Xavier S. Revelo

Regulation of obesity-related insulin resistance with gut anti-inflammatory agents.

Obesity has reached epidemic proportions, but little is known about its influence on the intestinal immune system. Here we show that the gut immune system is altered during high-fat diet (HFD) feeding and is a functional regulator of obesity-related insulin resistance (IR) that can be exploited therapeutically. Obesity induces a chronic phenotypic pro-inflammatory shift in bowel lamina propria immune cell populations. Reduction of the gut immune system, using beta7 integrin-deficient mice (Beta7(null)), decreases HFD-induced IR. Treatment of wild-type HFD C57BL/6 mice with the local gut anti-inflammatory, 5-aminosalicyclic acid (5-ASA), reverses bowel inflammation and improves metabolic parameters. These beneficial effects are dependent on adaptive and gut immunity and are associated with reduced gut permeability and endotoxemia, decreased visceral adipose tissue inflammation, and improved antigen-specific tolerance to luminal antigens. Thus, the mucosal immune system affects multiple pathways associated with systemic IR and represents a novel therapeutic target in this disease.

DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice

Reactive oxygen species (ROS) have been linked to a wide variety of pathologies, including obesity and diabetes, but ROS also act as endogenous signalling molecules, regulating numerous biological processes. DJ-1 is one of the most evolutionarily conserved proteins across species, and mutations in DJ-1 have been linked to some cases of Parkinsons disease. Here we show that DJ-1 maintains cellular metabolic homeostasis via modulating ROS levels in murine skeletal muscles, revealing a role of DJ-1 in maintaining efficient fuel utilization. We demonstrate that, in the absence of DJ-1, ROS uncouple mitochondrial respiration and activate AMP-activated protein kinase, which triggers Warburg-like metabolic reprogramming in muscle cells. Accordingly, DJ-1 knockout mice exhibit higher energy expenditure and are protected from obesity, insulin resistance and diabetes in the setting of fuel surplus. Our data suggest that promoting mitochondrial uncoupling may be a potential strategy for the treatment of obesity-associated metabolic disorders.

Perforin Is a Novel Immune Regulator of Obesity-Related Insulin Resistance

Obesity-related insulin resistance is associated with an influx of pathogenic T cells into visceral adipose tissue (VAT), but the mechanisms regulating lymphocyte balance in such tissues are unknown. Here we describe an important role for the immune cytotoxic effector molecule perforin in regulating this process. Perforin-deficient mice (Prf1null) show early increased body weight and adiposity, glucose intolerance, and insulin resistance when placed on high-fat diet (HFD). Regulatory effects of perforin on glucose tolerance are mechanistically linked to the control of T-cell proliferation and cytokine production in inflamed VAT. HFD-fed Prf1null mice have increased accumulation of proinflammatory IFN-γ–producing CD4+ and CD8+ T cells and M1-polarized macrophages in VAT. CD8+ T cells from the VAT of Prf1null mice have increased proliferation and impaired early apoptosis, suggesting a role for perforin in the regulation of T-cell turnover during HFD feeding. Transfer of CD8+ T cells from Prf1null mice into CD8-deficient mice (CD8null) resulted in worsening of metabolic parameters compared with wild-type donors. Improved metabolic parameters in HFD natural killer (NK) cell–deficient mice (NKnull) ruled out a role for NK cells as a single source of perforin in regulating glucose homeostasis. The findings support the importance of T-cell function in insulin resistance and suggest that modulation of lymphocyte homeostasis in inflamed VAT is one possible avenue for therapeutic intervention.

Are obesity-related insulin resistance and type 2 diabetes autoimmune diseases?

Obesity and associated insulin resistance predispose individuals to develop chronic metabolic diseases, such as type 2 diabetes and cardiovascular disease. Although these disorders affect a significant proportion of the global population, the underlying mechanisms of disease remain poorly understood. The discovery of elevated tumor necrosis factor-α in adipose tissue as an inducer of obesity-associated insulin resistance marked a new era of understanding that a subclinical inflammatory process underlies the insulin resistance and metabolic dysfunction that precedes type 2 diabetes. Advances in the field identified components of both the innate and adaptive immune response as key players in regulating such inflammatory processes. As antigen specificity is a hallmark of an adaptive immune response, its role in modulating the chronic inflammation that accompanies obesity and type 2 diabetes begs the question of whether insulin resistance and type 2 diabetes can have autoimmune components. In this Perspective, we summarize current data that pertain to the activation and perpetuation of adaptive immune responses during obesity and discuss key missing links and potential mechanisms for obesity-related insulin resistance and type 2 diabetes to be considered as potential autoimmune diseases.

Morphological and Inflammatory Changes in Visceral Adipose Tissue During Obesity

Obesity is a major health burden worldwide and is a major factor in the development of insulin resistance and metabolic complications such as type II diabetes. Chronic nutrient excess leads to visceral adipose tissue (VAT) expansion and dysfunction in an active process that involves the adipocytes, their supporting matrix, and immune cell infiltrates. These changes contribute to adipose tissue hypoxia, adipocyte cell stress, and ultimately cell death. Accumulation of lymphocytes, macrophages, and other immune cells around dying adipocytes forms the so-called “crown-like structure”, a histological hallmark of VAT in obesity. Cross talk between immune cells in adipose tissue dictates the overall inflammatory response, ultimately leading to the production of pro-inflammatory mediators which directly induce insulin resistance in VAT. In this review, we summarize recent studies demonstrating the dramatic changes that occur in visceral adipose tissue during obesity leading to low-grade chronic inflammation and metabolic disease.

Nucleic Acid-Targeting Pathways Promote Inflammation in Obesity-Related Insulin Resistance

Obesity-related inflammation of metabolic tissues, including visceral adipose tissue (VAT) and liver, are key factors in the development of insulin resistance (IR), though many of the contributing mechanisms remain unclear. We show that nucleic-acid-targeting pathways downstream of extracellular trap (ET) formation, unmethylated CpG DNA, or ribonucleic acids drive inflammation in IR. High-fat diet (HFD)-fed mice show increased release of ETs in VAT, decreased systemic clearance of ETs, and increased autoantibodies against conserved nuclear antigens. In HFD-fed mice, this excess of nucleic acids and related protein antigens worsens metabolic parameters through a number of mechanisms, including activation of VAT macrophages and expansion of plasmacytoid dendritic cells (pDCs) in the liver. Consistently, HFD-fed mice lacking critical responders of nucleic acid pathways, Toll-like receptors (TLR)7 and TLR9, show reduced metabolic inflammation and improved glucose homeostasis. Treatment of HFD-fed mice with inhibitors of ET formation or a TLR7/9 antagonist improves metabolic disease. These findings reveal a pathogenic role for nucleic acid targeting as a driver of metabolic inflammation in IR.

Type I interferon responses drive intrahepatic T cells to promote metabolic syndrome

Obesity-related insulin resistance correlates with type I interferon–driven activation and expansion of intrahepatic T cells. See the related Focus by Ma et al. Liver T cells—The missing link in obesity-associated diabetes Obesity is associated with increased risk of developing a range of disorders including cardiovascular diseases and type 2 diabetes. In obese individuals, accumulation of fat in the liver, termed nonalcoholic fatty liver disease (NAFLD), has been linked to the development of insulin resistance. Ghazarian et al. report that type I interferon–driven activation of CD8+ T cells in the liver correlates with insulin resistance in patients with NAFLD and in mouse models of obesity. Furthermore, the authors found that gut microbiome plays an important role in driving inflammation in the livers of obese mice. Their studies add to the growing recognition of the immune axis in metabolic disorders associated with obesity. Obesity-related insulin resistance is driven by low-grade chronic inflammation of metabolic tissues. In the liver, nonalcoholic fatty liver disease (NAFLD) is associated with hepatic insulin resistance and systemic glucose dysregulation. However, the immunological factors supporting these processes are poorly understood. We found that the liver accumulates pathogenic CD8+ T cell subsets, which control hepatic insulin sensitivity and gluconeogenesis during diet-induced obesity in mice. In a cohort of human patients, CD8+ T cells represent a dominant intrahepatic immune cell population that is linked to glucose dysregulation. Accumulation and activation of these cells are supported by type I interferon (IFN-I) responses in the liver. Livers from obese mice up-regulate critical interferon regulatory factors (IRFs), interferon stimulatory genes (ISGs), and IFNα protein, whereas IFNαR1−/− mice or CD8-specific IFNαR1−/− chimeric mice are protected from disease. IFNαR1 inhibitors improve metabolic parameters in mice, whereas CD8+ T cells and IFN-I responses correlate with NAFLD in human patients. Thus, IFN-I responses represent a central immunological axis that governs intrahepatic T cell pathogenicity during metabolic disease.

Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation

During obesity, macrophages can infiltrate metabolic tissues, and contribute to chronic low-grade inflammation, and mediate insulin resistance and diabetes. Recent studies have elucidated the metabolic role of JAK2, a key mediator downstream of various cytokines and growth factors. Our study addresses the essential role of macrophage JAK2 in the pathogenesis to obesity-associated inflammation and insulin resistance. During high-fat diet (HFD) feeding, macrophage-specific JAK2 knockout (M-JAK2−/−) mice gained less body weight compared to wildtype littermate control (M-JAK2+/+) mice and were protected from HFD-induced systemic insulin resistance. Histological analysis revealed smaller adipocytes and qPCR analysis showed upregulated expression of some adipogenesis markers in visceral adipose tissue (VAT) of HFD-fed M-JAK2−/− mice. There were decreased crown-like structures in VAT along with reduced mRNA expression of some macrophage markers and chemokines in liver and VAT of HFD-fed M-JAK2−/− mice. Peritoneal macrophages from M-JAK2−/− mice and Jak2 knockdown in macrophage cell line RAW 264.7 also showed lower levels of chemokine expression and reduced phosphorylated STAT3. However, leptin-dependent effects on augmenting chemokine expression in RAW 264.7 cells did not require JAK2. Collectively, our findings show that macrophage JAK2 deficiency improves systemic insulin sensitivity and reduces inflammation in VAT and liver in response to metabolic stress.

Diet-induced obesity enhances the severity of experimental autoimmune encephalomyelitis

We provide evidence to support our hypothesis that age-related hearing loss (ARHL) is associated with chronic neurodegenerative changes in the auditory systemwhich respond to systemic inflammation. This is supported by changes in themorphology and priming ofmicroglia observed exclusively in the auditory system of older mice with agerelated hearing loss, compared to younger mice with normal hearing. Ageing leads to changes in the peripheral immune system that manifest as inappropriate immune responses. In some older individuals, this may result in a state of low grade chronic inflammation known as inflammaging. Inflammaging contributes to progression of a number of age-related diseases including frailty and dementia and may play a role in ARHL.We have conducted two separate studies which have identified associations between age-related hearing loss and systemic inflammation. In both studies we have identified an association between the severity of hearing loss and systemic inflammatory status. We performed a cross-sectional analysis using 320 subjects aged between 60 and 89 years using a cohort from the National Study of Hearing. We have identified a positive association between the severity of hearing loss and inflammatory level, measured by white blood cell count (WBC). The association between worsening hearing loss and highWBCwas stronger for the very old (subjects aged 75 years or older). When subjects were stratified into tertiles according to their WBC, subjects with higher WBC had significantly poorer hearing compared to the subjects with lower WBC. In an ongoing longitudinal study, we are measuring changes in the hearing level of older people and their inflammatory statuses over a 3-year period to identify subjects at the greatest risk of worsening hearing loss. The current findings suggest there is a relationship between systemic inflammation and age-related pathology in the auditory system.