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Periodic Reporting for period 1 - Fit-The-Fat (IMMUNOMETABOLISM IN HUMAN OBESITY)

Reporting period: 2017-09-01 to 2019-08-31

In this project, I aimed to investigate the role of immune cells in the context of human obesity and type 2 diabetes (T2D), conditions tightly associated with insulin-resistance (i.e. resistance of tissues to insulin action). In particular, I studied T cells localized in the visceral fat of obese patients with and without T2D to elucidate whether they are relevant for the local inflammation occurring in the context of insulin-resistance. Identification of one or more T cell subsets with the potential to induce local inflammation and sustain insulin-resistance may help elucidating alternative mechanisms of T2D and promote the development of novel therapies for this disease. The question that I attempted to address with this project is: what are the features and functional properties of T cells at the site where inflammation is ongoing in human obesity? And what changes occur when T2D develops in this context? Thanks to this project I assessed the profile of T cell subsets in the visceral fat of obese patients with and without T2D and identified a subset with a proinflammatory profile endowed with the potential to induce insulin-resistance.
In this project I showed that there are unique features of T cells at the site of inflammation of human obesity (i.e. the visceral fat), both in the presence and absence of T2D. The established notion that the visceral fat in human obesity is enriched with proinflammatory T cells does not apply to T cells by default. This is shown by the evidence that: (i) a shortage of proinflammatory T cells is evident in obese visceral fat compared to the leanness condition; (ii) in the presence of T2D, T cells become hyper-activated and refractory to suppression; (iii) in the presence of T2D, a subset of CD4 T cells was found to be impaired in the visceral fat but endowed with a proinflammatory profile. These evidence will lay the ground for investigation of modulation of T cell responses for therapeutic intervention in the context of human obesity and T2D.
Results coming from this project were disseminated through outreaching activities, such as the European Researcher’s night (MeetMeTonight) and public events organized for patients at the San Raffaele Diabetes Research Institute. Furthermore, I was interviewed on the MSCA fellowship project and the articles were published on the official website of a patient organization and on the Gruppo San Donato (GSD) official journal. Data were also presented at the Ospedale San Raffaele Scientific Retreat, at the Department of Immunology of Ospedale San Raffaele and at the European Association for the Study of Obesity Congress. Moreover, an original article is now under revision in a scientific journal.
Thanks to this project, I have assessed the profile and function of T cell subsets in the visceral fat, both in physiology and in obesity. Moreover, I have identified a subset of T cells with the potential to induce insulin-resistance and foster the development of T2D in obese patients. Health care costs of obesity in EU are estimated around €32.8 billion a year, mainly due to co-morbidities such as T2D and cardiovascular diseases. Identification of alternative (immune-mediated?) mechanisms to halt insulin-resistance may allow the development of new drugs, with the potential to prevent the development of T2D and its secondary complications.
summary of project results for general audience