 있으며(그림 1), 

이로 인해 병원체 관련 분자 패턴(PAMP)의 위치가 이동하여 

비정상적인 숙주 면역 반응과 저급 염증을 유발할 수 있습니다[48](그림 1). 

담즙산 프로필의 변화, 

장내 펩타이드 분비 감소, 

단쇄 지방산(SCFA) 생산 감소 및 

분지 사슬 아미노산 수준 증가도 이상 생물체증 동안 관찰되었습니다 [49]. 

장내 미생물이 건강과 웰빙 상태를 유지하는 데 중요한 기여를 한다는 점을 고려할 때, 장내 미생물의 조절은 장내 미생물과 관련된 대사 장애를 예방하거나 치료하는 데 중요한 도구로 간주됩니다 [1].

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Figure 1. Link between gut microbiota and myokine-adipokine function. Schematic illustration of the several factors influencing the gut microbiota composition and how the gut microbiota and its derived metabolites have an important role in the control of the gut barrier function, bacterial compounds translocation, metabolic functions, and myokine-adipokine production. Although the link between gut microbiota and myokine-adipokine function is still unclear. AMPK, AMP-activated protein kinase; GLP-1, glucagon-like peptide-1; PYY, peptide YY; PAMPs, pathogen associated molecular patterns; SCFAs, short-chain fatty acids.

Several endogenous and exogenous factors affect the gut microbiota composition (e.g. diet, physical activity, antibiotics, genetic background) [1] (Figure 1). Among the different strategies that have been proposed to beneficially modulate the gut microbiota, dietary interventions, including supplementation with prebiotics (a substrate that is selectively utilized by host microorganisms conferring a health benefit, i.e. certain fibers and polyphenols) [50] and/or probiotics (live microorganism that, when administered in adequate amounts, improve host health) are considered the most feasible and efficient [49].

There are several mechanisms by which the microbiota can regulate host metabolism and health, many of which can be traced back to microbial metabolites [1]. Among these bacterial metabolites are the SCFAs that are produced by bacterial fermentation of indigestible foods (i.e. dietary source of polyphenols and complex carbohydrates) in the gastrointestinal tract (Figure 1) [51,52]. SCFAs bind to specific G protein coupled receptors (GPCRs) (i.e. GPR41 and GPR43), and the resulting activation of those receptors triggers the release of glucagon-like peptides (GLP-1 and GLP-2) and peptide YY (PYY) (Figure 1) which are involved in the control of energy homeostasis, fat storage, improvement of the gut barrier function, metabolic inflammation, glucose metabolism, and gut transit time [51]. Metabolites coming from polyphenols are able to activate AMPK via phosphorylation and modulating some proteins involved in adipogenesis, lipogenesis, and lipolysis in different tissues [52] (Figure 1).

Bile acids are also strongly influenced by the microbiota. Indeed, primary bile acids are converted in secondary bile acids via microbial modification in the gut [53]. While, primary bile acids are synthesized in the liver and are secreted in the duodenum where they emulsify ingested fats to be solubilized for digestion and absorption, they are also able to bind to specific receptors (i.e. TGR5 and FXR) expressed in the intestinal cells (Figure 1). TGR5 is a GPCR expressed on the enteroendocrine L-cells and its activation induces the secretion of GLP-1 and improves liver function and glucose tolerance in obese mice [54], whereas farnesoid X receptor (FXR) is a nuclear receptor that plays a key role in maintaining glucose tolerance and insulin sensitivity in a different manner than that observed for the enteroendocrine regulation [55]. A few studies on rodents have also described the role of primary bile acids supplementation in the modulation of the gut microbiota and their ability to influence serum level of adiponectin [56,57].

In 2007, we were the first to demonstrate that mice fed a high-fat diet develop a pro-inflammatory phenotype closely associated with an increase in the circulating levels of lipopolysaccharides (LPS), an endotoxin found on the cell membranes of Gram-negative bacteria. This condition was defined as metabolic endotoxemia [58]. Once in circulation, LPS reaches several organs including liver, adipose tissue and muscle where it perturbates their normal metabolism and participates in the onset and progression of inflammatory and metabolic diseases (Figure 1) [59]. Increases in circulating LPS have also been described in humans after a high-fat meal, with even worse effects in obese individuals [60]. Besides LPS, other PAMPs have been associated with a causal role on the regulation of similar metabolic pathways (Figure 1) [49].

Many other studies provide evidence for a causal role of the gut microbiota in metabolic regulation. For example, the pioneering work by Backhed et al. [61] was the first to show that germ-free mice (mice lacking a gut microbiota) were characterized by a lower fat mass and that colonizing these germ-free mice by transplanting a gut microbiota, induced increased fat mass together with higher production of leptin [62]. In 2008, Membrez et al. [63] described that mice treated with a cocktail of antibiotics were characterized by a lower fat mass and higher circulating levels of adiponectin. These data were in accordance with the findings that eradicating the vast majority of the gut microbiota in mice by using antibiotics and, at the same time, feeding them with a high-fat diet reduced low-grade inflammation, slowed fat mass development and improved insulin sensitivity [64]. Inversely to the leptin levels, the adiponectin levels are drastically decreased during obesity and low levels of adiponectin anticipate the development of diabetes and cardiovascular diseases [65,66]. During obesity, the altered adipokine secretion profile is also characterized by a high secretion of pro-inflammatory adipokines such as MCP-1, TNF-α and IL-6, which participates to the diabetic pathogenesis [65]. Mice having a genetic deficiency in the ob gene that codes for leptin (mutant ob/ob mice) are characterized by an altered gut microbiota and are severally obese with higher fat mass and lower muscles mass [67]. We discovered that changing the microbiota by using prebiotics (i.e. oligofructose) was associated with a lower fat mass, but a higher muscle mass [67]. In addition to the modulation of the gut microbiota composition, we and others have also shown that prebiotic feeding in rodents increased the number of L-cells in the distal part of the small intestine (jejunum) as well as in the lower part of the large intestine (proximal colon), and boosted the production and the release of the active form GLP-1, GLP-2, and PYY in the portal vein (for review Ref. [47]). As described above, SCFAs and bile acids are among the metabolites able to induce the release of those gut peptides (Figure 1). We also found that prebiotics are able to restore leptin sensitivity in high-fat diet-induced obese and diabetic rodents, thereby suggesting that the microbiota could be targeted to restore appropriate production of different adipokines [68]. Along these lines, it has been shown that mice lacking Myd88 specifically in the intestinal epithelial cells displayed significantly lower leptin levels when exposed to a high-fat diet as well as a lower resistin level, an adipokine involved in the development of insulin resistance [69]. Altogether, this set of data strongly suggest that the gut microbiota plays a major role in the regulation of different adipokines and that this is tightly associated with the activity of the innate immune system in the gut.

Of note, not all obese people develop metabolic comorbidities and some remain ‘metabolically healthy’. Klöting et al. [70] demonstrated that ‘healthy’ obese individuals had higher insulin-sensitive adiponectin levels than obese insulin-resistant subjects associated with a lower inflammatory tone and a reduced adipose-tissue macrophages infiltration. Beside the direct link between obesity and changes in the adipokine profile, so far, there is not yet evidence showing that this profile is modulated independently of fat mass changes. However, we hypothesize that targeting the adipose tissue via a modulation of the gut microbiota may represent a novel strategy to modulate the adipokine profile (e.g. increase of ‘beneficial’ adipokines such as the adiponectin).

In addition to prebiotics, probiotics have also been shown to be beneficial on aspects of obesity, steatosis, and insulin resistance. In this context, the next-generation beneficial bacterium, Akkermansia muciniphila, a mucin degrading bacterium that resides in the mucus layer (Figure 1) is gaining much attention. This bacterium is naturally present in the human digestive tract in large quantities (up to 3–5%) but decreases significantly with obesity and several other diseases [71]. Because of its health-promoting potential, it has been the focus of many recent studies. In mice, our group was the first to describe its ability to delay the development of diet-induced obesity and insulin resistance, namely via the modulation of the energy homeostasis and restoration of the gut barrier function (e.g. increase in the mucus layer thickness) (Figure 1) [72,73•,74•]. The abundance of A. muciniphila was also associated with higher L-cell activity (e.g. GLP-1 and GLP-2 secretion) which has been hypothesized as a key mechanisms by which this bacterium improves the gut barrier function and reduce metabolic endotoxemia [67,68]. In humans, a placebo-controlled study in overweight/obese insulin-resistant volunteers confirmed that supplementation with A. muciniphila could prevent the worsening of several metabolic parameters [75•].

The important role of the gut microbiota in tuning the host muscle metabolism in response to dietary and environmental changes, was further demonstrated by recent experimental animal studies. Lahiri et al. [76••] observed that germ-free mice displayed reduced muscle mass and signs of muscle atrophy with reduced muscle strength. They hypothesized that microbes and their metabolites, such as SCFAs, regulate skeletal muscle mass and function. Treating germ-free mice with a cocktail of SCFAs (a mix of acetate, butyrate and propionate) resulted in a reduced expression‎ of Atrogin-1 and an increased expression‎ of myoblast determinant protein 1 (MyoD), two key muscle genes associated with muscle atrophy and muscle differentiation respectively, and could partly restore muscle strength. Virtue et al. [77••] showed how tryptophan-derived metabolites produced by the gut microbiota controlled the expression‎ of specific microRNAs in white adipocytes in mice to regulate energy expenditure and insulin sensitivity.

Whether alteration in the composition and functionality of the gut microbiota can also be associated with modulation in the myokine-adipokine profile and function is a plausible, but little explored possibility (Figure 1). As briefly mentioned above, physical activity plays a key role in the modulation of the myokine-adipokine profile. Additionally, a recent, and elegant human and animal study demonstrated that physical activity can significantly impact on the composition of the gut microbiota and induce changes in the production of SCFAs, γ-aminobutyric acid, and branched-chain amino acids, thereby conferring metabolic benefits on glucose homeostasis and insulin sensitization in peripheral tissues [78•]. A study in elite rugby players showed that athletes have a greater gut microbial diversity compared to sedentary individuals [79•]. Interestingly, rugby players also had a high abundance of the species A. muciniphila [79•].

When it comes to the effects of exercise, duration and intensity of the physical activity are two important factors affecting the metabolism of several organs and tissues [80]. Although normal physical activity is considered to be beneficial for general health, extensive and prolonged exercise (endurance training) has been associated with an increase in intestinal permeability, compromising gut barrier function and resulting in the translocation of bacterial cell wall components such as LPS (Figure 1) [81,82]. This may ultimately lead to a transient state of inflammation which could potentially affect the myokine-adipokine profile. However, further studies are required to validate this hypothesis. Another way that the gut microbiota could affect host metabolism, is by chemically interacting with host cells and regulating gene expression‎ via epigenetic events such as DNA methyltransferases, DNA hydroxylases, histone acetyltransferases, histone deacetylases and histone methyltransferases. These effectors are mediated by gut derived metabolites such as SCFAs, particularly acetate and butyrate [83]. Since SCFAs are produced by fermentation of indigestible carbohydrates, this would be in agreement with studies reporting how dietary factors act on epigenetic pathways [84]. Interestingly, physical activity itself has also been associated with epigenetic adaptations, that are translated into gene-specific regulation of inflammatory and metabolic processes in human skeletal muscle under condition of high-fat diet [85•].

Although it is evident from the literature that the gut microbiota has the capacity to change the profile of myokines and adipokines, it is less clear whether this interaction is bidirectional: can myokines/adipokines modulate gut microbiota composition? In a recent review, Andrews et al. [86] described that different cytokines and chemokines can exert either positive or negative effects on the intestinal epithelial barrier integrity. For example, TNFα, interferon-γ, and other interleukins can alter tight junction morphology and may indirectly impact on gut microbial communities, as studies have shown that disruption of the gut barrier permeability impacts on the intestinal microbiome [87,88••]. It is therefore possible that myokines and adipokines can exert similar effects.

Conclusion

Taken together these findings suggest a close connection between diet, physical activity, gut microbiota, bacterial metabolites, gut barrier function, inflammation, and the regulation of the myokine-adipokine function. The identification of novel mediators and a better understanding of how these processes are linked mechanistically may eventually result in the discovery of new potential therapeutic strategies in the prevention of metabolic disorders. In particular, nutritional and non-nutritional strategies that target the gut microbiota, thereby modifying the profile of myokines and adipokines, may be of great importance.

Conflict of interest statement

P.D.C. is inventor of patent applications dealing with the use of Akkermansia muciniphila and its components in the context of obesity and related disorders. P.D.C. is co-founder of A-Mansia Biotech SA.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

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CRediT authorship contribution statement

Francesco Suriano: Conceptualization, Methodology, Writing - original draft, Writing - review & editing. Matthias Van Hul: Conceptualization, Methodology, Writing - original draft, Writing - review & editing. Patrice D Cani: Conceptualization, Methodology, Supervision, Funding acquisition, Writing - original draft, Writing - review & editing.

Acknowledgements

PDC is a senior research associate at FRS-FNRS (Fonds de la Recherche Scientifique), Belgium. He is supported by the Fonds Baillet Latour (Grant for Medical Research 2015), the Fonds de la Recherche Scientifique (FNRS, FRFS-WELBIO: WELBIO-CR-2019C-02R, and EOS program no.30770923).

References

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