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Mechanisms of Disease

Molecular Metabolism

Rubén Nogueiras Pozo
Group Leader | Associate Professor
ruben.nogueiras@usc.es
 
Lab: P0L4
Field of knowledge

The group is focused on the study of molecular mechanisms involved in obesity and its associated diseases such as type 2 diabetes, non-alcoholic fatty liver disease, and Alzheimer's disease. In particular, we focused on alterations in glucose homeostasis, insulin sensitivity and lipid metabolism, which cause a direct metabolic dysfunction. Moreover, we investigate whether defects in these molecular pathways may have an impact at later ages in the prevalence of neurodegenerative diseases, particularly in Alzheimer's disease. In the challenge to decipher the complex and multiple pathways leading to metabolic failure, we use different approaches such as genetically engineered mice, pharmacological tools, and in vitro assays. We have also established a close collaboration with several clinical groups in order to understand the translational potential of our preclinical data.

Research Lines

Members

Begoña Porteiro Couto
Juan de la Cierva researcher
begoporteirocouto@gmail.com
Cristina Iglesias García
Postdoctoral research associate
cristina.iglesias@usc.es
Natalia da Silva Lima
Postdoctoral research associate
natalia.lima@usc.es

 

Uxía Fernández Paz
PhD student
Paola Valero Ávila
FPI fellowship
Sara Martínez Martínez
FPU fellowship
Eva Novoa Deaño
PhD student
Alba López Cabaleiro
Xunta de Galicia fellowship
Tamara Parracho Martínez
Xunta de Galicia fellowship
Valentina Dorta Bouza
PhD student
José Iglesias Moure
Idis pre-doctoral fellowship

Selected Results

Figure 1. Schematic overview summarizing the expression of SARS-CoV-2 cell entry molecules (angiotensin converting enzyme 2 (ACE2) and the cellular transmembrane protease serine 2 (TMPRSS2)) in the liver of healthy patients and patients with type 2 diabetes or non-alcoholic steatohepatitis. For more info see: Fondevila MF et al, Journal of Hepatology 2021.

 

Figure 2. Schematic overview summarizing the role of the LPI/GPR55 system in the development of non-alcoholic fatty liver disease. LPI, the endogenous ligand of GPR55, induces AMP-activated protein kinase (AMPK) and activation of acetyl-CoA carboxylase (ACC), thereby increasing lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing beta oxidation. In addition, LPI promotes the initiation of hepatic stellate cells activation by stimulating GPR55 and activation of ACC. For more info see: Fondevila MF et al, Hepatology 2021.

 

Figure 3. Schematic overview summarizing the role of the hypothalamic dopamine system in the control of body weight. Activation of the dopamine system in hypothalamic neurons of the lateral hypothalamic area and zona incerta activate orexin neurons that finally stimulate the sympathetic nervous system and trigger brown adipose tissue thermogenesis, which ultimately decreases weight gain. In patients treated with cabergoline (dopamine receptor agonist), there is an improvement of the glycemic profile, increase of energy expenditure and a decrease in body weight. For more info see: Folgueira C et al, Nature Metabolism 2019.

 

Figure 4. Schematic overview summarizing the role of hypothalamic p53 in energy balance. Inactivation of p53 in hypothalamic AgRP neurons increments the sensitization of animals to high fat diet. Mice lacking p53 in AgRP neurons show hyperphagia, increased adiposity, lower brown adipose tissue thermogenesis and energy expenditure, which leads these mice to gain more weight. For more info see: Quiñones M et al, Nature Communications 2018.

 

Figure 5. Schematic overview summarizing the role p53 in the liver. The lack of p53 in the liver increases the expression of p63, causing inflammation, endoplasmic reticulum stress and stimulates lipogenesis, thereby increasing the storage of lipids in the liver. The activation of hepatic p53 causes the opposite effects and reduces the lipid content in the liver. For more info see: Porteiro B et al, Nature Communications 2017. 

 

Figure 6. Schematic overview summarizing the effects of the hypothalamic kappa opioid receptor (KOR) in the liver. The blockade of KOR within the lateral hypothalamic area (LHA) protects against diet- and melanin concentrating hormone-induced liver steatosis. For more info see: Imbernon M et al. Hepatology 2016.

Projects

UE project(s)

Well-Aging and the Tanycytic Control of Health (WATCH)
REF: 810331Duration: -
PI: Rubén Nogueiras Pozo
European Commission

National project(s)

Interacciones celulares y sistémicas entre el cáncer y la señalización metabólica - Redes de Investigación 2018
REF: RED2018-102379-TDuration: -
PI: Rubén Nogueiras Pozo
AGENCIA ESTATAL DE INVESTIGACION
Estudios de SIRT3 sobre las vías homeostáticas y hedónicas relacionadas con la obesidad- RETOS JI...
REF: PID2020-114350RJ-I00Duration: -
PI: María del Mar Quiñones Pérez
AGENCIA ESTATAL DE INVESTIGACION

Contracts Agreements Services

Convenio de colaboración entre a Consellería de Cultura, Educación e Universidade e a Universidad...
REF: 2021-CP085Duration: -
PI: Rubén Nogueiras Pozo
CONSELLERIA DE CULTURA, EDUCACION E UNIVERSIDADE

Alliances

Centro de Investigación Biomédica en Red: Fisiopatología de la Obesidad y Nutrición

Patents

Methods of using up-regulators of the expression of p53 and/or down-regulators or inhibitors of the expression of p63 for the treatment of NAFLD (Non-alcoholic fatty liver disease) and/or NASH (non-alcoholic steatohepatitis)
Aplication Nº: EP3366296 B1
Methods for using regulators for increasing the expression or activation nof p53 and/or regulators for reducing or inhibiting the expression of p63-alpha, for the treatment of non-alcoholic fatty liver disease (NAFLD) and/or non-alcoholic steatohepatitis
Aplication Nº: EP15382519