Histidine Phosphorylation and Obesity

Project Information

HisPO

Grant agreement ID: 891097

DOI

10.3030/891097

Project terminated on 30 September 2021

EC signature date 3 April 2020

Start date 1 May 2020

End date 30 April 2022

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 203 149,44

EU contribution

€ 203 149,44

Coordinated by

UNIVERSITAT BASEL
Switzerland

Periodic Reporting for period 1 - HisPO (Histidine Phosphorylation and Obesity)

Reporting period: 2020-05-01 to 2022-04-30

Summary of the context and overall objectives of the project

Protein histidine phosphorylation is a poorly characterized post-translational modification. Its importance in mammalian cellular function is emerging from the discovery of histidine kinases and phosphatases and their substrates. Recently, histidine phosphorylation has been involved in heart failure and cancer. Obesity and type 2 diabetes remain challenging disorders due to growing prevalence around the world and poorly efficient treatments. Regarding metabolic disorders, histidine phosphorylation state has been associated with insulin secretion regulation in pancreas. However, the role of histidine phosphorylation in insulin sensitivity in liver, skeletal muscle or adipose tissue and/or in obesity is still not known.
The main aim of the present project was to determine whether protein histidine phosphorylation plays a role in obesity-associated metabolic dysfunction. Thus, we determined if obesity modify global histidine phosphorylation level, histidine kinases and phosphatases expression or activity, and specific protein histidine phosphorylation. Then, we wanted to evaluate whether a change of histidine phosphorylation level can impact whole-body glucose metabolism and body weight/composition by using transgenic mice deficient in the main histidine phosphatase, LHPP.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The main objective of my proposed action was to determine if histidine phosphorylation changes upon obesity and to investigate the role of histidine phosphorylation in systemic glucose homeostasis. To achieve this, we used mice that were fed with a lipid rich diet to make them obese. We examined global pHis in the metabolic tissues of these animals. For that purpose, we used antibodies against phosphohistidine, developed at the Salk Institute (Tony Hunter lab) specifically recognizing the phosphoester (P-O) bond in serine, threonine, and tyrosine phosphorylation, the phosphoramidate (P–N) bond in pHis. We also used genetically modified animals to assess the impact of the loss of the most important phosphohistidine phosphatase the lysine-histidine-pyrophosphate phosphatase (LHPP). We evaluated metabolic phenotype of these mice to link any metabolic dysfunction with a change in histidine phosphorylation level.
We did not observe strong changes in global histidine phosphorylation in insulin sensitive organs from mice fed with a normal compared to a high-fat diet. The analysis of the LHPP KO animals mostly show changes in brown adipose tissue in favor with its activation.
Together, our study provides good preliminary results to be pursued to further explore the role of histidine phosphorylation in metabolic disease. The need of methodological improvements to study this post-translational modification is however still needed to ameliorate the amount and relevance of the obtained results.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Understanding a completely new area of biology and applying it to a disease with a growing prevalence is a major step in basic research. The proposed project may lead to discoveries on the role of histidine phosphorylation in physiology and pathophysiology, and in turn lead to new therapeutic strategies. There is need for such strategies because medical studies have shown that glucose-lowering drugs have little long-term benefits in diabetic patients. Indeed, it remains relevant to pursue basic research in this area and broaden our knowledge on the underlying mechanisms of metabolic disorders.

Can histine phosphorylation be involved in metabolic dysfunctions associated with obesity?