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The role of adipose tissue in obesity: beta cell crosstalk

Final Report Summary - ADIBET (The role of adipose tissue in obesity: beta cell crosstalk)

Obesity is a metabolic condition that is quickly reaching epidemic proportions both in Europe and beyond, due mainly to changes in lifestyle but also the aging of the population. Obesity increases the likelihood of cardiovascular disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. With high morbidity and mortality rates and numerous serious complications, obesity represents a huge health and economic burden for healthcare systems and for society as a whole.

Despite recent advancements, treatments currently available for obesity, such as gastric bypass surgery, have a questionable level of long-term effectiveness, availability, ease and comfort, and many have an elevated cost and risk of complications. Within this context, and having observed the changes in adipose and beta-cell mass that take place in both obesity and diabetes, the ADIBET project seeks to innovate treatment methods for obesity by unravelling the molecular basis of adipose tissue regulation and beta-cell crosstalk in vivo and by searching for new drug targets.

ADIBET project objectives are:

-To analyse adipocyte transcription and secretion profile during the etiopathogenesis of obesity, and to detect differences in adipocyte function and secretion due to depot localization, sex and age.
-To study the changes in islet gene expression during progression towards obesity.
-To identify factors secreted by adipose tissue which are able to control beta cell replication and apoptosis, and to characterise adipokine-mediated crosstalk with beta cells.
-To provide project researchers with complementary training and networking opportunities, and to disseminate the results obtained from the project.

In order to reach the aforementioned objectives, ADIBET researchers, using different animal models of obesity and diabetes, have performed the following work:

-Studied the transcriptomics of different adipose tissue depots in the pathogenesis of obesity.
-Analyzed the transcriptomics of beta-cell mass in obese animals.
- Using a systmes biology approach, integrated all the metabolic, transcriptomic and proteomic information to study the interaction between adipose tissue and pancreatic islets.
- Examine the role of key proteins (c-myc, wnt, igf, rkip) in beta cell physiology and mass regulation, and as well as during the onset of obesity.
- Explored the gene expression changes in the endothelium after onset and during the progression of hyperglycaemia in the absence of obesity.
- Using coculture of adipocytes and islets, to explore the biocomunication between these two tissues.
-Developed a web-based data integration and management tool in order to help the integration and analysis of all omics data generated by the ADIBET consortium.
-Participated in training workshops, conferences and secondments, or exchanges with ADIBET consortium partners, and presented their work at national and international conferences and published their results in international scientific journals.

Consequently, the main results stemming from the work described above include:

-Discovery of new adipokines able to control beta cell replication during the pathogenesis of obesity.
-Identification of new key beta cell mass regulators.
-Unravelling of gene expression correlation in the endothelium and in beta cell mass due to changes in blood glucose levels independent of obesity.
-Description of different TCF-L2 genotypes in type 2 diabetes and their impact on cell survival.
-Identification of the molecular determinants in the adipose tissue secretome that regulate pancreatic islet proliferation.
-Discovery of the target that regulates cell proliferation in pancreatic islets induced by the adipose tissue secretome.
-Observation of no synergy or additive effects above c-Myc only, even at very low level c-Myc activation, with a high-fat diet.
-Description of in vitro conditioned medium from adipocytes from obese diabetic, but not from obese controls, synergising with c-Myc in beta cell apoptosis and secretory defect.
-Observation of IGF-II reactivated after injury, and that the absence of IGF2 prevents effective beta cell recovery after injury.
-Conclusion that the factor in adipocyte conditioned medium that synergises with c-Myc in vitro is more likely to be free fatty acids rather than adipokines, and that palmitic acid is more toxic than oleic acid.

All these results help to gain an improved understanding of the molecular mechanisms that control beta cell plasticity and why, in certain obese patients, beta-cell mass fails to compensate for the metabolic needs of the body, leading to beta-cell failure and, consequently, diabetes.

This newly generated knowledge undoubtedly has a significant long-term potential impact for both the academic and scientific community and for society as a whole, which, over time, may be noticed in the following ways:

-Identification of genes/proteins as potential drug targets more effective and sustainable therapies for obesity and diabetes.
-Increased quantity and quality of scientific publications in international journals and of communications presented at international conferences by ADIBET researchers.
-Newly forged relationships and strengthened existing relationships involving ADIBET partners, leading to fruitful new international scientific collaborations.
-Greater competitive funding for new projects that may stem from the ADIBET project.
-Transferability of ADIBET results to the pharmaceutical industry, including patent commercialisation.
-Increased international projection of biomedical research stemming from Europe.
-Economic and social relief for countries in Europe and beyond whose healthcare systems deal with the burden of obesity and diabetes.

The ADIBET Consortium website is www.adibet.org.