Role of the Gut in Visceral Fat Inflammation and Metabolic Disorders

Abstract

Obesity and diabetes are rapidly increasing in both developed and developing countries with enormous personal and economic cost implications. Type 2 diabetes was recognized over 20 years ago, in the seminal Banting Lecture of Reaven ((1)), as part of a cluster of metabolic disorders including obesity (defined by BMI (weight (kg)/height (m)2)), hypertension and dyslipidemia (high triglycerides and low high-density lipoprotein-cholesterol) and with cardiovascular disease as an endpoint (in both senses of the word). Since then, both central adiposity and circulating inflammatory markers (such as C-reactive protein) are understood to also be critical predictors in the metabolic syndrome. Key questions of major importance are: (i) Why is visceral fat particularly deleterious; (ii) What generates the chronic low-grade inflammatory profile of obesity; and (iii) Are these linked to a common etiology of metabolic dysregulation. Since the pioneering work from the laboratories of Kissebah ((2)) and Björntorp ((3)) following the observations of Jean Vague, there has grown an increasingly sophisticated understanding of the critical role of deep visceral fat in the development of metabolic syndrome. Whereas BMI does relate to metabolic dysfunction, waist-to-hip ratio, as a measure of central adiposity, is a better indicator of metabolic dysfunction and end stage cardiovascular risk (for example see refs. (2),(4)). Epidemiological work has shown that abdominal circumference correlates directly with metabolic dysfunction whilst an opposite, apparently protective, role of lower body fat was observed ((5)). With the development of nuclear magnetic resonance and computed tomography techniques it has then been possible to further delineate abdominal fat into subcutaneous versus visceral actually within the peritoneal cavity. Using nuclear magnetic resonance, Miyazaki and colleagues ((6)) related insulin-stimulated glucose disposal individually to these adipose compartments and showed a highly significant relationship between impaired glucose disposal and increased visceral fat but no such relationship with subcutaneous. More recent results from the Framington Heart Study provided strong epidemiological support over a range of metabolic variables ((7)). Indeed, an analysis from this study even suggested a modest protective effect of abdominal subcutaneous fat in individuals in the highest tertile of visceral fat ((8)). Finally, it is not only metabolic variables that relate to visceral fat accumulation. Visceral abdominal fat area, for example, is associated with an increase in the risk, prevalence and aggressiveness of certain types of cancers, particularly colon and colorectal ((9),(10)). Interestingly, a subset of obese individuals, classified as “metabolically healthy obese,” account for ∼20% of the obese population ((11)). They are characterized by a lower visceral fat content, higher insulin sensitivity, and a favorable metabolic profile (lower triglycerides, inflammatory markers, and higher high-density lipoprotein-cholesterol) as compared to the “at-risk” obese population ((12)). Meigs and colleagues ((13)) reported that the prevalence of type 2 diabetes and cardiovascular disease is approximately six- and twofold higher, respectively in “at-risk” obese individuals as compared to those who exhibit a metabolically healthy obese-like phenotype. A recent review by Després and coworkers ((14)) summarizes the evidence for excess visceral adiposity as a predictor of insulin resistance and a “proatherogenic, thrombotic, and inflammatory profile” associated with increased cardiovascular disease risk and asks if this might not be the cholesterol of the 21st century. Defining various fat depots, both anatomically and metabolically, is critical to elucidate the origin as well as the metabolic sequelae of regional fat distribution. Functionally, adipose tissue is classified into brown and white adipose tissue, with the former dissipates energy through heat production whereas the latter stores energy as triglycerides. Advances in imaging technology enable further categorization of white adipose tissue into subcutaneous (directly beneath the skin) and visceral (within the peritoneal cavity) fat depots. The collective term of “visceral fat,” however, should be interpreted carefully as this may under-represent the distinctiveness of the various fat depots in the peritoneal cavity. For instance, perirenal, omental, and mesenteric fat are all “visceral fat” but their different anatomical locations imply that their metabolism may differ from each other as a consequence of unique local stimuli. Visceral adipose tissues are also known to have depot-specific structures. For example, omental and mesenteric fat are characterized by the presence of lymph nodes that are nonexistent in the perirenal and gonadal depots ((15)). These lymph nodes may be an important determinant of the metabolic characteristics of the depots as recently demonstrated by Lichtenstein and colleagues ((16)). Accordingly, the assumption of all visceral fat depots to be functionally and metabolically similar may be misleading. What further complicates our understanding of visceral fat is the inappropriate use of rodent epididymal fat. Whereas it is easily accessible, it is likely to be of limited relevance to humans as a representative fat depot in experimental models of obesity and diabetes. Since the discovery of a wide range of adipose tissue-derived secretory factors, including hormones, cytokines, and chemokines, adipose tissue has been acknowledged to be an endocrine organ that is also an important part of innate immunity. Some adipokines are proinflammatory, for example tumor necrosis factor-α ((17)) and interleukin (IL)-6 ((18)) which activate the nuclear factor-κB signaling cascade and subsequently induce the expression of an array of inflammatory genes, whereas others such as monocyte chemoattractant protein-1 ((19)) and IL-8 ((20)) are key chemokines that promote the migration and infiltration of monocytes/macrophages and neutrophils/lymphocytes, respectively, in response to inflammation. Adipose tissue, on the other hand, also produces anti-inflammatory factors: IL-1 receptor antagonist inhibits the binding of the proinflammatory IL-1α and IL-1β to their receptors ((21)); IL-10 reduces the release of proinflammatory factors (e.g., IL-1, IL-6, tumor necrosis factor-α, and IL-8) and promotes IL-1 receptor antagonist production ((22)); adiponectin has been well recognized as an anti-inflammatory adipokine ((23)) and there is some evidence that the effect is mediated by the induction of IL-10 expression ((24)). Distinct gene expression patterns, with both proinflammatory and complement genes over-represented in the omental as compared to subcutaneous fat, implicate a depot-specific role of adipose tissue in the innate immune system ((25)). Despite the increased production of anti-inflammatory cytokines ((21),(22)), the state of low-grade inflammation in obesity suggests a dominant effect of the proinflammatory cytokines on whole-body metabolism. More importantly, the association between the elevated circulating levels of inflammatory mediators and the prevalence of obesity-related metabolic complications including insulin resistance, type 2 diabetes, and cardiovascular disease ((26),(27)) suggests a potential role of adipose tissue-derived cytokines in the pathogenesis of metabolic disorders in obesity. The deleterious nature of inflammation is further highlighted by the proinflammatory state of omental fat, in which the increased release of proinflammatory cytokines including tumor necrosis factor-α ((28)), IL-6 ((29)), IL-8 ((29)), and plasminogen activator inhibitor-1 ((28)) as compared to subcutaneous fat has been implicated as a key determinant of the depot-specific metabolic effect of adipose tissue. We will return to the issue of differences between fat depots. Accumulation of activated macrophages in adipose tissue during obesity has been noted for some time ((30),(31)). Adipocyte hypertrophy and hyperplasia, which lead to local adipose hypoxia and the subsequent necrosis-like adipocyte cell death, have been generally accepted as one of the main driving forces for the infiltration of adipose tissue macrophages (ATMs) in obesity ((32),(33)). Activated ATMs aggregate around the necrosis-like adipocytes, collectively known as the crown-like structures, to remove cell debris and scavenge the residual lipid droplets as part of the normal process of adipose tissue remodeling ((34)). The formation of crown-like structures is rare in lean wild-type mice but is increased ∼30-fold in obese db/db mice ((34)). Macrophages are the major source of proinflammatory cytokines in adipose tissue. Attenuating ATM infiltration has been shown to partially ameliorate insulin resistance and hepatic steatosis in diet-induced obesity and the effect was associated with a decrease in the production of proinflammatory factors from the adipose tissue ((35),(36)). Conversely, inducing ATM infiltration by overexpressing monocyte chemoattractant protein-1 is sufficient to reduce insulin sensitivity without modulating body weight ((35)). Taken together, this indicates that ATM infiltration, in addition to hypertrophic adipocytes per se ((37)), is an important mediator of obesity-related metabolic abnormalities. More recently, it has been appreciated that there is phenotypic polarization of activated ATMs. Based on the expression of cell surface markers including integrins, scavenging receptors, signaling and adhesion molecules, macrophages are broadly identified as the classically activated M1 macrophages or the alternatively-activated M2 macrophages (recently reviewed by Mosser and Edwards ((38)) and Martinez and colleagues ((39))). In general, M1 macrophages produce proinflammatory cytokines that generate a cell-mediated immune response as part of host defense, whereas M2 includes tissue-remodeling macrophages that express IL-4, IL-13, and regulatory macrophages that produce high levels of immunosuppressive cytokines (e.g., IL-10). Results from animal studies have shown that adipose tissue inflammation in diet-induced obesity is associated with the recruitment of circulating cells that express an activated M1 phenotype (typically identified by surface expression of CD11c) which leads to an overall shift to a proinflammatory state within the affected adipose tissue ((40),(41),(42)). The importance of these CD11c+ cells is highlighted in a study by Patsouris and coworkers ((43)), in which the depletion of CD11c+ cells was shown to inhibit macrophage infiltration and to normalize insulin sensitivity in diet-induced obese mice. Several studies have described differences in either total macrophage number and/or macrophage phenotypes between fat depots. The abundance of infiltrating macrophages is approximately two- to fourfold higher in omental as compared to subcutaneous fat irrespective of adiposity levels ((44)). In obese mice, a comparative increase in macrophage infiltration in epididymal as compared to subcutaneous fat has been noted ((30),(45),(46)). Moreover, high-fat feeding has been reported to induce a concomitant increase in the percentage of MGL1− (M1) and a decrease in the percentage of MGL1+ (M2) ATMs in epididymal fat of obese mice, thereby resulting in a reduction in the M2:M1 ATMs ratio ((46)). Whether similar association between obesity and depot-specific distribution of ATM phenotypes exists in human, however, is not entirely clear. Both Aron-Wisnewsky and colleagues ((47)) and Wentworth and coworkers ((48)) studied ATM phenotypes in obese women. While the former showed that the M1:M2 ratio (defined as CD40+:CD206+) is 1.5-fold higher in omental as compared to subcutaneous fat, the latter reported a higher M1 (identified as CD11c+) ATM density in subcutaneous fat. It should be emphasized, however, that different surface markers have been used to distinguish ATM phenotypes in the above-mentioned studies, which may therefore limit the relevance of direct comparison between these findings. The mechanisms underlying the depot-specific heterogeneity of ATMs are unclear but are likely to be a consequence of depot-specific resident characteristics such as the intrinsic characteristics of adipocytes and/or anatomically specific external stimuli. Compared to cells in the subcutaneous depot, visceral adipocytes in general (a mixture of depots) have a smaller critical size triggering death ((49)). The increased susceptibility of visceral adipocytes to cellular death may therefore lead to differential macrophage infiltration in fat depots. The percentage of dead adipocytes, defined as perilipin-negative lipid droplets surrounded by macrophage crowns, in the epididymal fat is up to ∼16-fold higher compared to that in subcutaneous fat in mice during the course of high-fat feeding ((50)). Similarly, crown-like structure density in visceral fat (data from various visceral fat depots were pooled) of genetically obese (ob/ob and db/db) mice is threefold higher compared to subcutaneous fat in the corresponding animal group ((49)) and ∼30-fold higher in perivesicular fat compared to the same fat depot in lean wild-type mice ((34)). Phenotypic switching of the predominantly M2 resident macrophages may also contribute to the depot-specific differential abundance of macrophages. It has been shown that macrophages can adapt their functional patterns in response to a specific microenvironment by expressing distinct patterns of chemokines and cell surface markers ((51)). Using mature and differentiated human monocyte-derived macrophages to mimic resident macrophages, Porcheray and colleagues ((52)) demonstrated that the activation of a macrophage toward a specific phenotype is reversible in response to signal arrest or counter-stimulation. To explain the chronic proinflammatory state in visceral, but not necessarily subcutaneous, fat ((53)) the persistent presence of specific stimuli that promote the recruitment of proinflammatory macrophages and/or maintain the ATMs in the fat depot in the proinflammatory phenotype would therefore be necessary. There is an increasing body of evidence of a role for the gut in visceral fat hypertrophy and dysfunction. First, a key recent observation by Gummesson and colleagues ((54)) has been made of a highly significant relationship between gut “leakiness” at the level of the lower gastrointestinal tract and increased visceral adiposity in women who were normal to mildly overweight but otherwise healthy. Second, patients with Crohn's disease, a condition characterized by inflammation of the intestine, have a higher ratio of intra-abdominal to total abdominal fat compared to healthy controls ((55)) and the prevalence of “fat wrapping” (excess adipose tissue extension from the mesenteric attachment) is correlated with the biochemical and clinical activity of the disease ((56)). A causal relationship between gut inflammation and mesenteric fat dysfunction has been demonstrated in animal models. Rats with experimental colitis have 35% more mesenteric fat mass than controls, with no difference between groups in the other fat depots ((57)). In addition to the expansion of the fat depot, mesenteric fat alterations associated with gut inflammation are also characterized by an increase in macrophage infiltration and the release of proinflammatory cytokines ((58)). The effect of inflammation on gut barrier function is a key factor mediating the gut-visceral fat interactions. Inflammation increases gut permeability, as evident by the reduction in the thickness of the intestinal mucous layer with increased severity of inflammation ((59)). At the cellular level, proinflammatory cytokines (e.g., tumor necrosis factor-α and IL-1β) increase intestinal tight junction permeability by inducing the expression and activation of myosin light chain kinase, which results in a contraction of perijunctional actin-myosin filaments and the subsequent opening of the intestinal epithelial tight junction barrier ((60),(61)). The inflamed, and therefore “leaky,” gut may then allow passage of bacteria and/or bacterial components across the intestinal barrier. This phenomenon is demonstrated in a study by Cenac and coworkers ((62)), in which experimental colonic inflammation in mice resulted in an increase in paracellular permeability of the colon and the subsequent translocation of bacteria into the peritoneal organs and, presumably, the adjacent mesenteric fat. Exposure to gut microbiota and their metabolites alters mesenteric adipose tissue metabolism in a number of ways. First, lipopolysaccharide (LPS) derived from Gram-negative intestinal microbiota triggers an inflammatory response in adipocytes that, together with macrophage colony-stimulating factor infiltrated from the intestine, promotes ATM recruitment in the mesenteric fat depot ((63)). LPS also interacts with Toll-like receptor (TLR)-4, which is upstream of the nuclear factor-κB pathway, to induce the transcription of proinflammatory genes in ATMs ((64)). Second, immune cells in the mesenteric fat are under prolonged stimulation by bacterial antigens, leading to the activation of lymph node lymphoid cells and the subsequent enlargement of lymph node-containing fat depots (mainly omental and mesenteric fat) ((15),(65)). Third, bacterial stimuli may lead to local activation of peroxisome proliferator-activated receptor-γ and therefore induce adipocyte proliferation and differentiation in the mesenteric fat depot, although the underlying mechanisms remain largely unclear ((65)). Taken together, inflammation impairs gut barrier function and results in the leakage of microbial antigens. Mesenteric fat hypertrophy and/or hyperplasia associated with gut inflammation may have a defensive role in trapping the luminal bacteria and their products to prevent further inflammation in the peritoneal cavity. The metabolic consequences of impaired gut barrier function are not confined to mesenteric fat dysfunction, but also extend to a more general effect on whole-body metabolism. Endotoxins derived from gut bacteria are normally detoxified in the liver. In the case of an impaired gut barrier function, increased flux of endotoxin (predominantly LPS) may exceed the capacity of Kupffer cells in the liver so that the endotoxin enters the systemic circulation ((66)). In active Crohn's disease and ulcerative colitis patients, the circulating endotoxin level is 40–60% higher as compared to healthy controls and correlates with disease activity ((67)). LPS forms a complex with LPS-binding protein which then binds to CD14 (a protein expressed mainly in macrophages and to a lesser extent in neutrophils, monocytes, and liver) to initiate an acute immune response via the TLR4 and nuclear factor-κB pathways ((68)). An increase in circulating LPS leads to “metabolic endotoxemia,” a condition characterized by a low-grade proinflammatory state, insulin resistance and increased cardiovascular risk ((69)). This accords with the elevated plasma level of LPS-binding protein, a marker of subclinical endotoxemia, in overweight/obese individuals ((70)). Furthermore, intervention studies have revealed a direct effect of endotoxemia on whole-body metabolism. A chronic subcutaneous infusion of LPS increased fasting plasma glucose and insulin levels and reduced insulin sensitivity in mice, whereas experimental endotoxemia induced a transient inflammatory response (as evident by the increases in circulating inflammatory markers and mRNA expression of proinflammatory cytokines in subcutaneous fat) and insulin resistance in healthy humans ((71)). Available evidence indicates that obesity and metabolic health are influenced by the biology of the gut microbiota. Normal microbial colonization processes result in a gut microbiota that is stable over time. The composition of the gut microbiota varies between individuals and is widely accepted to be a contributing factor to variation in host physiology. The most direct evidence of this comes from colonization of germ-free mice by microbiota transplant experiments to generate a conventional host-microbiota system (known as conventionalization). The phenotype of the conventionalized animals correlates to that of the donor microbiota ((72)). The observations of gut microbiota having a lower Bacteroidetes:Firmicutes ratio (the two phyla accounting for 80–90% of the microbial community) in obese as compared to lean humans ((73)) implicates the association between microbial dysbiosis and obesity. Giving the trillions of microbes in the gut, elucidating the role of gut microbiota in the pathophysiology of obesity is extremely challenging. A feature of the gut microbiota is that diversity does not scale linearly with taxonomic resolution. Modern microbial diversity assessment is typically in terms of 16S ribosomal RNA sequence relationships. Individual sequences are considered as a surrogate for individual cells and classified based on their identity to known reference organisms. Fine scales of rRNA variation (e.g., 96–100% rRNA identity) are considered as an approximation of species-scale resolution and coarser scales (80–85% identity) as phylum or class resolution. At fine scales the gut microbiota is estimated to contain over 1,000 taxa (“species”) and high levels of interindividual variation in composition and relative abundance are seen, whereas at coarse scales there is limited individual variation in taxonomic composition with the microbiota, being heavily dominated by just two taxa (Bacteroidetes and Firmicutes). This strong bias of interindividual variation towards fine taxonomic scales creates a sampling challenge. To get an effective sample of a gut community at fine taxonomic scales requires tens of thousands of sequences. Taken together, gut microbiota composition is known to be different between obese and lean individuals, but available data on patterns of correlation between lean and obese communities is mostly at coarse scales. It is critical to use finer scales of taxonomic resolution to identify predictable patterns and specific members of the microbiota that influence the host system with regard to metabolic health. Gut microbiota potentially influence the pathophysiology of obesity-associated metabolic disorders by regulating intestinal permeability. Several species have been shown to promote the integrity of the gut barrier ((74),(75)). Amongst the most interesting of these are Bifidobacterium spp., putative gut barrier-protecting bacteria whose abundance have been found to be inversely correlated with obesity ((76)). Several studies addressing the link between diet-induced changes in microbiota, gut barrier dysfunction, and obesity have focused on Bifidobacteria. An obvious example is a recent study where mice were maintained on either normal chow or high-fat diet for 25 weeks; Bifidobacteria were present in mice on normal chow but below detectable levels in the feces of the diet-induced obese mice ((77)). Cani and colleagues ((78)) showed that a high-fat diet reduced the abundance of Bifidobacteria in mice and that this diet-induced microbiota change was associated with metabolic endotoxemia. Significantly, the effect was reversed by prebiotic dietary supplementations. The authors concluded that prebiotics-induced changes in gut microbiota, i.e., an increase in Bifidobacterium spp., Lactobacillus spp. and Clostridium coccoides–Eubacterium rectal cluster improve gut barrier function by inducing the production of glucagon-like peptide 2 from enteroendocrine cells ((79)), which subsequently increases epithelial proliferation and thickness of the epithelial mucosa ((80)). In addition, prebiotics also promote crossfeeding between Bifidobacteria and butyrate-producing anaerobes ((81)). Butyrate, a short-chain fatty acid produced during microbial fermentation, is a key energy substrate for colonic epithelial cells. Butyrate promotes colonocyte proliferation as well as inhibiting inflammation and therefore is important in maintaining the colonic defense barrier and overall health of the gut (recently reviewed by Hamer and coworkers ((82))). Whereas Crohn's disease patients have been shown to have reduced abundance of butyrate-producing bacteria ((83)), the association between butyrate, gut inflammation, and permeability is less well defined in obese humans ((84)). In contrast, some gut bacterial species induce inflammation and, subsequently, increase gut permeability. Two key factors here are the flagellin and endotoxin. Both are frequently present surface components of bacterial cells that induce a strong host response. The flagellin receptor TLR5 is a key mediator of gut microbe-initiated inflammatory response. Located on the basolateral surface of polarized epithelia and normally inaccessible to gut microbes, the binding of TLR5 with flagellin of the invasive pathogens induces proinflammatory gene expression in intestinal epithelial cells, presumably to defend against infection ((85)). When the epithelium is breached, as in the case of ulceration or otherwise damaged mucosa, flagellated bacteria including both pathogenic (e.g., Salmonella typhimurium) and commensal (e.g., Escherichia coli) types, will be able to initiate and/or sustain mucosal inflammation, which subsequently further compromises gut integrity ((86)). An important recent paper investigated the phenotype of the TLR5 knockout in relation to derangement of variables defining the metabolic syndrome ((87)). Mice deficient in TLR5 developed “hallmark features of the metabolic syndrome, including hyperlipidemia, hypertension, insulin resistance and increased adiposity” ((87)). Of major significance, treatment of the TLR5 knockout mice with a broad spectrum antibiotic greatly reduced gut bacterial load and ameliorated the dysmetabolic state compared to wild-type control. Analysis of gut microbiota showed consistent differences between knockout and wild-type mice. Furthermore, gut microbiota transferred from the TLR5 knockouts into wild-type germ-free hosts conferred many aspects of the dysmetabolic profile of the TLR5 knockout. This set of studies is of major importance as it focuses on a particular receptor which may play a central role in the gut dysfunction of obesity. Even more critical is that it suggests a feedback loop from this receptor that beneficially modulates gut microbiota profile. The nature of this feedback is not known but it is tempting to suggest that defensins and mucins may be involved ((88),(89)). Endotoxin is also proposed to drive inflammatory responses, the severity of which is likely to be greater where gut barrier function is impaired. Although most Gram-negative bacteria produce LPS, the composition of its lipid core varies and not all taxa are equally toxigenic. Notably members of the Proteobacteria typically exert a stronger effect than Bacteroides. In the context of impaired gut barrier function changes in community structure that result in higher abundance of proinflammatory organisms (flagellated or with less tolerated forms of endotoxin) are likely to exacerbate the inflammatory response. Taken together, data from animal studies reveal complex interactions between gut microbiota, permeability, and immune function. It is reasonable to infer a similar role of microbes in the human gut, though this is still largely unknown. Elucidating the relationships between microbiota and gut function is of importance, in particular to inform on the mechanisms, in addition to genetic predisposition, by which obesity-associated alterations of the gut microbial community occur. Gut microbiota can also contribute to the pathogenesis of obesity and/or its related metabolic complications via modulating energy homeostasis. Gut microbes process indigestible dietary polysaccharides by fermentation and subsequently increase the availability of energy substrates in the form of short-chain fatty acids including acetate, propionate, and butyrate ((90)). Whereas butyrate is mainly used as an energy source for colonic epithelial cells, acetate and propionate are delivered to the liver for de novo lipogenesis ((91)). The effect of gut microbiota on inducing host hepatic lipid production is demonstrated in a study by Backhed and colleagues ((72)), in which colonization of germ-free mice with cecal microbes from conventionally raised animals induced the mRNA expression of genes involved in the pathway of de novo fatty acid synthesis and increased liver triglyceride content by 2.3-fold. There is evidence that alterations of gut microbiota in obesity increase energy harvest and short-chain fatty acid production. By characterizing cecal microbiomes of genetically obese (ob/ob) and wild-type mice using metagenomic analysis, Turnbaugh and coworkers ((92)) showed that the obese microbiome is enriched for environmental gene tags which identify DNA sequences that encode enzymes involved in starch/sucrose, galactose, and butanoate metabolism to break down and metabolize otherwise indigestible polysaccharides. An increase in the fecal concentration of short-chain fatty acids in obese mice ((92)) and humans ((93)) also has been demonstrated. These data support the increased capacity of the obesity-associated gut microbiota to harvest energy from the diet, which subsequently leads to an influx of short-chain fatty acids into the systemic, and more importantly the portal, circulation. Given the role of the gut in mesenteric fat inflammation and deposition and energy homeostasis, it is tempting to postulate that the gut is an important driving force for the pathophysiology of visceral obesity and its related metabolic disorders, in particular fatty liver diseases—thanks to the portal system. Similar gut-liver interactions have been implicated as an important underlying mechanism by which alcoholic liver disease occurs ((94)). As summarized in Figure 1, it may all start with gut inflammation. As a consequence of alterations of gut microbiota composition and/or other external factors, gut barrier function is impaired and results in a “leaky gut.” The infiltration of microbial products into the mesenteric fat triggers an innate immune response and subsequently induces the production of proinflammatory cytokines from ATMs. The fat depot also expands as a protective mechanism to prevent the microbial antigens from further infiltrating the peritoneal cavity. Together these results in an increase flux of free-fatty acids and proinflammatory factors, originating from both gut microbiota and the visceral fat depot, to the liver via the portal circulation. The gut as a central player in development of systemic inflammation and the metabolic syndrome. Proinflammatory dietary components (e.g., saturated fat), hyperphagia, and genetic predisposition may combine to alter the gut microbiota and place an increased microbial and caloric load on the gut. If the gut is unable to handle this increased load, then inflammation and gut barrier dysfunction will result. Impairment or leakiness of the gut barrier will see an increased delivery of bacteria and/or bacterial metabolites to the second line of defense, the mesenteric fat contiguous with the gut. There is then evidence that this mesenteric fat, which has a strikingly immune system-like gene profile, exhibits adipocyte hypertrophy, increased proinflammatory gene expression and cytokine production and, over time, macrophage infiltration and activation. The adipose-derived cytokines and increased fatty acid flux from the expanded fat mass will impact on the liver via direct portal access, resulting in an inflamed, steatotic, and insulin resistant liver. This may then progress to systemic dysfunction and feed forward to further exacerbate the intestinal and adipose dysfunction. When the availability of free-fatty acids exceeds the capacity of both fat oxidation and triglyceride export as very-low-density lipoprotein, an excess of lipid accumulates in the liver. Subsequently, the increase in lipid derivatives (e.g., ceramide and diacylglycerol), together with proinflammatory factors from the portal circulation ((95)), activate inflammatory pathways in the liver. These events lead to common obesity-associated liver diseases including nonalcoholic fatty liver disease and hepatic insulin resistance. The diseased liver, of course, leads to further metabolic abnormalities. Hepatic insulin resistance impairs the suppression of glucose production in the liver. Together with increased lipogenesis, the liver contributes to the elevated circulating levels of glucose and fatty acids that induce insulin secretion, elicit peripheral insulin resistance and eventually lead to a vicious cycle of metabolic dysfunction ((96)). Inflammation has been implicated as an important contributor to the pathogenesis of obesity-related metabolic disorders. Understanding the genesis of that inflammation is critical. The rapidly growing body of literature summarized here invites consideration of a link between gut inflammation/permeability and mesenteric fat dysfunction and then on to liver inflammation and hepatic and systemic insulin resistance. To date the origin of gut inflammation is not entirely clear and it appears to be multifactorial, shown to be at least host genotype- ((73)) and diet-dependent ((77),(97)). Elucidating the mechanisms underlying gut inflammation will be critical to develop gut-specific approaches for the treatment of obesity-related metabolic disorders. There is a dramatically growing literature in gut health which is beyond the scope of this review. However, the reader is directed to a number of recent articles which focus on modifying the gut microbial community using inter alia, resistant starches, prebiotics and/or prebiotics, which seem to provide promising approaches in improving gut function and metabolic variables (for example see refs. (98),(99),(100)). L.H.S. and A.G. are, or have been, employed by AstraZeneca. The other authors declared no conflict of interest.