Abstract
Context
Human obesity is associated with increased circulating TNF-α, a proinflammatory cytokine that induces hepatocyte cell death.
Objective
The potential beneficial effects of acylated ...and desacyl ghrelin in the progression of nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis in obesity via the inhibition of TNF-α–induced hepatocyte apoptosis, autophagic cell death, and pyroptosis were investigated.
Design, Settings, and Participants
Plasma ghrelin isoforms and TNF-α were measured in 158 participants, and hepatocyte cell death was evaluated in liver biopsies from 76 patients with morbid obesity undergoing bariatric surgery with available liver echography and pathology analysis. The effect of acylated and desacyl ghrelin on basal and TNF-α–induced cell death was determined in vitro in human HepG2 hepatocytes.
Results
Circulating TNF-α and the acylated/desacyl ghrelin ratio were increased, whereas desacyl ghrelin levels were decreased in patients with obesity and NAFLD. Six months after bariatric surgery, decreased acylated/desacyl ghrelin levels, and improved hepatic function were found. Patients with obesity and type 2 diabetes showed increased hepatic ghrelin O-acyltransferase transcripts as well as an increased hepatic apoptosis, pyroptosis, and compromised autophagy. In HepG2 hepatocytes, acylated and desacyl ghrelin treatment reduced TNF-α–induced apoptosis, evidenced by lower caspase-8 and caspase-3 cleavage, as well as TUNEL-positive cells and pyroptosis, revealed by decreased caspase-1 activation and lower high-mobility group box 1 expression. Moreover, acylated ghrelin suppressed TNF-α–activated hepatocyte autophagy, as evidenced by a decreased LC3B-II/I ratio and increased p62 accumulation via AMPK/mTOR.
Conclusions
Ghrelin constitutes a protective factor against hepatocyte cell death. The increased acylated/desacyl ghrelin ratio in patients with obesity and NAFLD might constitute a compensatory mechanism to overcome TNF-α–induced hepatocyte apoptosis, autophagy, and pyroptosis.
Ghrelin acts as a survival factor by reducing TNF-α–induced apoptosis, autophagy, and pyroptosis mediated by HMGB1 in human hepatocytes, and thus prevents the progression of NAFLD to NASH.
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Obesity is characterized by adipose tissue expansion, extracellular matrix remodelling and unresolved inflammation that contribute to insulin resistance and fibrosis. Adipose tissue ...macrophages represent the most abundant class of immune cells in adipose tissue inflammation and could be key mediators of adipocyte dysfunction and fibrosis in obesity. Although macrophage activation states are classically defined by the M1/M2 polarization nomenclature, novel studies have revealed a more complex range of macrophage phenotypes in response to external condition or the surrounding microenvironment. Here, we discuss the plasticity of adipose tissue macrophages (ATMs) in response to their microenvironment in obesity, with special focus on macrophage infiltration and polarization, and their contribution to adipose tissue fibrosis. A better understanding of the role of ATMs as regulators of adipose tissue remodelling may provide novel therapeutic strategies against obesity and associated metabolic diseases.
Background and Purpose
Glucagon‐like peptide‐1 (GLP‐1) analogues improve glycaemic control in type 2 diabetic (T2D) patients and cause weight loss in obese subjects by as yet unknown mechanisms. We ...recently demonstrated that the GLP‐1 receptor, which is present in adipocytes and the stromal vascular fraction of human adipose tissue (AT), is up‐regulated in AT of insulin‐resistant morbidly obese subjects compared with healthy lean subjects. The aim of this study was to explore the effects of in vitro and in vivo administration of GLP‐1 and its analogues on AT and adipocyte functions from T2D morbidly obese subjects.
Experimental Approach
We analysed the effects of GLP‐1 on human AT and isolated adipocytes in vitro and the effects of GLP‐1 mimetics on AT of morbidly obese T2D subjects in vivo.
Key Results
GLP‐1 down‐regulated the expression of lipogenic genes when administered during in vitro differentiation of human adipocytes from morbidly obese patients. GLP‐1 also decreased the expression of adipogenic/lipogenic genes in AT explants and mature adipocytes, while increasing that of lipolytic markers and adiponectin. In 3T3‐L1 adipocytes, GLP‐1 decreased free cytosolic Ca2+ concentration (Ca2+i). GLP‐1‐induced responses were only partially blocked by GLP‐1 receptor antagonist exendin (9–39). Moreover, administration of exenatide or liraglutide reduced adipogenic and inflammatory marker mRNA in AT of T2D obese subjects.
Conclusions and Implications
Our data suggest that the beneficial effects of GLP‐1 are associated with changes in the adipogenic potential and ability of AT to expand, via activation of the canonical GLP‐1 receptor and an additional, as yet unknown, receptor.
Obesity is a widely prevalent pathology with a high exponential growth worldwide. Altered lipid accumulation by adipose tissue is one of the main causes of obesity and exploring lipid homeostasis in ...this tissue may represent a source for the identification of possible therapeutic targets. The study of the proteome and the post-translational modifications of proteins, specifically acetylation due to its involvement in energy metabolism, may be of great interest to understand the molecular mechanisms involved in adipose tissue dysfunction in obesity. The objective of this study was to characterize the subcutaneous and omental adipose tissue acetylome in conditions of obesity and insulin resistance and to describe the importance of acetylation of key molecules in adipose tissue to use them as therapeutic targets. The results describe for the first time the acetylome of subcutaneous and omental adipose tissue under physiological and physiopathological conditions such as obesity and insulin resistance. New evidence showed different acetylation patterns between two main depots and highlight the molecular complexity of adipose tissue. Results showed changes in FABP4 acetylation in subcutaneous fat in relation to insulin resistance, thus unveiling a potential marker of depot-specific dysfunctional expansion in obesity-associated metabolic disease. Furthermore, it is shown that the acetylation of FABP4 affects its function, modulating the capacity of differentiation in adipocytes. In conclusion, this study demonstrates a profound, depot-specific alteration of adipose tissue acetylome, wherein the acetylation of FABP4 may play a key role in adipocyte differentiation and lipid accumulation.
Urbanization projects, understood as those supplying basic services for cities, such as drinking water, sewers, communication services, power, and lighting, are normally short-term extremely ...scattered actions, and it can be difficult to track their environmental impact. The present article’s main contribution is to employ the project budgets of public urbanization work to provide an instrument for environmental improvement, thereby helping public procurement, including sustainability criteria. Two urban projects in Seville, Spain are studied: the first substitutes existing services, and the second also includes gardens and playgrounds in the street margins. The methodology finds the construction elements that must be controlled in each project from the perspective of three indicators: carbon, water footprints, and embodied energy. The main impacts found are due to only four construction units: concrete, aggregates, asphalt, and ceramic pipes for the sewer system, that represent 70% or more of the total impact in all indicators studied. The public developer can focus procurement on those few elements in order to exert a lower impact and to significantly reduce the environmental burden of urbanization projects.
Adipose tissue dysregulation in obesity strongly influences systemic metabolic homeostasis and is often linked to insulin resistance (IR). However, the molecular mechanisms underlying adipose tissue ...dysfunction in obesity are not fully understood. Herein, a proteomic analysis of subcutaneous (SC) and omental (OM) fat from lean subjects and obese individuals with different degrees of insulin sensitivity was performed to identify adipose tissue biomarkers related to obesity‐associated metabolic disease. Our results suggest that dysregulation of both adipose tissue extracellular matrix (ECM) organization and intracellular trafficking processes may be associated with IR in obesity. Thus, abnormal accumulation of the small leucine‐rich proteoglycan, lumican, as observed in SC fat of IR obese individuals, modifies collagen I organization, impairs adipogenesis and activates stress processes endoplasmic reticulum and oxidative stress in adipocytes. In OM fat, IR is associated with increased levels of the negative regulator of the Rab family of small GTPases, GDI2, which alters lipid storage in adipocytes by inhibiting insulin‐stimulated binding of the Rab protein, Rab18, to lipid droplets. Together, these results indicate that lumican and GDI2 might play depot‐dependent, pathogenic roles in obesity‐associated IR. Our findings provide novel insights into the differential maladaptive responses of SC and OM adipose tissue linking obesity to IR.
Dwelling renovation has gained major importance in the European Union due to the current need for the urban regeneration of many cities, most of whose existing buildings (approximately 60%) were ...built in the 1960s to 1980s. These renovations require improvements in aspects such as structural integrity, accessibility, and the updating of deteriorated or obsolescent installations. This reveals that building renovations constitute a key factor in the future of the European building sector and must be included in strategies both for the reduction of this sector’s environmental impact and for climate change mitigation. In order to determine the effectiveness of renovations and their impact, the HEREVEA (Huella Ecológica de la Rehabilitacion de Viviendas en Andalucia or Ecological Footprint of the Renovation of Dwellings in Andalusia) model is proposed on data obtained from the project’s bill of quantities, its ecological footprint is assessed, and the economic-environmental feasibility of different proposals are evaluated simultaneously. The resulting model is integrated into a geographic information system, which allows georeferenced results. The tool can be used for sustainable and resilient planning policy-making at all government levels, and for the decision-making processes. In this paper, economic and environmental indicators are, for the first time, simultaneously assessed through statistical normalization obtained from 50 cases analyzed in the city of Seville. Furthermore, five case studies are assessed in detail in order to determine the sensitivity of the model. These renovations represent less than 30% of the cost and 6% of the ecological footprint of a new construction project. During the subsequent 25 years, the energy efficiency improvements could significantly reduce the CO2 emissions that are due to direct consumption.
High-fat (HF) diets trigger an increase in adipose tissue and body weight (BW) and disordered eating behavior. Our study deals with the hypothesis that circadian distribution of energy intake is more ...relevant for BW dynamics than diet composition. Four-week-old mice were exposed for 8 wk to a HF diet and compared with animals receiving control chow. HF mice progressively increased BW, decreased the amount of nocturnal (1800–0900 h) calories (energy or food intake) (30%) and increased diurnal (0900–1800 h) caloric intake (energy or food intake), although total daily intake was identical between groups. Animals were killed at 3-h intervals and plasma insulin, leptin, corticosterone, glucose, and fatty acid levels quantified. Adipose tissue was weighed, and enzymatic activities integral to the pentose phosphate pathway (PPP) assayed in lumbar adipose tissue. Phosphorylated AMP-dependent protein kinase and fatty acid synthase were quantified by Western blotting. In HF mice, there was a shift in the circadian oscillations of plasma parameters together with an inhibition of PPP activity and a decrease in phosphorylated AMP-dependent protein kinase and fatty acid synthase. In a second experiment, HF mice were forced to adhere to a circadian pattern of food intake similar to that in control animals. In this case, BW, adipose tissue, morning plasma parameters and PPP activity appeared to be normal. These data indicate that disordered feeding behavior can trigger BW gain independently of food composition and daily energy intake. Because PPP is the main source of reduced nicotinamide adenine dinucleotide phosphate, we suggest that PPP inhibition might be an early marker of adipose dysfunction in diet-induced obesity.
Acute leptin increase as well as endogenous hyperleptinemia evoked by high-fat diets (HF) activate fatty acid metabolism in nonadipose tissues. This supports the notion that hyperleptinemia is ...pivotal to prevent/delay steatosis during periods of positive energy balance. We have previously shown that long-term HF spares ectopic accumulation of lipids specifically in the miocardium. Because carnitine palmitoyltransferase I (CPT-I) allows mitochondrial uptake/oxidation of fatty acids, we have hypothesized that leptin drives cardiac CPT-I activity. In the current study, hyperleptinemia was induced in C57BL/6J mice either by exogenous leptin administration or by means of HF, and the ability of malonyl-coenzyme A (malonyl-CoA) (the main endogenous inhibitor of CPT-I) to inhibit cardiac CPT was analyzed. IC50 values of malonyl-CoA were 8.1 ± 1.5 μmol/liter in controls vs. 69.3 ± 5.2 μmol/liter (P < 0.01) in leptin-treated mice. This effect was also observed in cardiac explants incubated with leptin and was blocked by triciribine, a compound shown to inhibit proteinkinase B (Akt) phosphorylation (pAkt). In accordance, acute leptin evoked an increase of cardiac pAkt levels, which correlated with CPT sensitivity to malonyl-CoA. Otherwise, the inhibitory effect of malonyl-CoA was hindered in HF hyperleptinemic mice, and in this case, pAkt levels also correlated with CPT sensitivity to malonyl-CoA. Our data show that leptin reduces the sensitivity of cardiac CPT-I to malonyl-CoA and suggest the involvement of an Akt-related signaling pathway in this effect. This mechanism appears to be sensitive to both acute and chronic hyperleptinemia. We conclude that this action of leptin is pivotal to drive cardiac metabolism under situations associated to hyperleptinemia.
Leptin reduces the sensitivity of carnitine palmitoyltransferase to malonyl-CoA by a protein kinase B (Akt)-related mechanism and prevents cardiac steatosis in obesity.
We aimed to evaluate the association between adipose tissue (AT) dysfunction, autoimmunity, and disease activity in rheumatoid arthritis (RA). A cross-sectional study including 150 RA patients and 50 ...healthy donors and longitudinal study with 122 RA patients treated with anti-tumor necrosis factor (TNF)-α, anti-interleukin 6 receptor (IL6R) or anti-CD20 therapies for 6 months were carried out. In vitro experiments with human AT and adipocyte and macrophage cell lines were performed. A collagen-induced arthritis mouse model was developed. The insulin resistance and the altered adipocytokine profile were associated with disease activity, the presence of anti-citrullinated proteins anti-bodies (ACPAs), and worse response to therapy in RA. AT in the context of arthritis is characterized by an inflammatory state alongside the infiltration of macrophages and B/plasmatic cells, where ACPAs can have a direct impact, inducing inflammation and insulin resistance in macrophages and promoting a defective adipocyte differentiation, partially restored by biologicals.
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•IR is related to disease activity, inflammation, and autoimmunity in RA patients•IR state and adipocytokines might be associated with a worse response to biologics•Visfatin could be used as a potential biomarker of subclinical atherosclerosis•ACPAs might directly impact adipose tissue
Health sciences; Rheumatology; Immunology.
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