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Review

Regulation of body fat mass by the gut microbiota: Possible mediation by the brain Erik Schéle a , Louise Grahnemo b , Fredrik Anesten a , Anna Hallén b,c , Fredrik Bäckhed b,c,∗ , John-Olov Jansson a,∗ a

Institute of Neuroscience and Physiology/Endocrinology, The Sahlgrenska Academy at the University of Gothenburg, S-413 45 Gothenburg, Sweden The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, The Sahlgrenska Academy at the University of Gothenburg, S-413 45 Gothenburg, Sweden c Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark b

a r t i c l e

i n f o

Article history: Received 16 January 2015 Received in revised form 27 March 2015 Accepted 31 March 2015 Available online xxx

a b s t r a c t New insight suggests gut microbiota as a component in energy balance. However, the underlying mechanisms by which gut microbiota can impact metabolic regulation is unclear. A recent study from our lab shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. In this article we will review this study further. © 2015 Published by Elsevier Inc.

Keywords: Obesity Gut microbiota BDNF GLP-1

Contents Gut microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Obesity and gut microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Possible mechanisms of metabolic signaling by gut microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Bariatric surgery and gut microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 The brain as a regulator of energy balance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 BDNF in central energy balance regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Central BDNF in germ free and conventionally raised mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 GLP-1 in central energy balance regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Central GLP-1 in germ free and conventionally raised mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

∗ Corresponding author at: The Sahlgrenska Academy at the University of Gothenburg, Institute of Neuroscience and Physiology/Endocrinology, S-413 45 Göteborg, Sweden. Tel.: +46 31 3427833/+46 31 786 3526; fax: +46 31 7863840. E-mail addresses: [email protected] (F. Bäckhed), [email protected] (J.-O. Jansson). http://dx.doi.org/10.1016/j.peptides.2015.03.027 0196-9781/© 2015 Published by Elsevier Inc.

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Gut microbiota Our gastrointestinal tract is first colonized by microbiota during and short after birth. At first infants are mainly exposed to microbes that originate from the mother. The complexity of the gut microbiota gradually increases, and after 3 year of age the gut microbiota resembles that of an adult [33]. In adulthood the gut microbiota outnumber our own cells by 10 fold and our own genes by 1000 fold. The gut microbiota has therefore often been referred to as “the forgotten organ” [18,42,45]. The human gut microbiota is a complex community including the life forms bacteria and archaea, but dominated by bacteria mainly from the phyla Firmicutes and Bacteroidetes [45,63]. A conserved microbial core is shared among individuals, but in addition each person has a distinct and variable part of gut microbiota [45]. During health, the composition of gut microbiota remains relatively stable and balanced, whilst it has been suggested that rupture of this balance, dysbiosis, can be associated with the susceptibility to disease [39]. In addition to disease, antibiotics could cause dysbiosis. Clostridium difficile infection could, for example, emerge from antibiotic treatment linked to gut microbiota imbalance [1]. Recurrent C. difficile infection has been difficult to treat but interestingly, recent studies have shown symptom resolution after fecal transplantation from healthy donors [1]. This highlights the importance of a balanced gut microbiota for health. Diet is another major contributing factor for the regulation of gut microbiota, as long-term dietary habits have profound effect on human gut microbiota composition [14]. Studies of populations with distinct dietary habits have shown that gut microbiota composition change accordingly to their main macro nutrient ingested, and often the composition is optimized for maximal energy extraction from that particular macro nutrient [14]. In fact, gut microbiota have a symbiotic relationship with its host, providing aid with digestion in exchange for nutrients and a favorable environment. The effect of gut microbiota on host physiology is not limited to the gastrointestinal tract. Emerging evidence suggest that gut microbiota could influence the central nervous system (CNS) [48]. Several studies show that gut microbiota may induce anxiety, improve memory and promote pain perception [4,17,22,35,50,72], all typically regulated by the CNS. Furthermore, gut microbiota may protect against stress by inhibiting the hypothalamic–pituitary–adrenal (HPA) axis [59].

Obesity and gut microbiota Obesity and its associated diseases are now among our most serious public health threats. Recently, there has been a growing interest in a completely new explanation for obesity, the influence by gut microbiota [6,7]. New insight suggests that gut microbiota is an integral component of energy balance, and can be regarded as an organ that contributes to efficient energy metabolism [61,65]. The germ free mouse, that completely lacks gut microbiota, is a common model to study the interplay between gut microbiota and metabolism. Total lack of microbiota is a non-physiological condition, and it is nonspecific in its nature. However, it has proven to be a good model for understanding the most constitutive functions of gut microbiota. In addition, data from alternative models such as probiotic- or antibiotic treatment could be problematic to interpret due to the immense complexity of gut microbiota, as well as our so far unsatisfactory knowledge of its constituents and their interrelations. Studies on germ free mice clearly show that gut microbiota increase adiposity and impair glucose metabolism in the host (Fig. 1) [6,8,47]. Remarkably, the host fat mass in mice with gut microbiota is increased despite decreased food intake [6]. In humans, obesity is associated with reduced microbial diversity

Fig. 1. Gut microbiota is introduced at birth through normal colonization in conventionally raised mice. At birth and at 6 weeks of age conventionally raised mice have equal fat mass as germ free mice, which completely lack gut microbiota. At 12–14 weeks of age conventionally raised mice have significantly more fat mass than germ free mice. At both 6 weeks of age (see also Figs. 2 and 3) and 12–14 weeks of age brain-derived neurotrophic factor (BDNF) and glucagon-like peptide 1 (GLP-1) expression in the hypothalamus and brainstem is lower in normal conventionally raised mice [56], raising the possibility that impaired BDNF and/or GLP-1 signaling could contribute to the fat mass inducing effects of gut microbiota.

in the gut [63], including decreased levels of the bacteria phylum Bacteroidetes in favor of the phylum Firmicutes [29]. Several studies have shown that gut microbiota is altered also in patients with type 2 diabetes (T2D) [25,27,46]. Genomic data from gut microbiota has even been proposed to have a better predictive value than body mass index in separating T2D subjects from controls [25]. Moreover, gut microbiota composition is altered in response to changes in the relative intake of dietary fat versus carbohydrates, as well as in response to total energy intake [29]. Thus, the gut microbiota may be important in metabolic regulation in humans. However, these studies do not separate cause and consequence; can alteration in microbial composition cause obesity or is altered gut microbiota simply a consequence of already developed obesity? Experiments in which lean germ free mice gain more body weight upon transplanted gut microbiota from an obese donor than from a lean donor, support the view that gut microbiota actually do contribute to the development of adiposity in the host [62]. Similarly, through fecal transplantation, gut microbiota from a lean donors was associated with an improved glucose homeostasis, lipid metabolism and insulin sensitivity in patients with metabolic syndrome [71]. Possible mechanisms of metabolic signaling by gut microbiota The underlying mechanisms by which gut microbiota can impact upon metabolic regulation are unclear. It could be explained, at least in part, by the fact that gut microbiota increase the capacity to harvest and store energy [61]. Germ free rats have reduced levels of intestinal short-chain fatty acids (SCFA), the end product of gut microbiota fermented carbohydrates, and higher levels of calories in their excretion indicating that their ability to harvest energy from food is impaired [24,70]. Different microbiota compositions are more or less effective in fermenting carbohydrates resulting in variable amounts of SCFAs [53]. In addition, fecal microbiota from obese humans has an overall better capacity to harvest energy [63]. Germ free mice have lower levels of stored triglycerides in the liver and increased intestinal expression of fasting-induced adipose factor (Fiaf or ANGPTL4), an inhibitor of cellular triglyceride uptake [6,7,67]. The activation of

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AMP-activated protein kinase, which senses cellular energy status, is also increased in colonic epithelial cells and liver of germ free mice indicting that these cells are deprived of sufficient energy supply [7,15]. Gut microbiota, through the above mentioned SCFAs, has been shown to protect against inflammation and to modulate the release of gut hormones from enteroendocrine cells such as glucagon-like peptide 1 (GLP-1) and (3-36) peptide YY ((3-36) PYY), possibly through binding of SCFAs to the G-protein-coupled receptors GPR41 and GPR43 [34,54,60]. In germ free mice, GLP-1 levels are elevated which slows intestinal transit, allowing for greater nutrition absorption [68]. Bariatric surgery and gut microbiota To date, the most effective treatment of severe obesity is bariatric surgery [58], where Roux-en-Y gastric bypass (RYGB) is the most common procedure. Interestingly, RYGB drastically improves glucose metabolism, even prior to weight loss [51]. RYGB also results in an altered composition of the gut microbiota, and it has been suggested that changes in gut microbiota composition could contribute to the improved glucose metabolism after RYGB surgery, possibly through modulated bile acid levels and induced farsenoid-X receptor (FXR) signaling in the host [31,52]. The brain as a regulator of energy balance To better understand how the gut microbiota impact on energy balance, we need to better understand how it communicates with and regulates brain centers critical for energy homeostasis, such as the brain stem and hypothalamus [21,57]. These parts of the brain receive information about the nutritional status from the body, in particular from adipose tissue, about nutrient storage and from the gastrointestinal tract about feeding status and nutrients [21,57]. Leptin, which is produced by adipocytes in relation to adipose tissue mass, is a key factor influencing hypothalamic nuclei, in particular the arcuate nucleus, to suppress fat mass. Within the arcuate nucleus leptin suppresses fat mass by binding to its receptor on neurons that express neuropeptide Y (NPY) and agouti-related protein (AgRP), and on neurons that express pro-opiomelanocortin (POMC) and cocaine and amphetamine regulated transcript (CART). Neurons that express NPY and AgRP are inhibited by leptin while neurons that express POMC and CART are stimulated. NPY and AgRP promote feeding and decrease energy expenditure, while the POMC derivative ␣-melanocortin stimulating hormone (␣-MSH), and CART exhibit anorectic effects. Thus, the influence of leptin on the hypothalamus results in the suppression of fat mass via parallel effects on several types of neurons [16,57]. The gut is in close contact with the CNS through endocrine (e.g. ghrelin, peptide-YY and glucagon-like peptode-1) and nervous routes. These routes signal in relation to both food content and nutritional status of the gut [16,37,57]. Ghrelin, for example, is produced by the stomach and increase before a meal, and fall after a meal [13]. Ghrelin has been showed to increase food intake, likely by activating neurons that express NPY and AgRP [10,66]. In addition to hypothalamic nuclei, signals from the gut reach the brainstem nuclei nucleus of the solitary tract (NTS), a relay site for both rostrally and caudally directed transmission involved in energy balance regulation [21]. Therefore, there is a close communication between the gut and energy balance regulating sites of the brain. This is mediated by enteroendocrine hormones such as ghrelin, (3-36) PYY and GLP-1 as well as by the vagus nerve. Despite this, there has been very little information about how the gut microbiota, the second major component of the gut lumen besides food, impacts upon the hypothalamus and brain stem in relation to energy balance control.

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BDNF in central energy balance regulation Brain-derived neurotrophic factor (BDNF) expression in the brain could have a connection with gut microbiota, as discussed below [56]. BDNF is a member of the neurotrophin family. The neurotrophins are important contributors to the formation and modulation of neuronal wiring through the influence on neuronal survival, differentiation, synapse formation and plasticity [9]. Both BDNF and the BDNF receptor, tropomyosin related kinase B (TrkB), are widely distributed throughout various brain sites, including hypothalamic nuclei and the NTS in the brainstem [12,73,74]. Some enrichment of BDNF has been observed in the ventromedial hypothalamus [41]. Most BDNF signaling may be assigned to paracrine and autocrine activity, since often both BDNF and TrkB are localized to the same discrete brain regions or even found on the same neurons [36]. However, not all sites that express TrkB express BDNF, indicating possible trans-regional BDNF signaling activity [74]. Growing evidence suggests BDNF to be important for the CNS regulation of energy balance. Chronic central injection of BDNF to rats results in decreased food intake and reduced body weight [44]. Moreover, transgenic mice with reduced levels of either BDNF or TrkB, or total ablation of brain specific BDNF, have increased food intake and subsequent obesity [32,49,73]. In humans, mutation in the TrkB gene or loss of function of BDNF allele is associated with hyperphagia and obesity [20,75]. Selective deletion of BDNF in the ventromedial hypothalamus (VMH) and dorsomedial hypothalamus (DMH) of adult mice results in increased food intake and obesity [65]. Furthermore, food restriction causes a drastic reduction in BDNF mRNA expression in the VMH, and reduction of BDNF protein in the dorsal vagal complex DVC of the brainstem, while no regulation of BDNF was observed in the cerebral cortex [2,73]. Thus, BDNF in the VMH and the DVC are most likely selectively important targets for its effects in energy balance regulation. BDNF in the VMH is induced by circulating leptin [26]. Still, BDNF neurons in the VMH do not express leptin receptors, suggesting a mediator acting downstream of leptin that induces BDNF production [30]. A likely candidate is ␣-MSH, as activation of its receptor melanocortin-4 receptor (MC4R) increase the expression of BDNF in the VMH and DVC, and as it is activated by leptin [3,73]. The rodent BDNF gene has nine exons, with solely the ninth exon containing coding region. Upon transcription, several unique transcripts with different 5 UTRs and 3 UTRs can be generated depending on where on the untranslated regions the transcription is initiated and ended. The various transcripts all encode the same BDNF protein, but are expressed differentially throughout neural development, at different sites of the CNS, and respond differently upon stimulation [41].

Central BDNF in germ free and conventionally raised mice A recent study from our research group shows, for the first time, a link between gut microbiota and energy balance circuitries in the hypothalamus and brainstem. We found that the expression of the gene coding for the anti-obesity peptide BDNF was decreased in the hypothalamus and brain stem of adult conventionally raised mice with gut microbiota compared to germ free mice [56]. We suggest that the decreased expression of BDNF contributes to increased fat mass in conventionally raised mice compared to germ free mice. This is supported by our observation that BDNF expression in the hypothalamus is decreased already in young conventionally raised mice with equal fat mass as germ free mice (Fig. 2). The higher fat mass in older conventionally raised mice results in higher serum leptin and higher ␣-MSH expression in

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Fig. 2. Young (6 weeks) body fat matched conventionally raised mice with gut microbiota (n = 8) have decreased expression of brain-derived neurotrophic factor (Bdnf) and the BDNF receptor tropomyosin related kinase B (Trkb) in the hypothalamus compared to germ free mice (n = 6). Data are adapted from an earlier publication [56], and presented as group means ± SEM. The levels of conventionally raised are relative to the mean level of germ free, which is set to 100%. Student’s t test was used for statistical comparison. * P < 0.05; ** P < 0.01.

the hypothalamus, which would normally increase hypothalamic BDNF levels [37,40,73]. Therefore, it is remarkable that conventionally raised mice still have decreased hypothalamic BDNF expression [56]. Based on these results, we suggest that gut microbiota itself decreases BDNF expression in both young and adult conventionally raised mice. Low BDNF levels could then mediate the relative increase in body fat seen in these mice with gut microbiota at adulthood, rather than being a consequence of their comparatively high body fat. During food shortage or impaired nutritional uptake, BDNF decreases as a consequence of low leptin [26]. In conventionally raised mice, which have improved nutritional uptake, we have surprisingly observed a decrease in BDNF mRNA [56]. Thus, we can exclude the possibility that decreased BDNF in conventionally raised mice is a compensatory mechanism to suppress the increased fat mass due to improved nutritional uptake. Instead, decreased BDNF could be the cause of relative adiposity in conventionally raised mice. However, the mechanism by which decreased BDNF could mediate the body weight inducing properties by gut microbiota remains to be investigated. We have also observed a decreased expression of the BDNF receptor TrkB in the hypothalamus of young conventionally raised mice (Fig. 2). A simultaneous regulation of both BDNF and TrkB has been reported previously [69]. This indicates that the biological effects of BDNF could be impaired even further by gut microbiota. Others have reported regulation of central BDNF as a result of gut microbiota modulation. BDNF levels were higher in the hippocampus and lower in the amygdala in mice after changes in gut microbiota induced by antibiotics [4]. Two studies with germ free mice show, however, the expression of BDNF to be reduced both in hippocampus and amygdala as well as in the cingular cortex [22,59]. The reason for the discrepancy between these studies is unknown. Infecting mice with a parasite causing chronic intestinal inflammation decreased the expression of hippocampal BDNF in mice. BDNF expression was restored again after treatment with probiotic [5]. It has been suggested that changes of BDNF in hippocampus, amygdala and cingular cortex, as a result of gut microbiota modulation, could be linked to changes in behaviors such as anxiety. In fact, germ free mice show reduced anxiety according to several studies [11,22,38]. GLP-1 in central energy balance regulation Glucagon-like peptide 1 (GLP-1) could have a connection with gut microbiota, as discussed below [56]. GLP-1 is encoded by the

Fig. 3. Young (6 weeks) body fat matched conventionally raised mice (n = 8) have decreased expression of glucagon-like peptide 1 (GLP-1), as measure by proglucagon (Gcg) mRNA, and glucagon-like peptide 1 receptor (Glp1r) in the brainstem compared to germ free mice (n = 6). Data are adapted from an earlier publication [56], and presented as group means ± SEM. The levels of conventionally raised are relative to the mean level of germ free, which is set to 100%. Student’s t test was used for statistical comparison. ** P < 0.01.

proglucagon (Gcg) gene, and is produced both in the periphery mainly by L-cells in the gut [23], and centrally almost exclusively by neurons in the NTS of the brainstem [28]. GLP-1 producing neurons in the NTS project to several parts of the brain including hypothalamic nuclei [28]. Peripheral GLP-1 lowers blood glucose by both stimulating insulin secretion and by suppressing glucagon secretion, and GLP-1 also inhibits gastric emptying. GLP-1 in the circulation is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP4) [23]. Centrally administered GLP-1 decreases food intake, suggesting GLP-1 to have a role in central energy balance regulation [64]. In addition, the central expression of Gcg is reduced by food restriction and induced by leptin [19]. Since central GLP-1 in mainly produced in the NTS and GLP-1 in the blood is rapidly degraded, it is likely that much of the central action of GLP-1 originates from GLP-1 producing neurons in the NTS. Noteworthy, neurons in the NTS exchange information with the gut through the vagus nerve [55]. This provides a possible route by which GLP-1 can serve as a mediator for information exchange between gut and brain, including between and the gut microbiota and energy regulating parts of the brain. Central GLP-1 in germ free and conventionally raised mice We have shown that the expression of the anti-obesity peptide GLP-1 in the brainstem, as measured by the precursor proglucagon (Gcg) mRNA, was decreased in adult conventionally raised mice compared with germ free mice [56]. A decreased GLP-1 expression in conventionally raised mice could contribute to their larger body fat mass. This is supported by our observation that young conventionally raised mice, with equal fat mass as the germ free mice, already have decreased Gcg expression in the brainstem (Fig. 3). Therefore, decreased GLP-1 expression in conventionally raised mice is more likely to cause a relative increase in body fat rather than being a consequence of high fat mass. Furthermore, GLP-1 is induced by leptin and conventionally raised mice have comparatively high serum leptin [6,19]. Collectively, these data may exclude the possibility of low leptin being a factor that decreases Gcg expression in conventionally raised mice. GLP-1 levels are reduced during food shortage or impaired nutritional uptake [19]. However, conventionally raised mice, which have improved nutritional uptake compared to germ free mice [61], still have decreased Gcg expression in the brainstem [56]. This excludes the possibility of decreased GLP-1 in conventionally raised mice as a compensatory mechanism that suppresses the

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References

Fig. 4. We propose that gut microbiota could modulate neuronal circuitries in the brain to increase fat mass. We suggest that decreased levels of fat suppressing brainderived neurotrophic factor (BDNF) and its receptor tropomyosin related kinase B (Trk-B), as well as decreased levels glucagon-like peptide 1 (GLP-1) may contribute to the fat inducing properties of gut microbiota. Normally, increased fat mass will impose a negative feedback mechanism on the brain through leptin to decrease fat mass. We suggest that gut microbiota may impair this effect of leptin.

increased fat mass as a result of improved nutritional uptake in conventionally raised mice. Instead, decreased GLP-1 could be the cause of relative obesity seen in conventionally raised mice. There are data indicating that gut microbiota speed up intestinal transit through decreased colonic GLP-1. Germ free mice were found to have increased plasma GLP-1 and increased Gcg expression in the colon, resulting in slower intestinal transit and thereby allowing for better nutrient absorption [68]. Interestingly, central GLP-1 producing neurons are almost exclusively located in the NTS in the brainstem [28], an area which receive information about the gut [55], and possibly also the gut microbiota, through vagal afferents. In addition, neurons in the NTS project to several parts of the brain, including many of the energy balance regulating nuclei of the hypothalamus [28].

Summary During the recent decades a dramatic increase in the incidence of obesity and obesity related illness has occurred worldwide. Today, there is no efficient obesity treatment other than invasive bariatric surgery. Increasing evidence suggests that modulation of our gut microbiota as a promising way to treat obesity and obesity related disease. From studies with germ free mice, we conclude that the gut microbiota modulates energy balance regulating circuitries in the hypothalamus and brainstem. Specifically, gut microbiota seem to decrease the fat suppressing peptides BDNF and GLP-1, a regulation that could contribute to increased fat mass induced by gut microbiota (Fig. 4). In future studies it will be important to identify mechanisms by which gut microbiota could modulate BDNF and GLP-1 in the hypothalamus and brain stem to induce fat mass.

Acknowledgments This work was supported by grants from Swedish Research Council (K2013-54X-09894-19-3 and 325-2008-7534), Johan och Jakob Söderbergs Foundation, Marcus Borgströms Foundation, Nilsson-Ehle Foundation, NovoNordisk Foundation, Inga-Britt och Arne Lunbergs Foundation, Swedish Medical Society, Swedish Society for Medical Research, Kungl och Hvitfeldtska Foundation, EC FP7 funding (Health-F2-2010-259772, FP7/2007-2013 Grant Agreement 245009, Full4Health FP7-KBBE-2010-4-266408, TORNADO [grant 222720]). Thanks to Suzanne L Dickson for reading and commenting on the text.

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Please cite this article in press as: Schéle E, et al. Regulation of body fat mass by the gut microbiota: Possible mediation by the brain. Peptides (2015), http://dx.doi.org/10.1016/j.peptides.2015.03.027