This line includes several sub-lines of research:

1.1. Characterisation of new factors involved in the regulation of developmentand function of different types of adipose tissue and their implication in susceptibility to developmentobesity.
Dysfunction of adipose tissue is crucial in the developmentof obesity, diabetes subject2, metabolic syndrome, fatty liver, and other obesity-associated comorbidities. White adipose tissue is the main energy storage organ, and is also an important endocrine organ, so its proper function is essential for maintaining energy-metabolic homeostasis. It is important to note that white adipose tissue is highly heterogeneous, with visceral fat being associated with insulin resistance and cardiometabolic risk, while subcutaneous fat has a protective effect. Brown adipose tissue and beige adipocytes are thermogenic, acting as energy dissipators, and their activation is beneficial in obesity, triglyceride metabolism, glucose homeostasis and insulin sensitivity. While white adipose tissue expands during obesity and ageing, brown adipose tissue activity decreases. On the other hand, bone marrow adipose tissue represents an important bone marrow volume and increases with obesity and age. However, its function and regulation is much less well understood than that of white or brown adipose tissue. Understanding the factors that control the trainingof the different types of adipocytes, as well as the expansion capacity of adipose tissue, is critical in the fight against the obesity epidemic. Our current focus of our programs of studyis on characterising the role of transcription factor PRDM1 and proteins involved in cell cycle regulation (Cdks, cyclins).

1.2. Obesity, pre-diabetes and diabetes subject2: role of microbiota and probiotics
In parallel to obesity, the prevalence of diabetes mellitus subject2 has been increasing in recent years, as the link between excess body fat and diabetes mellitus subject2 is clear. The relationship between the two is so close that the term "Diabesity" has been coined. Pre-diabetes is a stage prior to diabetes that is characterised by moderately elevated blood sugar levels, but not high enough to be diagnosed as diabetes subject2.

In recent years, numerous scientific programs of studyhave linked the composition of the gut microbiota to the developmentof obesity and diabetes subject2. In fact, relevant differences have been described between the microbiota of normal-weight and obese people. In this context, it has been proposed that the administration of certain probiotics could be a therapeutic strategy for weight control, glycaemic control and diabetes prevention. In this context, some of the projects at developmentare included in this areaof research.

1.3. Role of nutrient transporters in different pathophysiological situations
Nutrient transporters play an important role in the pathophysiology of metabolic diseases such as obesity, insulin resistance and diabetes subject2, as well as in neurodegenerative diseases and cancer. Specifically, glucose transporters are of fundamental importance in energy metabolism as they mediate its entranceand exit to the different cells, and are therefore fundamental in processes leading to obesity. Our groupat researchis working on the characterisation of the function of the GLUT12 transporter, one of the least studied glucose transporters, in some of the aforementioned pathologies.

Obesity is associated with the developmentof metabolic diseases such as diabetes subject2, fatty liver and certain cancers and leads to a decrease in life expectancy because it promotes a variety of cellular processes that lead to ageing. It is well known that ageing is accompanied by an increase in visceral fat and the developmentof metabolic complications. Both ageing and obesity have been identified as chronic inflammatory pathologies under Degree. Inflammation associated with ageing(inflammaging) is considered a risk factor for most age-related diseases and thus morbidity and mortality in the elderly. However, the underlying mechanisms have not been fully identified. Our researchfocuses on:

2.1. Identify the mechanisms involved in the chronic inflammation that occurs in obesity and ageing.including the study of profilein lipid mediators specialised in the resolution of inflammation.

2.2. Conduct an integrated study of the pathophysiological and metabolic changes occurring in metabolic organs core topicduring ageing and obesityThe study will focus on adipose tissue (white, brown, beige and bone marrow), muscle and the gastrointestinal tract (fatty liver, altered intestinal function and microbiota).

2.3. Characterise the actions and mechanisms of action of DHA supplementation and physical exercise. DHA supplementation and physical exercise in animal models of obesity and ageing, as well as in post-menopausal women.

2.4. To study the therapeutic potential of various pro-resolving lipid mediators of inflammation, such as Maresin 1, in obesity and associated comorbidities (insulin resistance, fatty liver, intestinal inflammation).such as Maresin 1, in obesity and associated comorbidities (insulin resistance, fatty liver, intestinal inflammation).

Funding Entity: Ministry of Science and Innovation 

Referencia: PID2019-106982RB-I00

Acronym: OBLIMPO

researcher principal: Prof. María Jesús Moreno Aliaga

Duration: June 2020 to May 2023

Principal Researcher: Mª Jesús Moreno Aliaga

project development of nutritional formulas for the pre-diabetic population based on micro-organisms with normoglycaemic capacity.

Referencia: 0011-1365-2020-000249.

Period and place of execution: 01/04/2020 to 31/03/2022

Participants:

Genbioma Aplicaciones S.L

University of Navarra

Public University of Navarra

Funding entity: Grants for the realisation of projects of research and development 2020. department of development Economic and Business. S3 Strategic Projects Service. Business Innovation Section.

"This business has received a financial aid co-financed 50% by the European Regional Fund development through the ERDF Operational Programme 2014-2020 of Navarra".

Funding Entity: Government of Navarre Industry

Reference: PI026 Acronym: BIOAGEMT

researcher principal: Pedro González Muniesa

The number and proportion of people over 60 years of age is growing in virtually all countries. According to the World Health Organisation (WHO), by 2025, the estimated number of older people worldwide will reach 1.2 billion, with approximately 840 million in low-income countries. Population ageing is therefore considered a social, health and economic challenge core topic. In Europe, the population over 65 years of age is around 17.4% and is expected to reach almost 30% by 2060. Currently, in Navarre, the over-64s account for around 19% of the population. It is therefore necessary to promote healthy and active ageing, enabling the population to age with the maximum functional capacity, health and quality of life.

Given the biological complexity of the ageing process, and the inter-individual variability (chronological age is not always associated with biological age), there are no effective tools to assess healthy ageing at the individual or population level. There is therefore a growing interest in identifying biomarkers to establish the key characteristics/mechanisms of healthy ageing.

Ageing is a phenomenon characterised by a chronic inflammatory state of low Degree, commonly called inflammaging, which is considered a risk factor for the development of most age-related diseases and thus for morbidity and mortality in the elderly. Moreover, obesity and unhealthy nutrition favour the development of a chronic inflammatory state, so that in adulthood obesity may accelerate and enhance the inflammation that occurs during ageing. This inflammation may affect telomere length, shortening telomeres and may accelerate the ageing process. Moreover, inflammation at the gut level may also affect the composition of the microbiota, and there is evidence that the microbiota has an enormous impact on health. Indeed, it has been suggested that alterations in the composition of the microbiota that occur with age are linked to an increased predisposition to develop metabolic diseases, such as diabetes, and even neurocognitive impairment or Alzheimer's disease.

Therefore, the present project aims to carry out an integrated study to characterise changes in microbiota composition, telomere length and relevant metabolic markers such as FGF21 and other age-related inflammatory factors, and how obesity could aggravate these changes, and in contrast, how the practice of physical exercise could attenuate them, favouring healthy ageing. Studies will be carried out both in animal models of obesity and ageing and in samples of overweight/obese postmenopausal women, a stage particularly susceptible to the development of metabolic complications associated with ageing and obesity.

The present project will allow the identification of biomarkers of ageing risk to enable personalised dietary and lifestyle strategies for promote healthy ageing. And it could allow a future development of diagnostic/prognostic kits. Therefore, the proposed project is considered to have a relevant impact at the health and social level and also for the industrial sector (food, biotechnology and pharmaceuticals).

Funding entity: Government of Navarre- department de development Económico (projects research and development Centros)

Reference: PC056-057. Acronym: ALZOBIN

Principal Researcher: Mª Jesús Moreno Aliaga

In recent decades, increased life expectancy and a sedentary lifestyle have resulted in an ageing and obese society. This translates into a higher incidence of diabetes, cardiovascular and/or neurodegenerative diseases that cause millions of deaths each year and significantly increase the associated healthcare costs. On the other hand, ageing, and related neurological disorders, are complex phenomena characterised by a chronic inflammatory state of low Degree (a process that also occurs in obesity) known as inflammaging. Alzheimer's disease (AD) is the most prevalent neurological disorder in Spain, with a prevalence of 5-10% among people over 65 years of age. The main risk factor for AD is advanced age but obesity has recently been identified as another transcendental risk factor for the development of this pathology. Although the exact mechanism by which obesity facilitates the development of AD is not known, it has been suggested that altered secretion of pro-inflammatory adipokines may induce neuroinflammation, impairing cognitive function.

However, to date there are no effective pharmacological treatments for either of these two diseases. The main goal of this project is to characterise whether proteins of the p27-Cdk2 axis can become a new therapeutic target for the treatment of obesity and the risk of AD.

Our hypothesis is based on the fact that, at the molecular level, several studies have defined essential pathophysiological functions of different components of the cell cycle machinery in AD and obesity. Thus, p27 inhibits Cdk2 and Cdk5, kinases involved in the phosphorylation of Tau, one of the main histopathological markers of AD. In addition, the role of the p27-Cdk2 axis in neurogenesis has been demonstrated and, on the other hand, p27 knockout mice show higher levels of proinflammatory cytokines, which would point to its role in the inflammaging process. Furthermore, preliminary studies and in silico studies of our group suggest a variation of different axis proteins in relation to ageing, AD severity Degree and obesity in brain and adipose tissue samples. However, to date, no study has analysed the possible link between the p27-Cdk2 axis and these diseases.

To this end, the levels of p27, Cdk2, cyclin A/E (in human adipose tissue and brain samples) will be analysed and whether they are modulated by ageing, AD or obesity and the correlation of these changes with neuropathological, cognitive or inflammatory markers. The effects of the absence of p27 (p27 KO mice), during the ageing process and the susceptibility to develop obesity with a high-fat per diem expenses will also be studied in animal models. On the other hand, the possible therapeutic effects of the administration of Bortezomib (a drug used in the treatment of haematological pathologies that, among other actions, increases p27 levels) will be evaluated in animals with accelerated senescence (SAMP8), fed with a control or high-fat per diem expenses , analysing the susceptibility to prevent / reverse the cognitive deficits associated with senescence and obesity induced by per diem expenses.

The results of this project will be of great relevance as they respond to the important social, medical and economic challenge of an increasingly ageing, obese population with a higher prevalence of cognitive impairment, and the need to find effective interventions and/or therapies for healthier ageing.

Reference: BFU2015-65937-R

researcher principal: Prof. María Jesús Moreno Aliaga; Co-IP: Silvia Lorente

Funding Entity: Ministry of Economy and Competitiveness

Obesity is associated with the development of metabolic diseases including diabetes subject 2. Obesity leads to a decrease in life expectancy by promoting various cellular processes that lead to ageing. It is well known that ageing is accompanied by increased visceral fat accumulation and the development of metabolic complications. Both ageing and obesity have been identified as pathologies of chronic inflammatory origin under Degree. Inflammation associated with ageing (inflammaging) has been considered as a risk factor for most age-related diseases and thus for morbidity/mortality in the elderly. However, the underlying mechanisms have not been fully established.

The resolution of inflammation is an active process involving the production of pro-resolving lipid mediators such as lipoxins, resolvins, protectins and maresins. We hypothesise that chronic inflammation associated with obesity and ageing could be result due to insufficient production of these pro-resolving lipid mediators, especially in adipose tissue. On the other hand, it has been shown that the expression of an altered transcriptional pattern could also be a factor in the development inflammation associated with obesity and ageing. Therefore, the first goal of this project is to characterise the mechanisms involved in the chronic inflammation that occurs in obesity and ageing.

Given that omega-3 polyunsaturated fatty acids (n-3 PUFA) are precursors in the synthesis of pro-resolving lipid mediators and are also involved in transcriptional regulation, our project proposes that long-term dietary supplementation with n-3 PUFA, alone or in combination with regular physical exercise, could promote resolve local and systemic inflammation associated with obesity and ageing. We therefore set out to study the pathophysiological mechanisms of inflammation in ageing and the potential benefits of long-term dietary supplementation with DHA, an n-3 PUFA, as well as physical exercise in mice with obesity induced by per diem expenses. In this model, we will focus on the study of the biology and metabolism of adipose tissue (white, beige and brown) with special emphasis on the characterisation of the transcriptional pattern and pro-resolving lipid mediators of inflammatory character, as well as their impact on gluco-lipid metabolism. Pathophysiological alterations of muscle and gastrointestinal tract (liver, intestinal function and its microbiota) will also be studied.

On the other hand, a nutritional intervention study will also be carried out in overweight/obese post-menopausal women to characterise the effects of the administration of a DHA-rich dietary supplement and/or a progressive resistance physical exercise programme. Their actions on weight loss and fat mass, insulin sensitivity and inflammatory markers of adipose tissue will be studied as well as the profile of gene expression, miRNAs and lipidomics. Finally, in vitro mechanistic studies will be performed on human adipocytes, alone or in co-culture with macrophages, muscle and intestinal cells that will allow a better characterisation of the interactions between these tissues in the context of obesity and inflammatory pathologies.

Reference: 67-2015

researcher principal: María Jesús Moreno Aliaga

Funding Entity: Government of Navarre

Obesity is considered a chronic inflammatory pathology of low Degree. Furthermore, this obesity-associated inflammatory state has been proposed as a link to several obesity-associated disorders such as insulin resistance, cardiovascular disease and metabolic syndrome. Obesity has also been associated with a higher prevalence and worse prognosis of inflammatory bowel disease. Moreover, obesity-associated neuroinflammation has been linked to the development of central insulin resistance, neurocognitive disorders and Alzheimer's disease. It is now known that the resolution of inflammation is an active process involving local bioactive mediators produced in the final phase of inflammatory processes, such as resolvins, protectins and maresin (derived from omega-3 fatty acids).

Our hypothesis is that chronic inflammation associated with obesity and the development of metabolic, intestinal and neurocognitive disorders is accompanied by a deficit in the levels of these pro-resolving lipid mediators of inflammation. Therefore, the first goal of the present study is to determine whether there are differences in the levels of pro-inflammatory lipid mediators in adipose tissue and intestinal mucosa between lean and obese subjects. On the other hand, and taking into account the relationship between neuroinflammation and Alzheimer's disease, we also set out to analyse whether the development of Alzheimer's disease is associated with a reduction in the levels of these pro-resolving mediators.

Moreover, treatment with these lipid mediators could be a potential therapy to combat chronic inflammation associated with obesity. Therefore, we also aim to determine the efficacy of oral administration of maresin 1 (MaR1) in obese mice on adipose tissue inflammation and insulin resistance, on intestinal function, and on neuroinflammation and potential cognitive impairment associated with obesity. Its actions on the intestinal microbiota will also be analysed.

Finally, studies will be carried out in cell cultures of adipocytes and Caco-2 cells, a model of human intestinal epithelium, to further investigate the mechanisms of action of MaR1 and its ability to reverse inflammation-induced functional alterations.

→ Asunción Redín

Paola E. Gámez

Adrián Idoate

Alejandro Martínez

Ana Velasco

Irene Vides

This line is considered a central axis for the generation of basic knowledge for the orientation and the development of the rest of the lines of the Centre. However, it is expected that the findings derived from this area will allow the identification of biomarkers of inflammation and ageing, as well as the characterisation of new therapeutic/nutritional targets, which will eventually allow the identification of compounds and molecules that can be part of future food supplements (with activating effects on the energy expense , reduction of white fat and activation of brown fat, and regulators of lipid and glucose metabolism and intestinal absorption).

This research will also allow the identification of new candidates as potential biomarkers for the diagnosis, prognosis and/or treatment of obesity and associated metabolic pathologies.