Obesity alters adipose tissue metabolic and endocrine function and leads to an increased release of fatty acids, hormones, and proinflammatory molecules that contribute to obesity associated complications. To further characterize the changes that occur in adipose tissue with increasing adiposity, we profiled transcript expression in perigonadal adipose tissue from groups of mice in which adiposity varied due to sex, diet, and the obesity-related mutations agouti (Ay) and obese (Lepob). We found that the expression of 1,304 transcripts correlated significantly with body mass. Of the 100 most significantly correlated genes, 30% encoded proteins that are characteristic of macrophages and are positively correlated with body mass. Immunohistochemical analysis of perigonadal, perirenal, mesenteric, and subcutaneous adipose tissue revealed that the percentage of cells expressing the macrophage marker F4/80 (F4/80+) was significantly and positively correlated with both adipocyte size and body mass. Similar relationships were found in human subcutaneous adipose tissue stained for the macrophage antigen CD68. Bone marrow transplant studies and quantitation of macrophage number in adipose tissue from macrophage-deficient (Csf1op/op) mice suggest that these F4/80+ cells are CSF-1 dependent, bone marrow-derived adipose tissue macrophages. Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for almost all adipose tissue TNF-alpha expression and significant amounts of iNOS and IL-6 expression. Adipose tissue macrophage numbers increase in obesity and participate in inflammatory pathways that are activated in adipose tissues of obese individuals.

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Obesity is associated with macrophage accumulation in adipose tissue

Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.

/pdf/inflammation-and-metabolic-disorders-1u8s009p99.pdf

Inflammation and metabolic disorders

Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance However, the underlying molecular pathways are largely unknown In this report, we show that many inflammation and macrophage-specific genes are dramatically upregulated in white adipose tissue (WAT) in mouse models of genetic and high-fat diet-induced obesity (DIO) The upregulation is progressively increased in WAT of mice with DIO and precedes a dramatic increase in circulating-insulin level Upon treatment with rosiglitazone, an insulin-sensitizing drug, these macrophage-originated genes are downregulated Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue

/pdf/chronic-inflammation-in-fat-plays-a-crucial-role-in-the-1sc0uiuvmi.pdf

Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance.

The metabolic syndrome

Adipose tissue is a complex, essential, and highly active metabolic and endocrine organ. Besides adipocytes, adipose tissue contains connective tissue matrix, nerve tissue, stromovascular cells, and immune cells. Together these components function as an integrated unit. Adipose tissue not only responds to afferent signals from traditional hormone systems and the central nervous system but also expresses and secretes factors with important endocrine functions. These factors include leptin, other cytokines, adiponectin, complement components, plasminogen activator inhibitor-1, proteins of the renin-angiotensin system, and resistin. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by the adverse metabolic consequences of both adipose tissue excess and deficiency. A better understanding of the endocrine function of adipose tissue will likely lead to more rational therapy for these increasingly prevalent disorders. This review presents an overview of the endocrine functions of adipose tissue.

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Adipose Tissue as an Endocrine Organ

Tumor necrosis factor-alpha (TNF-alpha) has been shown to have certain catabolic effects on fat cells and whole animals. An induction of TNF-alpha messenger RNA expression was observed in adipose tissue from four different rodent models of obesity and diabetes. TNF-alpha protein was also elevated locally and systemically. Neutralization of TNF-alpha in obese fa/fa rats caused a significant increase in the peripheral uptake of glucose in response to insulin. These results indicate a role for TNF-alpha in obesity and particularly in the insulin resistance and diabetes that often accompany obesity.

http://science.sciencemag.org/content/sci/259/5091/87.full.pdf

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

Treatment with AeriSeal is an alternate treatment option to achieve lung volume reduction in patients with severe COPD and emphysema who are not eligible for valve treatment. This study aimed to assess the safety and mode of action of a modified staged treatment algorithm with a staged treatment with lower dose of AeriSeal.We performed a prospective, multicenter feasibility study. AeriSeal was administered during two sequential bronchoscopies: 2 subsegments of a lobe treated with two 5 mL doses, followed by two 10 mL doses in a contralateral lobe after 6 weeks.A total of 14 patients (36% male, mean FEV1 28.4% ± 6.7% of predicted) were enrolled. Ten patients completed both treatments, four were treated unilaterally. AeriSeal treatment resulted in significant TLVR (median 220.5 mL) at 3 months follow up. There were no significant changes from baseline at 12 months in lung function, exercise capacity and quality of life. During the 3-month post-treatment period, respiratory SAEs included 5 COPD exacerbations in 4 (28.6%) subjects, post-treatment acute inflammatory response (PAIR) in 2 (14.3%) subjects, and 1 respiratory failure event in 1 (7.1%) subject.The staged and lower dosed administration of AeriSeal does not impact the overall safety profile in terms of reducing the type and frequency of respiratory SAEs previously reported for a single-stage treatment. A larger volume of AeriSeal than used in this study may be necessary to provide meaningful clinical benefits. 

A multicenter, prospective, single-arm clinical investigation of a modified staged treatment algorithm using the AeriSeal system - The STAGE trial.

Background: Absence of collateral ventilation (CV) in the target lobe is essential for effective endobronchial Zephyr Valve (ZV) treatment in emphysema patients. Closure of the fissure gap with AeriSeal Foam (AF) with successful ZV treatment has been reported (Ing A et al. J Bronchol Interven Pulmonl. 2020;27(1):e14). CONVERT is a multicenter, single arm study to confirm this finding (NCT04559464). Aims and Objectives: Evaluate AF to occlude collateral channels to convert a CV+ lung lobe to having little to no CV. A secondary objective is ZV treatment in the CV- converted patients. Methods: Study will enroll 140 subjects with Chartis® confirmed CV+ status. Up to 40mL AF may be delivered over 2 sessions per a unique fissure defect. CV assessed at 45 days post-AF and if CV-, treatment with ZV. Typical clinical outcomes will be assessed at 3 and 6 months post-ZV. Results: 32 subjects (16M/16F), mean±SD; age 65.2±7.0 yrs; post-BD FEV1 31.9±9.1% pred.; RV 224±38% pred. have been enrolled and treated with AF (21 in one session; 11 in 2 sessions - 6wk apart) across all lobes (11 RUL, 5 RLL, 12 LUL, 4 LLL). 83% of the subjects completing the first stage have successfully converted and treated with ZV. Enrollment and follow-up are ongoing. AEs to date include post-AF acute inflammatory response, 37.5%; lobar pneumonitis 12.5%; cough 9%; COPD exacerbations 9%. All AEs managed with standard of care. Conclusions: AF can safely and effectively occlude collateral channels and convert a CV+ lobe to having little to no CV. Emphysema patients with a defined fissure gap in the target lobe may have an option for BLVR with ZV after closure of the fissure gap with AeriSeal Foam.

Narinder S. Shargill

Papers

Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance

A multicenter, prospective, single-arm clinical investigation of a modified staged treatment algorithm using the AeriSeal system - The STAGE trial.

CONVERT Trial: Collateral ventilation conversion by closure of fissure defect with AeriSeal Foam for BLVR with Zephyr valves

A Meta-Analysis of Zephyr Endobronchial Valves for Management of Persistent Air Leaks