Obesity Regulation through Gut Microbiota Modulation and Adipose Tissue Browning

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Obesity Regulation through Gut Microbiota Modulation and Adipose Tissue Browning

Yejin Cho¹, Rahman Md. Shamim^2,3 and Yong-Sik Kim^1,2,3*

1College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, Korea

2Department of Microbiology, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, Korea

3Institute of Tissue Regeneration, College of Medicine, Soonchunhyang University, Cheonan, Chung-nam 31151, Korea Received July 11, 2019 /Revised July 29, 2019 /Accepted August 5, 2019

Obesity, represented by abnormal fat accumulation due to an imbalance between energy intake and expenditure, is a major public health issue worldwide, leading to multiple noncommunicable diseases, including atherosclerosis, hypertension, type 2 diabetes, and cancer. Diverse solutions have been pro- posed to combat obesity. Attention has focused on two types of adipose tissues as a promising therapeutic target in obesity: traditional brown and beige or brite. Unlike energy-storing white adipose (endocrine) tissue, traditional brown adipose tissue and beige adipose tissue have energy-dissipating thermogenic properties. Both types of tissue are present in adult humans and inducible through ex- ternal stimuli, such as cold exposure, β3-adrenergic receptor agonists, and phytochemicals. Among these stimuli, microbiota present in the human intestinal tract participate in multiple metabolic activities. Modulation of gut microbiota may offer a potent and possibly curative strategy against various metabolic diseases. Numerous studies have focused on the effects of established antiobesity treatments on the gut microenvironment or brown-adipose-tissue activation. In this review, we focus main- ly on stimuli known to alleviate obesity, weight gain, and metabolic diseases, in addition to known and possible inter-relations between gut microbiota modulation and similar interventions and adipose tissue browning. The findings may pave the way toward new strategies against obesity.

Key words : Brown adipose tissue, gut microbiota, obesity, thermogenesis, Ucp1

*Corresponding author

*Tel : +82-41-570-2413, Fax : +82-41-575-2412

*E-mail : [email protected]

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

ISSN (Print) 1225-9918 ISSN (Online) 2287-3406 Journal of Life Science 2019 Vol. 29. No. 8. 922~940 DOI : https://doi.org/10.5352/JLS.2019.29.8.922

Introduction

Obesity is usually represented by anomalous or inordi- nate fat accumulation that can harm one’s health, and is thought to result from an upset energy balance owing to either overabundant energy intake or deficient energy expenditure [49]. It has been receiving increasing attention as a major global issue of public health. If obesity is roughly defined as a body–mass index (BMI) of 30 or over and overweight as a BMI of 25 or higher, then more than 1.9 billion adults and 124 million children and adolescents were obese or overweight in 2016, which means that the obese pop- ulation has almost tripled since 1975[90]. Given that obesity is tightly linked with multiple chronic noncommunicable diseases including diabetes, cancers, and cardiovascular and

musculoskeletal disorders [89], innumerable societal and bi- omedical efforts have been applied to the fight against obesity.

Although the primary intervention for patients with obesity is aimed at lifestyle changes including diet, behavioral patterns, and physical activity, those who find this approach ineffective have relied upon medication, medical devices, and surgical interventions [56]. Pharmacotherapy with a lifestyle intervention contributes to weight loss, but the efficacy often ceases after discontinuation of the medication [9].

Bariatric surgery impressively reduces body weight and alleviates the comorbidities of obesity (especially of extreme obesity), yet the financial burden and serious risks to health hinder its widespread clinical application [92]. Medical devices with minimal invasiveness have been approved for short-time use, and the weight loss persists after their removal; however, the device use is limited to patients without active gastric diseases, nonsteroidal anti-inflammatory drug use, or previous gastric surgical procedures [56]. Thus, sus- tainable noninvasive remedies with fewer adverse effects have been pursued.

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White, Brown, and Beige Adipose Tissues

Three distinct types of mammalian adipose tissue have been found so far: white, brown, and beige (or brite, brown- in-white). White adipose tissue (WAT), which has tradition- ally been the best-known type of adipose tissue, is currently thought to be an active endocrine organ (secreting proteins and steroid hormones) rather than a mere energy repository [58]. On the other hand, two types of major thermogenic adipose tissues—brown and beige—dissipate energy, usually in the form of heat, as uncoupling protein 1 (UCP1) uncouples anion flow or the oxidative phosphorylation pathway from ATP synthesis [112]. “Classical” brown-adipocyte development starts prenatally in dermomyotomes, and transdifferentiation into brown adipocytes is known to be irreversible in vivo after the commitment phase; by contrast, beige adipocytes have inducible and reversible traits: tempo- rary expression of thermogenic attributes depending on ex- ternal stimuli such as cold acclimation, tissue injury, and prolonged treatment with PPARγ (peroxisome proliferator- activated receptor γ) or β3-adrenergic receptor agonists [51, 130]. This formation of UCP1-rich thermogenic adipocytes in white adipose depots is referred to as browning [19].

Previously, brown adipose tissues (BATs) have been thought to be present and practically useful in small mam- mals and infants, whereas adult human brown adipocytes have been thought to merely exist or manifest hardly any activity [47]. Nevertheless, significant brown adipose depots have been revealed to be present in adult humans [123], especially more frequently among lean people [120]. Further- more, human thermogenic adipose activity has been found to be inducible by such stimuli as cold exposure, dietary polyphenol consumption, stimulation of the sympathetic nervous system, β-adrenergic receptor agonists, and combi- nations of the above-mentioned factors [13, 26, 87, 110, 120].

Such findings have led to a paradigm shift in the remedies for obesity and for associated metabolic disorders: from traditional quantitative changes in adipose tissue to the induction of a thermogenic brown or beige adipose tissue.

Numerous measures were explored recently to promote brown adipose thermogenesis, including irisin and thyroid hormone induction, β3-adrenergic receptor agonists, thiazo- lidinediones, and phytochemicals [11, 12, 117, 126]. Among such browning stimuli, in this review, we will focus on the effects of the gut microbiota.

The Gut Microbiota as a Modulator of Human Metab- olism

Trillions of microbial cells coexist with human host cells, especially within intestines, and engage in numerous pro- tective, structural, and metabolic activities. The gut microbiome interacts with the host similarly to the way a complex endocrine organ does, thereby 1) affecting distant organs and systems by the release of metabolic products into the circulation and 2) being affected by hormonal signals se- creted by the host. Hence, it is suggested that the gut microbiota—at least in part—is causally linked to major metabolic disorders including obesity [24]. When the microbiotas of subjects that have received browning-inducing stimuli are transplanted to germ-free recipients, the browning of WAT and activation of BAT strengthen in the recipients [115].

Such findings suggest that the gut microbiota is responsible for the transdifferentiation of adipocytes and controls thermogenic functions (Fig. 1). Thus, modulation of the gut microbiota through dietary manipulation, exposure to a lower temperature, or probiotic or nutraceutical supplements may be promising antiobesity treatments.

Probiotics and Prebiotics Are Expected to Promote Adipocyte Browning

Firmicutes and Bacteroidetes are the most dominant taxa of the human gut microbiota, although some elusive but significant variations are present across different human pop- ulations [16]. Bifidobacterium and Lactobacillus are the most extensively utilized bacterial genera because of various probiotic properties [104]. Thus, they are currently promising candidates for a browning inducer. Accumulated data on probiotic and synbiotic interventions into obesity and metabolic diseases back up the potential therapeutic effects of the intestinal microbiota (Table 1). Lactobacillus reuteri 263, a probiotic strain known to alleviate renal fibrosis and insulin resistance, has been found to upregulate thermogenesis in WAT; to induce the expression of browning-related genes, including Ucp1, Pparγ, Prdm16, Pgc1α, Bmp7, and Fgf21; and to upregulate mitochondrial respiration in WAT [21].

There are documented cases where supplements reversed the changes in the gut microbiota composition caused by genetically or nutritionally induced obesity (Table 2). Li et al. have demonstrated that fucosylated chondroitin sulfate, a sulfated polysaccharide in the sea cucumber Isostichopus badionotus, normalizes multiple metabolic-syndrome–re- lated indices [65]. An et al. have reported that cordycepin,

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Fig. 1. Effects of gut microbiota on the differentiation into brown adipocytes. In response to thermogenic stimuli, preadipocytes differentiated by bone morphogenetic proteins (BMPs) [118, 124] show browning and the following changes. Activation of brown preadipocytes and beiging of white adipocytes are promoted by transcription factors including Pparγ, Prdm16 (PR domain–containing 16), and Pgc1α (Pparγ-coactivator 1α), concomitantly with mitochondrial biogenesis genes represented by Ucp1. BAT: Brown adipose tissue; MSC: Mesenchymal stem cell.

a major active ingredient of Cordyceps militaris, attenuates an increase in fat mass and body weight and reverses the gut microbiome alteration induced by a high-fat diet [7].

Decreased ambient temperature, in concert with Ucp1 induction, changes gut microbiome composition to suppress diet-induced obesity [136]. Concretely speaking, the most well-pronounced microbiota alterations after such antiobesity manipulations are downregulated Firmicutes and upregulated Bacteroidetes. On the other hand, type 2 diabetes mellitus (T2DM) patients and mice with high-fat diet–

induced obesity have shown a lower proportion of Firmi- cutes and a higher relative abundance of Bacteroidetes in the gut microbiota, with additional upregulation of gut Proteobacteria in T2DM patients [7, 104]. Thus, the phylum ratio of Firmicutes to Bacteroidetes is deemed to be worth further studies for the promotion of energy expenditure and WAT browning. Still, the specific correlation between the intestinal microflora and reduced body weight gain were left for further studies.

Bacterial Metabolites That Are Expected to Promote Adipocyte Browning

The gut microbiota ferments indigestible dietary fiber and produces diverse metabolites, mostly consisting of short-

chain fatty acids (SCFAs) as final byproducts [72]. Most SCFAs found in human intestines are acetate (C2), propionate (C3), and butyrate (C4) [25]. SCFAs act as the signals from the microbiota, thereby affecting host fatty-acid, sugar, and cholesterol metabolic pathways; promoting fatty acid ca- tabolism; and suppressing fat accumulation in adipose tissue and gluconeogenesis in the liver [24, 31].

Kong et al. have found that high-calorie diets can alter the gut microbiota by making it less diverse and more enriched with obesity-related genera, which partly contribute to the weight gain and metabolic disorders. Additionally, these diets can suppress SCFA-producing bacteria [62]. It is widely known that probiotics improve the gut microenvironment by neutralizing the high-calorie diet-induced proinflammatory bacteria [33, 70]. Fecal fermentation products of dietary fiber derived from common beans (Phaseolus vulgaris) hinder the expression of some transcription factors critical for adipogenesis, PPARγ and C/EBPα, thereby hampering adipocytic differentiation in its early stage [69]. Nonetheless, the fermentation product increases the expression of other transcription factors, PPARδ and UCP2, which induce adipocyte energy expenditure [69]. Because various types of dietary fiber are foods for the hindgut microbiota, the composition of consumed fiber affects the composition of the gut

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Fig. 2. Mechanisms of known antiobesity interventions intended to modify human metabolism and centered on gut microbiota modulation. BCoAT: Butyryl-CoA: acetate coenzyme A-transferase; DIO2: Type 2 deiodinase; GPR43: G-protein-coupled receptor 43; IL-6: Interleukin 6; LPS: Lipopolysaccharide; mmdA: Methylmalonyl-CoA decarboxylase; SCFA: Short chain fatty acid; TGR5 (GPBAR1): G protein-coupled bile acid receptor 1; TNF-α: Tumor necrosis factor-alpha.

microbiota, resulting in different types of SCFAs [69].

Cholic acids have been demonstrated to promote Ucp1- dependent thermogenesis and formation of multilocular lipid droplets and to suppress diet-induced weight gain under thermoneutrality in mice [137]. The composition of secon- dary bile acids is modified differently, depending on the gut microbiota, and greatly affects the cholesterol level [54, 113].

The microbiota profile induced by a high-fat diet drastically raises serum levels of cholesterols and triglycerides, and the profile of serum parameters is normalized by simvastatin, a drug known to decrease low-density lipoprotein cholesterol and prevent cardiovascular diseases [46]. The attenuation of the hypolipidemic effect of simvastatin by an induced gut microbiota alteration is believed to be related to the regulation of bile acid synthesis from cholesterol [46]. Neverthe- less, those authors could not ascertain whether this effect is primarily triggered by downregulation of gram-positive bacteria, upregulation of gram-negative bacteria, or a combination.

Lifestyle Changes Inducing Adipose Browning and Microbiota Modulation

Caloric restriction where intake of necessary nutrients is guaranteed restrains body weight gain, recovers insulin sensitivity, and promotes browning of white fat depots, con-

currently with modification of the gut microbiota [36, 37].

The caloric-restriction-induced microbiota is believed to decrease blood lipopolysaccharide levels by downregulating major enzymes through suppression of Kdo2-lipid A biosynthesis and the lipid A-Ara4N pathway, and to hinder bacterial lipopolysaccharide biosynthesis [36]. The alteration of the intestinal microenvironment, concurrent with the above properties, is deemed to be the chief cause of such metabolic alterations including improved glucose tolerance and insulin sensitivity.

It has been well established that physical exercise can also alter the human gut microbiota positively although the effect of physical activity on BAT activation is less remarkable.

Allen et al. have demonstrated that exercise leads to the in- duction of SCFA-regulating genes BCoAT (butyryl-CoA: ace- tate coenzyme A-transferase) and MmdA (methylmalonyl- CoA decarboxylase) and increases fecal SCFA concentration in lean people [4]. Exercise changes butyrate-regulating bac- terial groups, with upregulation of Roseburia spp., Lachnospira spp., Clostridiales spp., Faecalibacterium spp., and Lachnospi- raceae spp. and downregulation of Bacteroides spp. and Rikenella spp., especially in lean subjects [4]. These changes, however, are rolled back after a washout period returning to a sedentary lifestyle [4]. In rodent studies, exercise was found to induce subcutaneous WAT beiging, but the under-

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lying mechanism and applicability to humans are not yet clear [32]. The conclusions of rodent and human studies have been inconsistent, but moderate physical activity tends to not raise BAT thermogenic activity.

Conclusion

In this review, we covered antiobesity interventions that normalize metabolism by manipulating the gut microbiota and promoting thermogenesis in adipose depots (Fig. 2).

Nevertheless, because the idea of inducing browning as a countermeasure against obesity and metabolic disorders came to the fore only recently, there is still a lot to be dis- covered about the underlying mechanisms. In addition, the attributes of different fat depots and the inter-relations among adipose tissues and other organs are important for the practical application of microbiota-based techniques to a clinical human antiobesity program and require further research. The effects of identical treatments can be different, or even opposite, depending on such factors as sex, the loca- tion of fat depots, and the BMI of the subjects [4, 135]. The causal relations must also be thoroughly examined: the pos- sibility that a common cause of a microbial change and of browning promotion exists—or the causality has been un- derstood reversely—should never be ignored [83]. Thus, ex- tensive preclinical and clinical trials are needed to determine proper ways to introduce specific phyla of the gut microbiota into a human recipient without adverse effects or inter- ference by the patient’s existing normal microflora, and to guarantee the effectiveness of such treatments.

Acknowledgement

This research was supported by the research fund of Soonchunhyang University.

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초록：장내 미생물의 조절과 지방세포의 갈색지방화를 통한 비만 조절 연구

조예진¹․라만 엠디 샤밈^2,3․김용식^1,2,3*

(¹순천향대학교 의과대학 의학과, ²순천향대학교 의과대학 미생물학교실, ³순천향대학교 의과대학 조직재생연구소)

비만은 에너지 섭취와 소비의 불균형으로 인해 유발되는 비정상적인 지방 축적으로, 근래에 다양한 만성질환을 초래하는 주요 국제 보건 문제로 부상하였다. 이러한 이유로, 비만 문제에 대한 여러 해결책들이 제시되고 있다.

에너지를 저장하며 내분비 작용을 하는 백색 지방과 달리 열을 생성하여 에너지를 발산하는 두 종류의 지방조직 인 갈색 지방과 베이지색 지방이 성인에 존재하며 외부 자극에 의해 유도될 수 있다는 것이 밝혀진 이래로, 이들 은 비만 치료의 유망한 표적으로서 각광받고 있다. 이러한 외부 자극 중, 인간 장관계에서 인간과 공존하는 장내 미생물총은 다양한 대사 작용에 참여하며, 이를 조절하는 것이 여러 대사 질환의 치료에 유력한 작용을 할 것으로 보인다. 따라서, 다양한 연구에서 항비만 치료가 장내 미생물 환경 전환이나 갈색 지방 조직 활성화에 미치는 영 향에 초점을 맞추고 있다. 본 총설에서는 비만과 체중 증가, 대사 질환을 해소하는 것으로 알려진 자극과, 장내 미생물총의 변화나 갈색지방의 활성화를 야기하는 자극과, 이 자극들과 장내 미생물총의 조작, 지방조직의 갈색화 사이에서 알려져 있거나 있을 수 있는 상관관계를 중점적으로 다루고자 한다.

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Physiol. Endocrinol. Metab. 310, E346-354.