Researchers from the University of Granada have conducted a review of the scientific literature on the role of the ‘fat mass and obesity-associated’ (FTO) gene in the relationship between depression and obesity

Scientists from the University of Granada (UGR) have highlighted that the possible role attributed to the ‘fat mass and obesity-associated’ (FTO) gene in the comorbidity of depression and obesity can only be confirmed by conducting more studies involving individuals suffering from both diseases, together with more in-depth analysis of the different clinical subtypes of depression, as some are more prone to being accompanied by obesity than others.

In their study, which has been published in the prestigious journal Neuroscience & Biobehavioral Reviews, the researchers conducted an exhaustive systematic review of the scientific literature published to date on this topic, to better understand the role of this gene in the relationship between these two diseases.

Depression and obesity are both extremely common diseases in our society, with serious implications not only on a personal and family level but also for public, occupational, and economic health. Depression is currently considered the world’s leading cause of disability. No less serious, obesity is considered a pandemic constituting the main risk factor for other diseases that cause mortality, such as cardiovascular disease, type-2 diabetes, or cancer.

Juan Antonio Zarza Rebollo, a researcher from the UGR’s Department of Biochemistry and Molecular Biology II and the main author of this work, explains: “Depression and obesity have a strong bidirectional relationship—that is, obesity increases the risk of developing depression; and vice-versa, people with depression are at higher risk of becoming obese. Furthermore, it is common for depression and obesity to present as comorbidities—that is, they appear at the same time and coexist in the same individual, which poses an even greater health risk”.

There are different factors that increase the risk that an individual will develop depression and obesity simultaneously. These factors include having low self-esteem, having suffered maltreatment or abuse in childhood, social stigma, or a low level of family and social support. All of these can impact on the biology of each individual, where there are certain physiological mechanisms (which involve the hypothalamic-pituitary-adrenal axis or inflammation) or genetic risk variants that can play an important role in the appearance of these pathologies.

According to the “Ramón y Cajal” research fellow Margarita Rivera (coordinator of this work and of the research on physical health and mental health of this group and also a lecturer in the UGR’s Department of Biochemistry and Molecular Biology II): “The study of the underlying genetic factors involved in the comorbidity between depression and obesity is one of the active lines of research of our group. Specifically, the FTO gene has been investigated by this and other international research groups as a possible genetic link between both pathologies”.

A limited but important role

The role of genes in the development of these diseases is limited and cannot be considered a determining factor (that is, there is no “obesity gene” or “depression gene”). Esther Molina, a co-author of this research and lecturer at the UGR’s Department of Nursing, explains, however, that “there are genetic variants common to both disorders that confer a greater risk of developing these diseases on those who carry those variants because they can interact with the environment, giving rise to an individual risk for these pathologies. Hence, we find that some individuals are more likely to develop them than others”.

This systematic review was undertaken to derive insights from the published scientific evidence on the possible role that one particular gene, the FTO gene, may play in comorbid depression and obesity. This gene contains an area that varies from person to person, known as a polymorphism.

“The presence of the so-called ‘risk’ variant of this polymorphism has been linked by numerous studies to a greater probability of suffering from obesity and to an increase in body weight in humans. Although there are no studies that associate it with depression independently, the FTO gene is highly expressed in the brain, and recent studies have described functions that may participate in important brain mechanisms. All of this leads us to believe that this gene may play a key role in the appearance of comorbid depression and obesity”, notes Zarza-Rebollo.

The authors of this work, all of whom belong to the “Federico Olóriz” Institute of Neurosciences and the Biomedical Research Centre of the UGR, have shown that there are very few studies analysing the role of this gene in comorbid obesity and depression. Therefore, it is necessary to conduct more studies where individuals with both pathologies are analysed simultaneously. According to Margarita Rivera, “at the same time, it is important that future studies take into account the different subtypes of depression, since they have different characteristics not only at the clinical level but also in terms of metabolism and weight-gain. Different subtypes of depression are likely to have different genetic profiles. By characterising the samples by the different depression subtypes, we may be able to illuminate the role played by the FTO gene and possibly other genes in those depression subtypes that are more prone to triggering weight-gain”.

“A better understanding of the role of genetics in comorbid depression and obesity opens the door to early detection of those individuals with a higher risk of developing this comorbidity and to being able to design more personalized (and more effective) prevention and treatment strategies for them”, stresses Esther Molina.

Bibliography:

Juan Antonio Zarza-Rebollo, Esther Molina, and Margarita Rivera (2021), ‘The role of the FTO gene in the relationship between depression and obesity: A systematic review’, Neuroscience & Biobehavioral Reviews 127, 630–7.

Image caption:

The UGR research team that carried out this work

Media enquiries:

Esther Molina Rivas, Department of Nursing, “Federico Olóriz” Institute of Neurosciences and the Biomedical Research Centre of the University of Granada

Tel.: Laboratory: +34 958 241000 ext. 20342. Faculty of Health Sciences Office: +34 958 248750

Email: emrivas@ugr.es

Margarita Rivera Sánchez

Department of Biochemistry and Molecular Biology II, “Federico Olóriz” Institute of Neurosciences and the Biomedical Research Centre of the University of Granada

Tel.: Laboratory and office: +34 958 241000 ext. 20343

Email: mrivera@ugr.es

An international study, in which the University of Granada (UGR) is participating as part of the ProyectORCE project, has obtained new data on the Prehistoric humans who inhabited the Guadix-Baza basin, thanks to an analysis of the teeth of herbivorous animals such as mammoths, hippopotamuses, rhinoceroses, horses, deer, and bison

This study, in which the University of Helsinki (Finland) is also participating, reveals that our ancestors could only inhabit this area when Mediterranean ecosystems provided extra productivity, since these first hominids required a high amount of energy, and resources there were insufficient during the cooler and drier climatic phases

The first humans to inhabit the Guadix-Baza basin (Province of Granada) during Prehistory (from 1.5 million to 400,000 years ago) looked for areas of high vegetation in order to survive, but they could only inhabit this area when the productivity of Mediterranean ecosystems was especially abundant, since these ancestors required a high amount of energy, and resources there were insufficient during the cooler and drier climatic phases.

These are the main conclusions drawn from a study led by researchers from the Universities of Helsinki and Granada and published in the journal Quaternary Science Reviews. This was an interdisciplinary, international study in which, as well as the aforementioned universities, the Catalan Institute of Human Paleoecology and Social Evolution (IPHES, Tarragona) and the Universities of Zaragoza, Barcelona, ​​Salamanca, Complutense de Madrid, and Tübingen (Germany) also participated. The work was conducted within the framework of the ProyectORCE project, coordinated by the UGR and financed by the Junta (regional government) of Andalusia.

4.5 million years of history reflected in teeth

To arrive at these conclusions, the scientists analysed the teeth of herbivorous animals—such as mammoths, hippopotamuses, rhinoceroses, horses, deer, and bison—found at the different archaeological sites at Orce (Granada). This is the first study to analyse the faunal evolution and the ecological changes that took place over a period of four million years in the Guadix-Baza basin, which is located in the Granada Geopark.

Teeth are anatomical structures that are directly related to diet. To determine the significance of the main types of vegetables consumed in that epoch, two techniques developed by Mikael Fortelius (lecturer at the University of Helsinki and Visiting Scholar at the UGR) were applied to a dozen sites that date back as far back as 4.5 million years ago (Baza-1 site) to as recently as 400,000 years ago (Solana del Zamborino site, Fonelas). The two techniques involved studying patterns of wear in the animal teeth and the structural characteristics of their dental remains (known as the “ecometric method”).

On the one hand, dental wear is linked to the nature of the food consumed by the animal: the harder it is (and the lower the consumption of vegetables), the greater the deterioration of the teeth. On the other hand, the presence or absence of certain dental functional traits correlates closely with rainfall and, above all, with primary productivity—that is, with the quantity and quality of plant matter available to herbivores.

Habitat type revealed

One of the great debates that have surrounded the first human settlement of the European continent is the type of habitat that our oldest ancestors occupied. Some scholars claim that the first humans went out “in pursuit” of the habitat of origin—that is, the savannah. But the results of this study, led by Juha Saarinen of the University of Helsinki, show that, in fact, these primitive groups lived in habitats very similar to those still in existence today in much of the Iberian Peninsula: Mediterranean woodland. It is well known that the climate associated with these ecosystems is extremely seasonal, with summers dominated by a persistent drought, in which productivity falls to a minimum, especially when coupled with extended autumn and spring droughts.

The maximum productivity is found at Solana del Zamborino (Fonelas), a very interesting archaeological site dated to approximately 400,000 years ago, which coincides with one of the warmest and most humid periods of the last two million years. Following this, in terms of productivity, is a paleontological site, Baza-1, in which, due to its age (4.5 million years old), the presence of hominids is not to be expected.

At the opposite extreme are the paleontological sites with the lowest productivity: Huélago (2.5 million years), Fonelas-P1 (2 million years), and the Orce-based sites of Fuente Nueva-1 (2.2 million years) and Venta Micena (1.6 million years). The likelihood of finding evidence of a human presence at these sites is very low or inexistent. In between, with high productivity, are the emblematic sites of Barranco León (1.4 million years old) and Fuente Nueva-3 (1.2 million), the oldest locations with evidence of a human presence in the western part of Europe.

Human presence is also documented at Huéscar-1 (1 million years) and Cúllar-Baza-1 (Cúllar, 800,000 years) albeit on a very small scale. Finally, there are other sites that could likely have been home to our ancestors but that, for the moment, yield no clear evidence: Barranco del Paso (Orce, 1.8 million years old) and Mencal-9 (Pedro Martínez, 1.7 million years). Therefore, this study constitutes a hugely significant methodological contribution in the quest for locations that would potentially have been habitable for the very first Europeans.

Humans, major energy consumers

But why did our most distant ancestors require such productive habitats? “In the first place, because we are a very gregarious species that needed to live in relatively large groups, possibly of more than 30 individuals”, explains Juan Manuel Jiménez Arenas, the director of ProyectORCE and a researcher from the UGR’s Department of Prehistory and Archaeology.

“This gave us an important evolutionary advantage in relation to, on the one hand, inbreeding (probably one of the triggers for the disappearance of Neanderthals) and, on the other, the presence of predators. Likewise, social cohesion would contribute to survival in a complex and conflictive environment. In addition, humans have tremendously large brains relative to our body mass. Remember that this organ consumes an extraordinary amount of energy for its low weight (just 2% of total body mass vs. 20% of energy consumption in today’s humans)”, notes Jiménez Arenas.

Furthermore, the inability to produce fire or work with it would render certain foods of plant origin inedible. Lastly, the lithic technology or tools available to the first settlers of the European continent did not lend themselves to making intensive use of the available resources. “To exemplify this, our study reveals that our ancestors could not currently live in the Orce area. Hence, given the means to which they had access, the earliest settlers of Europe could not cope with an overexploitation of the territory, as is the case today. Therefore, it was Nature that determined the presence of our ancestors—it was not they who imposed themselves on Nature”, concludes Jiménez Arenas.

Bibliography:

Saarinen J, Oksanen O, Žliobaitė I, Fortelius M, DeMiguel D, Azanza B, Bocherens H, Luzón C, Solano-García JA, Yravedra J, Courtenay LA, Blain H-A, Sánchez-Bandera C, Serrano-Ramos A, Rodríguez-Alba JJ, Viranta S, Barsky D, Tallavaara M, Oms O, Agustí J, Ochando J, Carrión J, Jiménez-Arenas JM (2021), ‘Pliocene to Middle Pleistocene climate history in the Guadix-Baza Basin, and the environmental conditions of early Homo dispersal in Europe’, Quaternary Science Reviews 268: 107132. 

https://doi.org/10.1016/j.quascirev.2021.107132

Image captions:

Reconstruction of the palaeoenvironment that would have been found in Orce 1.5 million years ago. Recreation by Mauricio Antón from data derived from the Georgian site of Dmanisi

Juha Saarinen, main author of the work, at the Venta Micena site (Orce, Granada) during the 2018 campaign. Photo by Susana Girón

Evolution of productivity over the last 4.5 million years from the main paleontological and archaeological sites of the Guadix-Baza basin. The full squares correspond to sites where evidence of a human presence has been found. The blank squares represent those without evidence of a human presence. The section of the graph shadowed with grey lines indicates the range of productivity where the probability of human presence is low. The dotted lines represent the interval where the appearance of a human presence is highly probable. CG-B = Guadix-Baza Basin. Modified from Saarinen et al. (2021)

The present-day landscape at Orce. Photo by Susana Girón

Media enquiries:

Juan Manuel Jimenez Arenas, Department of Prehistory and Archaeology, University of Granada

Email: jumajia@ugr.es

According to family aggregation studies, this disease has a hereditary component, with approximately 10% of patients having one or more relatives affected by it

A team of scientists from the University of Granada (UGR) and GENYO (Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research—led by Pablo Roman-Naranjo and Jose Antonio López-Escámez, researcher in charge of the Biohealth Research Institute in Granada (ibs.GRANADA)—has identified new genes associated with familial Meniere’s disease.

Meniere’s disease is a disorder of the inner ear that is characterised by repeated episodes of vertigo and persistent noise in the ears (tinnitus), leading to progressive hearing loss.

This disease has a hereditary component, as identified in family aggregation studies, with approximately 10% of patients having one or more relatives affected by it. In this new study, published in the journal Hearing Research, a total of 62 families affected by this disease (mainly from Spain) were analysed. The results point to the existence of a relationship between familial Meniere’s disease and various ear-genes, the main candidate being the MYO7A gene, which encodes a protein called myosin VIIa that is specific to inner-ear hair cells.

The correct functioning of the ear relies on thousands of genes. When these genes are altered by rare mutations, this may reduce both the individual’s ability to keep their balance and to hear properly. In the case of Meniere’s disease, the researchers in this study propose a “digenic inheritance” model, in which rare mutations in at least two genes are necessary.

The origin of this disease in some families seems to lie in rare mutations of the MYO7A gene, together with mutations in other genes, such as CDH23, PCDH15, or ADGRV1 (that is, genes with which MYO7A interacts). This hypothesis is based on the results obtained in the present study: nine of the families presented rare mutations in these genes.

As the article notes, these genes are expressed in a specific area of ​​the ear: the stereocilia of the neurosensory cells of the inner ear. These cells are responsible for the transmission of sound in the organ of Corti, as well as the perception of acceleration in the posterior labyrinth, sending nerve impulses to the central nervous system. Stereocilia are found in each of these cells. According to the authors, mutations in MYO7A and other genes would cause alterations in several proteins that keep the stereocilia bundled together, ultimately causing hearing loss and vertigo.

“We suggest that rare mutations in the MYO7A gene, either by itself or combined with other mutations in genes that interact with MYO7A, would cause alterations in the morphostructure of the stereocilia and a loss of cohesiveness between them, with an abnormal opening of the mechanotransduction complex (located in the cilia) and, finally, hearing loss and/or vertigo. The MYO7A gene has been associated with familial sensorineural hearing loss or retinitis pigmentosa—another rare disease that causes blindness”, explain the authors.

The ‘Otology and Otoneurology CTS495’ research group, led by López-Escámez, coordinates genomic studies in collaboration with over 15 hospitals in Spain, Italy, and Switzerland and participates in several research projects on Meniere’s disease funded by the “Carlos III” Health Institute (PI20-1126), the Department for Health and Families (PI027-2020), and the Department for Economic Transformation, Industry, Knowledge, and Universities (PI20-00303).

The study of Meniere’s disease and the identification of new genes that can explain its origin can help to decipher the mechanisms underlying it and thereby facilitate its early genetic diagnosis, as well as contribute to the development and application of new drugs in its treatment.

Bibliography:

Roman-Naranjo, P., Moleon, MDC., Aran, I. et al. (2021). ‘Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial Meniere disease’, Hearing Research, 409 (108329).

doi:10.1016/j.heares.2021.108329

https://www.sciencedirect.com/science/article/pii/S0378595521001635

Image captions:

Photo of the ‘Otology and Otoneurology CTS495’ Research Group

Proteins involved in bundling together the stereocilia of the sensory cells of the inner ear

Media enquiries:

José Antonio López Escámez, Department of Surgery and Surgical Specialties, University of Granada

Tel.: +34 958 24 96 75

Email: jalopezescamez@ugr.es