ADAPT

Adipokines as Drug Targets to Combat Adverse Effects of Excess Adipose Tissue

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 Obiettivo del progetto (Objective)

'Obesity represents the major risk factor for the cardiometabolic syndrome, which is an epidemic disease that generates a severe global socio-economic burden for the public health systems. Enhanced production of proinflammatory adipocytokines by expanded adipose tissue is now considered as a key event in the pathogenesis of this syndrome. This process involves i) the systemic release of adipokines, preferentially by visceral abdominal fat and ii) the paracrine, adipokine-mediated crosstalk between periorganic fat and different organs including skeletal and cardiac muscle. Members of the ADAPT consortium have pioneered this novel view of adipose tissue as an active endocrine organ. However, there is very limited knowledge if adipokines and their downstream signalling pathways may represent “drugable” targets potentially opening new avenues to combat the devastating complications linked to obesity and the cardiometabolic syndrome. Therefore, the major goal of this project is to identify novel or existing adipocytokines as drug targets that could be used to reverse obesity-associated inflammation and adverse reactions related to excess fat, as outlined in the work programme. For this purpose the mustidisciplinary ADAPT consortium has been formed which integrates basic and clinical science, bioinformatics, in silico drug design and the specific expertise of a large pharmaceutical company. To reach the objectives, a stepwise strategy will be used including i) the identification of novel adipocytokines and the cellular sources and regulation of adipokine production, ii) the analysis of intraorgan crosstalk within adipose tissue which plays a pivotal role in adipose tissue inflammation, iii) the assessment of interorgan crosstalk with a focus on skeletal and cardiac muscle and the role of brown fat and iv) the pharmacological and clinical evaluation of adipokines as drug targets and potential biomarkers.'

Introduzione (Teaser)

Obesity is the major risk factor in cardiometabolic syndrome, a condition that puts patients at risk from heart attacks, strokes and complications of diabetes. An EU-funded project has completed research into the role of certain signalling proteins involved to facilitate the identification of new drug targets.

Descrizione progetto (Article)

One of the symptoms of cardiometabolic syndrome is inflammation in key sites such as white fat tissue, liver and immune cells. The likely culprits belong to a group of molecules called proinflammatory cytokines that set off a cascade of events that could lead to complications of obesity.

However, there is very limited information on adipocytokines and their downstream effects that may be the root cause of conditions like atherosclerosis, type 2 diabetes and rheumatoid arthritis. The 'Adipokines as drug targets to combat adverse effects of excess adipose tissue' (ADAPT) project set out to identify adipokines that could be modulated with new drugs to treat obesity-related inflammation and other adverse conditions linked with excess fat.

ADAPT scientists focused on finding new adipokines and determining the cross-talk between these compounds and other key molecular players involved in disease linked to obesity. Their findings promise to have substantial impact on the development of new anti-diabetic drugs in particular.

The team identified and characterised new adipokines and biomarkers. Chemical cross-talk was identified between macrophages (cells involved in immunity) and fat cells as well as preadipocytes, which can develop into mature fat cells.

Links between adipokine expression and different clinical symptoms of metabolic syndrome were also investigated at length. Moreover, novel assays were developed to detect signalling between fatty acids and adipokines.

Reduced insulin sensitivity is a key feature of type 2 diabetes and ADAPT scientists elucidated details on the mode of operation of hormone-sensitive lipase (HSL) in insulin resistance. The scientists also analysed the protein dipeptidyl peptidase-4 (DPP4) as a new adipokine, potentially linking obesity to the metabolic syndrome.

The storage site of fat tissue can be a crucial factor, prompting the scientists to study cardiac mass in relation to abdominal and thoracic fat deposits. They also collected data on the dynamics of adipose tissue turnover in health and disease.

The ADAPT project has classified adipose tissue as a hormone-producing tissue (endocrine organ) in its own right. As such, the molecules it produces can be up- or down-regulated, as appropriate to control their effects on other cells and tissues that result in disease. The development of new pharmaceuticals on this basis could revolutionise healthcare and the blight of obesity.