Endothelin receptor antagonism improves glucose handling, dyslipidemia, and adipose tissue inflammation in obese mice

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Abstract

Endothelin-1 (ET-1) is elevated in patients with obesity; however, its contribution to the pathophysiology related to obesity is not fully understood. We hypothesized that high ET-1 levels cause dyslipidemia, inflammation, and insulin resistance within the adipose tissue of obese mice. To test this hypothesis, male C57BL/6J mice were fed either normal diet (NMD) or high-fat diet (HFD) for 8 weeks followed by 2 weeks of treatment with either vehicle, atrasentan (ETA receptor antagonist, 10 mg/kg/day) or bosentan (ETA/ETB receptor antagonist, 100 mg/kg/day). Atrasentan and bosentan lowered circulating non-esterified free fatty acids and triglycerides seen in HFD mice, while atrasentan-treated mice had significantly lower liver triglycerides compared with non-treated HFD mice. ET-1 receptor blockade significantly improved insulin tolerance compared with insulin-resistant HFD mice and lowered expression of genes in epididymal white adipose tissue (eWAT) associated with insulin resistance and inflammation. Flow cytometric analyses of eWAT indicated that HFD mice had significantly higher percentages of both CD4+ and CD8+ T cells compared with NMD mice, which was attenuated by treatment with atrasentan or bosentan. Atrasentan treatment also abolished the decrease in eosinophils seen in HFD mice. Taken together, these data indicate that ETA and ETA/ETB receptor blockade improves peripheral glucose homeostasis, dyslipidemia and liver triglycerides, and also attenuates the pro-inflammatory immune profile in eWAT of mice fed HFD. These data suggest a potential use for ETA and ETA/ETB receptor blockers in the treatment of obesity-associated dyslipidemia and insulin resistance.

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Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.

Zobair Younossi, Aaron Koenig, Dinan Abdelatif … (2016)

Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver disease worldwide. We estimated the global prevalence, incidence, progression, and outcomes of NAFLD and nonalcoholic steatohepatitis (NASH). PubMed/MEDLINE were searched from 1989 to 2015 for terms involving epidemiology and progression of NAFLD. Exclusions included selected groups (studies that exclusively enrolled morbidly obese or diabetics or pediatric) and no data on alcohol consumption or other liver diseases. Incidence of hepatocellular carcinoma (HCC), cirrhosis, overall mortality, and liver-related mortality were determined. NASH required histological diagnosis. All studies were reviewed by three independent investigators. Analysis was stratified by region, diagnostic technique, biopsy indication, and study population. We used random-effects models to provide point estimates (95% confidence interval [CI]) of prevalence, incidence, mortality and incidence rate ratios, and metaregression with subgroup analysis to account for heterogeneity. Of 729 studies, 86 were included with a sample size of 8,515,431 from 22 countries. Global prevalence of NAFLD is 25.24% (95% CI: 22.10-28.65) with highest prevalence in the Middle East and South America and lowest in Africa. Metabolic comorbidities associated with NAFLD included obesity (51.34%; 95% CI: 41.38-61.20), type 2 diabetes (22.51%; 95% CI: 17.92-27.89), hyperlipidemia (69.16%; 95% CI: 49.91-83.46%), hypertension (39.34%; 95% CI: 33.15-45.88), and metabolic syndrome (42.54%; 95% CI: 30.06-56.05). Fibrosis progression proportion, and mean annual rate of progression in NASH were 40.76% (95% CI: 34.69-47.13) and 0.09 (95% CI: 0.06-0.12). HCC incidence among NAFLD patients was 0.44 per 1,000 person-years (range, 0.29-0.66). Liver-specific mortality and overall mortality among NAFLD and NASH were 0.77 per 1,000 (range, 0.33-1.77) and 11.77 per 1,000 person-years (range, 7.10-19.53) and 15.44 per 1,000 (range, 11.72-20.34) and 25.56 per 1,000 person-years (range, 6.29-103.80). Incidence risk ratios for liver-specific and overall mortality for NAFLD were 1.94 (range, 1.28-2.92) and 1.05 (range, 0.70-1.56).

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Margarida Saraiva, Anne O'Garra (2010)

Interleukin-10 (IL-10), a cytokine with anti-inflammatory properties, has a central role in infection by limiting the immune response to pathogens and thereby preventing damage to the host. Recently, an increasing interest in how IL10 expression is regulated in different immune cells has revealed some of the molecular mechanisms involved at the levels of signal transduction, epigenetics, transcription factor binding and gene activation. Understanding the specific molecular events that regulate the production of IL-10 will help to answer the remaining questions that are important for the design of new strategies of immune intervention.

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CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity.

Satoshi Nishimura, Ichiro Manabe, Mika Nagasaki … (2009)

Inflammation is increasingly regarded as a key process underlying metabolic diseases in obese individuals. In particular, obese adipose tissue shows features characteristic of active local inflammation. At present, however, little is known about the sequence of events that comprises the inflammatory cascade or the mechanism by which inflammation develops. We found that large numbers of CD8(+) effector T cells infiltrated obese epididymal adipose tissue in mice fed a high-fat diet, whereas the numbers of CD4(+) helper and regulatory T cells were diminished. The infiltration by CD8(+) T cells preceded the accumulation of macrophages, and immunological and genetic depletion of CD8(+) T cells lowered macrophage infiltration and adipose tissue inflammation and ameliorated systemic insulin resistance. Conversely, adoptive transfer of CD8(+) T cells to CD8-deficient mice aggravated adipose inflammation. Coculture and other in vitro experiments revealed a vicious cycle of interactions between CD8(+) T cells, macrophages and adipose tissue. Our findings suggest that obese adipose tissue activates CD8(+) T cells, which, in turn, promote the recruitment and activation of macrophages in this tissue. These results support the notion that CD8(+) T cells have an essential role in the initiation and propagation of adipose inflammation.