Image showing the endothelial healing process in mice 3 days following carotid artery injury. © Coralie Fontaine.

A commonly used treatment in some forms of breast cancer, tamoxifen acts on the cancer cells by blocking the estrogen receptor (ER)a and thereby inhibiting their proliferation. However, the action of this drug appears to be more complex than that, with the addition of protective effects on the arteries that could reduce the risk of developing cardiovascular disease. Researchers from Inserm and Université Toulouse III – Paul Sabatier at the Institute of Cardiovascular and Metabolic Diseases have studied the effects of tamoxifen on the arteries in animal models in order to better understand its mechanism of action and refine its clinical use. Their findings have been published in the journal Circulation Research.

Following breast cancer, women are at increased risk of developing cardiovascular disease. Several studies have confirmed this association, highlighting risk factors common to both disease types as well as the toxicity of certain cancer treatments, such as chemotherapies, to the cardiovascular system. However, experimental and clinical data suggest that tamoxifen – a hormone therapy that reduces the risk of recurrence of certain forms of breast cancer[1] – also has protective effects against cardiovascular disease.

In the cancer cells, tamoxifen acts as an anti-estrogen: without eradicating the production of this hormone, it takes its place in its receptors (the ERa receptors), thereby blocking the proliferation of these cells.

Different mechanisms of action

In their study, the researchers have shown that tamoxifen accelerates arterial healing by promoting the renewal of the endothelial cell layer that protects the arteries, thereby revealing a novel beneficial effect of this drug in terms of cardiovascular risk.

In order to explain this novel beneficial action of tamoxifen, the team shows that contrary to its inhibiting effect on the cancer cells, the drug mimics the action of the estrogens in the arteries, bringing about their healing.

Whereas estradiol (the main estrogen) induces this effect by directly activating the estrogen receptors in the arterial endothelial cells, the researchers show that tamoxifen produces this same effect on the arteries by also activating the estrogen receptors, but in another cell type (the underlying smooth muscle cells).

This research therefore shines a new light on the action of tamoxifen, showing that this molecule can mimic the action of estrogens by targeting the different functions of their receptors in different cell types.

These findings could have various clinical implications, particularly because they enable a deeper understanding of the spectrum of action of this drug that is prescribed to thousands of patients in oncology.

“The vision we have of tamoxifen at present is that of a hormone therapy that blocks the receptors present on the cancer cells, but this only partially explains its action. Our study emphasizes that this drug mimics estrogens by targeting pathways that are not always the ones we expect. We have revealed a protective effect on the arteries through an indirect action on the endothelial cells, but this action could also affect the immune system cells, which play a key role in the immune surveillance of tumors”, emphasize Jean-François Arnal, professor at Université Toulouse III – Paul Sabatier, and Coralie Fontaine, Inserm researcher, who have coordinated this research.

[1]So-called “hormone-dependent” cancers, for which the cancer cells express the estrogen receptor

Diet plays a major role in the composition of our gut microbiota. From what we consume, the gut bacteria produce organic compounds known as metabolites, which can affect our health. © Adobe Stock

An imbalanced diet has been linked to a disruption of the gut microbiota, which promotes metabolic diseases such as diabetes. Researchers from Inserm, Sorbonne Université, Paris hospitals group AP-HP and the French National Research Institute for Agriculture, Food and Environment (INRAE) in collaboration with a Swedish team have shown, in a large European cohort, that changes in the composition of the gut microbiota lead to increased blood levels of the molecule imidazole propionate. A molecule known to render the body’s cells resistant to insulin, thereby increasing the risk of developing type 2 diabetes. Their findings have been published in Nature Communications.

Diet plays a major role in the composition of our gut microbiota. From what we consume, the gut bacteria produce organic compounds known as metabolites, which can affect our health if they are present in too large or too small a quantity in our body.

Previous studies have shown that changes in the makeup of the gut microbiota and the production of certain metabolites can directly influence the development of type 2 diabetes.

Other recent research suggests that an alteration of the gut microbiota disrupts the metabolism of histidine, an amino acid found in many foods, leading to increased levels of the metabolite imidazole propionate. This molecule blocks the action of insulin, preventing it from lowering blood glucose levels.

The present study published in Nature Communications confirms these initial findings in a large European cohort of 1990 participants from France, Germany and Denmark, called METACARDIS. Coordinated by Inserm, the objective of this cohort is to study the impact of changes in the gut microbiota on the onset and progression of cardiometabolic diseases and associated pathologies. “METACARDIS is a unique and valuable database in that it allows us to access very detailed characteristics of each person enrolled in the cohort with large amounts of phenotypic, metabolic, and bacterial genetic data,” emphasizes the project’s coordinator, physician Karine Clément, teacher-researcher in nutrition at Sorbonne Université.

She and her colleagues show that in the cohort, subjects with prediabetes[1] or type 2 diabetes do indeed have higher levels of imidazole propionate in their blood. The gut microbiota of these subjects is also characterized by a significant depletion of bacteria.

The researchers suggest that these alterations in the bacterial composition of the microbiota are linked to an imbalanced diet. They cause a disruption in the metabolism of histidine, which in turn leads to an increase in imidazole propionate and problems regulating blood glucose. The risk of developing type 2 diabetes then becomes higher.

“Our study suggests that people with poor diets have increased levels of imidazole propionate and that there is a clear link between the depleted composition of the microbiota, diet and type 2 diabetes. Its aim is to convey a message of prevention, emphasizing that a more varied diet can enrich the microbiota. This study also has therapeutic implications since we could envisage the future development of drugs to modify the synthesis of certain metabolites such as imidazole propionate,” explains Clément.

A number of questions continue to be raised and are expected to be elucidated in future research based on METACARDIS. In particular, the researchers want to understand how the elevation of one or more metabolites can predict, in people with diabetes, the risk of developing other complications, such as those affecting the cardiovascular system. They also want to study how increased imidazole propionate levels in people with prediabetes could increase their risk of developing type 2 diabetes earlier on in their clinical course.

This large-scale research project, based on close collaboration between several European scientific teams, has received support from the European Community (7th Framework Programme FP7-Metacardis), as well as from the Leducq Foundation.

[1] Prediabetes is a blood glucose disorder at a less advanced stage than diabetes itself. It is characterized by fasting blood glucose levels of between 1.10 g/L and 1.25 g/L (normal fasting blood glucose is below 1.10 g/L). The risk of going on to develop type 2 diabetes is increased.

Animal and vegetable sources of omega-3 such as salmon, avocado, flax seeds, eggs, butter, nuts, almonds, pumpkin seeds, parsley leaves and colzal oil. © Fotolia

Omega-3 fatty acids* are essential, necessarily supplied by the diet and indispensable to brain development. Scientists from INRAE and University of Bordeaux, working in collaboration with INSERM, Laval and Toronto Universities in Canada and other partners (Harvard, Fondation Basque, etc.) have focused in particular on the impact of the maternal diet during gestation and lactation on the brain development of their offspring. They have thus shown for the first time in mice how an insufficient intake of omega-3 in the mother can alter the development of neuronal networks in the offspring, causing memory deficits. They have also deciphered the molecular mechanisms underpinning these effects. This unprecedented work, which is the result of several years of research, is published on 30 November 2020 in Nature Communications.

Essential fatty acids (omega 3 and 6) are massively incorporated in the brain of offspring via the maternal diet during gestation and lactation. Patchy scientific findings indicated that an insufficient consumption of these fatty acids by the mother during the perinatal period constitutes a risk factor for cognitive deficits in children (language, memory, learning, etc.). But what is the causal mechanism?

INRAE scientists from the Nouvelle-Aquitaine Research Centre and University of Bordeaux, and their colleagues, focused on a particular cell type in the brain: the microglial cells (or microglia) that participate in the shaping of the neuronal networks sustaining memory abilities. These brain macrophages lie at the interface between the environment and neurons.

During brain development, the microglia “sculpt” neuronal networks by “engulfing” useless synapses – the connectors between neurons – and only retaining those that are essential for satisfactory brain functioning.

The scientists focused their studies on a mouse model to determine whether maternal omega 3 status – and hence that of offspring – could exert an effect on microglia activity.

Omega 3 deficiency impacts the activity of a particular cell type in the mouse brain

The results showed for the first time that an insufficient intake of omega 3 via the maternal diet affects the activity of microglia in the developing brain; these cells adopt abnormal functioning and become hyperphagic; i.e. they lose the ability to recognise the synapses that needed to be deleted, hence “engulfing” too many of them. The neuronal network is thus poorly formed, causing deficits in the offspring memory capacities. The scientists were also able to decipher the molecular mechanisms responsible for this abnormal microglial activity.

To study this link between omega 3 intake and brain development, the scientists also developed several innovative technologies to evaluate the modification of microglial behaviour towards synapses, to analyse their lipid content, and to test different molecules in order to identify those responsible for this dysfunction and determine how it could be restored.

This work offers new perspectives for research, and studies will continue in humans in order to better understand the links between omega 3 and brain development.

* _{Omega 3 fatty acids are a family of essential fatty acids. This contains the fatty acids that are essential to developing satisfactory functioning of the body, but they can only be supplied by diet. They are found in numerous vegetable oils (walnut, rapeseed, linseed, etc.) and in the flesh of fatty fish.}

POMC neurons (orange dots) in the hypothalamus of a mouse, located at the base of the brain. Photo taken from a mouse using a confocal microscope.© Danaé Nuzzaci / CNRS / CSGA

You just finished a good meal and are feeling full? Researchers from the CNRS, Inrae, University of Burgundy, Université de Paris, Inserm, and University of Luxembourg¹ have just revealed the mechanisms in our brains that lead to this state. They involve a series of reactions triggered by a rise in blood glucose levels. This study, which was conducted on mice, is published in Cell Reports on 3 March 2020.

The neuronal circuits in our brain governing feelings of hunger and satiety can modify their connections, thereby adjusting feeding behaviour to living conditions and maintaining a balance between food intake and calorie expenditure. Scientists suspect that this plasticity could be altered for obese subjects.

In a new study conducted on mice, a team led by Alexandre Benani, a CNRS researcher at the Centre for Taste and Feeding Behavior (CNRS/Inrae/University of Burgundy/AgroSup Dijon), has shown that these circuits are activated on the time scale of a meal, subsequently regulating feeding behaviour. However, this activation does not occur through a change in the circuit’s “connections.”

Remodelling of the satiety circuit of POMC neurons after a balanced meal. Red box: area corresponding to the photo at right.© Alexandre Benani / CNRS / CSGA

Scientists focused on POMC neurons in the hypothalamus, located at the base of the brain, which are known for limiting food intake. They are connected to a large number of neurons from other parts of the brain, with the connections of this circuit being malleable: they can be made and unmade very quickly based on hormonal fluctuations. Researchers observed that this neuronal circuit is not modified after a balanced meal, but that other nerve cells associated with POMC neurons, known as astrocytes, actually change form.

Astrocytes are star-shaped nerve cells that were first studied for their supporting role with respect to neurons. Under usual conditions, they sheathe POMC neurons and act somewhat like brake pads by limiting their activity. After a meal, blood glucose levels (glycaemia) temporarily increase, with astrocytes detecting this signal and retracting in less than one hour: once this “brake” is released, POMC neurons are activated, ultimately promoting the feeling of satiety.

Surprisingly, a meal that is high in fats does not lead to this remodelling. Does this mean that lipids are less effective in satisfying hunger? The scientists are trying to determine whether they trigger satiety through another circuit. It also remains to be seen whether sweeteners have the same effects, or whether they lure the brain by providing an addictive sensation of sweetness without satisfying hunger.

¹ The study was led by the Centre for Taste and Feeding Behavior (CNRS/Inrae/University of Burgundy/Agrosup Dijon), in close collaboration with colleagues from the Institute of Molecular and Cellular Pharmacology (CNRS/Université Côte d’Azur), Institute for Functional Genomics (CNRS/Inserm/ University of Montpellier), and University of Luxembourg, along with contributions from l’Unité de biologie fonctionnelle et adaptative (CNRS/Université de Paris) and Institute of Psychiatry and Neuroscience of Paris (Inserm/Université de Paris).