Special Interview with Dr. Ilaria Barchetta

We are glad to have a special interview with Dr. Ilaria Barchetta in terms of her article "Expression of TGR5 in adipose tissue in relation to metabolic impairment and adipose tissue dysfunction in human obesity" published in Metabolism and Target Organ Damage on Sep 17, 2021. This study demonstrates that increased VAT TGR5 is associated with VAT dysfunction and impaired lipid trafficking and predicts the presence of metabolic disorders in human obesity, which ranks among the top 5 most viewed and downloaded in our journal. 

It also received much positive feedback when it was promoted on our journal's various social media. Here are the questions from readers and editors. Dr. Barchetta answered these questions carefully in detail one by one. 

1. Regarding the method, it is noted that your studies evaluated a group of 50 morbidly obese individuals undergoing bariatric surgery. However, data on a non-obese control group would probably strengthen your findings. Would you like to comment on this point?

For the aims of this study, we obtained fragments of omental fat, a visceral depot mostly represented in conditions of obesity, and then we focused on changes in TGR5 expression in relation to the adipose tissue micro-environment and metabolic phenotype in obese individuals. Previous investigations compared the expression levels of TGR5 mRNA in subcutaneous fat from both non-obese and obese cohorts, finding higher TGR5 expression in conditions of obesity. In the same cohort, a relationship was observed between greater TGR5 and dysmetabolic parameters ^[1].

Starting from these premises, we aimed at specifically exploring TGR5 within an obese population and correlating these findings with the metabolic phenotype. By comparing sub-groups of patients with differential omental TGR5 expression, we observed that the prevalence of type 2 diabetes triplicated and the one of metabolic syndrome doubled among patients in the lowest compared to the highest TGR5 expression group. Moreover, these cohorts were not different in terms of body mass index or distribution, but only in the quality of the omental fat, which displayed signs of altered lipid trafficking and meta-inflammation in patients with greater TGR5, and these findings were finally associated with the presence of clinically detectable metabolic disease. In conclusion, this investigation was designed to investigate determinants of TGR5 expression changes in obesity and led to demonstrate the existence of a strong association between TGR5 and the presence of metabolically unhealthy obesity, regardless of body mass index per se.

We see the point that data on TGR5 expression also non-obese healthy individuals would have provided further insights into TGR5 and metabolism in "basal conditions", i.e., absence of excessive caloric intake and fat mass expansion. However, obtaining omental fragments from healthy individuals may expose ethical concerns, since visceral fat biopsies can only be taken during surgery, which needs clinical reasons to be performed; this, by definition, excluded potential healthy donors to be recruited for this investigation.

2. Regarding the interpretation of findings, it can be speculated that under metabolic stressful conditions, such as calorie overload, and inflammation, metabolic regulators such as TGR5 may be over-expressed in the attempt to contrast further visceral fat mass expansion and adipose tissue dysfunction. If this is the case, how could it be explained that the administration of exogenous bile salt derivatives which are capable to activate TGR5 signaling has not achieved particularly impressive results for example in the treatment of NASH and T2D? 

This is a very good point. Our study demonstrated low TGR5 expression in the visceral adipose tissue in presence of local inflammation and concomitant clinically detectable metabolic disease. These findings may reflect the compensatory over-expression of TGR5 in the adipose tissue when it is stressed from chronic caloric overload, as in patients with severe obesity. Once metabolic disease occurs, it is unknown whether TGR5 activation may restore metabolic homeostasis and we do not have data on the potential benefit of TGR5 stimulation in reversing inflammatory changes in the adipose tissue. Our data give a cross-sectional description of qualitative changes in omental fat in patients with obesity and metabolic syndrome, which are associated with higher local TGR5 levels. Another interpretation of our study results is that in dysmetabolic patients with obesity, an impaired and/or insufficient TGR5 activation leads to higher TGR5 levels, as for negative feedback. So, higher TGR5 levels may just reflect a tentative of inducing the TGR5-associated metabolic pathway, in presence of a failure of this axis (altered bile acids balance? altered downstream signaling?). Hence, clinical data on TGR5 modulation by bile acids showed limited efficacy and some contrasting results. On the one hand, this may induce speculation that modifications of the TGR5 downstream cascade may occur in obesity and predispose to the development of metabolic disease; indeed, TGR5 hyper-activation may not reflect in favorable metabolic outcomes in these individuals. On the other hand, differential sites of TGR5 activation may lead to dissimilar effects on metabolism, as recently shown in a report demonstrating that the specific activation of TGR5 at enterohepatic rather than peripheral level, had potentially beneficial effects on NASH and glucose tolerance in pre-clinical models^[2].

3. What are the foreseeable lines of research in this area in the near future?

Starting from the previous considerations, investigating TGR5 in the enterohepatic axis in relation to gut metabolites and local mucosal inflammation could provide novel knowledge in the clinical setting. Also, studies should be extended to lean dysmetabolic individuals and subjects belonging to the normal weight category and suffering from sarcopenia, who represent a considerable rate of individuals at high risk of metabolic and cardiovascular disease.

4. Could you please provide some suggestions about which research aspects our journal should mostly focus on in the future to promote the long-term development of our journal?

I really believe that the focus on liver impairment in presence of metabolic disease is a target to maintain and further develop for this journal, as no therapy for this condition has been identified yet whereas clinical evidence on its detrimental effects on morbidity and mortality is rapidly growing also in the general population.

References

1. Svensson PA, Olsson M, Andersson-Assarsson JC, et al. The TGR5 gene is expressed in human subcutaneous adipose tissue and is associated with obesity, weight loss and resting metabolic rate. Biochem Biophys Res Commun 2013;433:563-6. doi: 10.1016/j.bbrc.2013.03.031
2. Gillard J, Picalausa C, Ullmer C, Adorini L, Staels B, Tailleux A, Leclercq IA. Enterohepatic Takeda G-Protein Coupled Receptor 5 Agonism in Metabolic Dysfunction-Associated Fatty Liver Disease and Related Glucose Dysmetabolism. Nutrients. 2022; 14(13):2707. https://doi.org/10.3390/nu14132707

Author's biography: 

Ilaria Barchetta, MD, PhD, is a Specialist in Internal Medicine, and holds a PhD degree in Clinical and Experimental Hepatology. She has been recently appointed as tenure track assistant professor (RTD-B) in Endocrinology at Sapienza University of Rome, Italy. She has focused her PhD and 5-year post-doc studies working on diabetes and clinical correlates of ectopic fat distribution, adipose tissue inflammation and non-alcoholic fatty liver disease. Her studies at Sapienza University were integrated with a post-doc period spent at Lund University, Sweden, funded by an award from the Italian Diabetes Society, working on the role of proneurotensin, an intestinal peptide promoting gut fat absorption, in determining metabolic diseases and NAFLD/NASH.

As a clinical researcher, she is involved in study design, data collection, advanced statistics (degree in Biostatistics, Sapienza University), data interpretation and scientific writing. For her research achievements, she has been awarded several honors and competitive funding; among all, in 2016 she was awarded a National Research Grant from Eli Lilly Foundation for carrying out a 3-year research project on diabetes and bone health. She is the author of 68 papers published in International peer-review journals (source Scopus: H index: 19, 1462 citations as of Aug 2) up to now. She was awarded the top peer reviewer in Biology and Biochemistry in September 2019. Her most cited article "Strong association between non alcoholic fatty liver disease (NAFLD) and low 25(OH) vitamin D levels in an adult population with normal serum liver enzymes" published in Sep 2021 has been cited 220 times (source Publons).

Respectfully Submitted by the Editorial Office 
Metabolism and Target Organ Damage