Rafael Simó: “We should talk about “obesities” instead of “obesity” because more and more phenotypes are described, in which genetic, metabolic, environmental, socio-cultural and mental health factors combine in different ways”.

Dr. Rafael Simó is Head of the Endocrinology and Nutrition Service at Vall d’Hebron University Hospital, Director of the Diabetes and Metabolism Research Unit at Vall d’Hebron Research Institute (VHIR), Deputy Director of Clinical Research at the same institution and President of the Clinical Research Committee of the Vall d’Hebron Campus. Dr. Simó is also Professor of Medicine and Endocrinology at the Universitat Autònoma de Barcelona and co-founder of the VHIR spin-off “Endolipid Therapeutics”.

Obesity is a complex multifactorial disease in which genetics, metabolism and behaviour have a great influence. What influence does the mental part have in this disease?

Before answering this question, I think it is worth emphasising the concept that we should actually talk about “obesities”, rather than “obesity”, because more and more phenotypes are described, in which genetic, metabolic, environmental, socio-cultural and mental health factors combine in different ways. It is not possible to say clearly what weight the mental part carries, because it depends on the individual obesity phenotype. However, it is clear that neuropsychological aspects play a significant role in the pathogenesis of weight gain. In many cases a real vicious circle is generated. Thus, for example, a person without obesity who develops depression may increase adiposity due to antidepressant treatment and, in turn, this adiposity worsens the depression due to reduced sensitivity to dopamine. On the other hand, individual perception of excess weight is highly variable, which will determine whether preventive measures are taken at the right time or at a more advanced stage, which is more difficult to reverse.

The phrase “We are what we eat” is attributed to the German philosopher and anthropologist Ludwig Feuerbach in 1850. Is this phrase still relevant today?

The two fundamental axes of Ludwig Andreas Feuerback’s thought were the anthropological conception of all religion and the materialistic critique of all speculative thought. It is therefore not surprising that Feuerbach used this phrase as a complaint of the need to provide a good livelihood for the underprivileged classes. In fact, from an epidemiological and anthropological point of view, humanity is clearly divided into overweight and underweight sectors of the planet, a very high percentage of which overlap with the economic resources of the populations that comprise it. However, from an individual point of view, we all have a friend who “eats like a horse” and does not put on weight. Evidently, differences in metabolism and calorie expenditure due to factors that still need to be investigated are key to explaining this different behaviour. It is also important to mention that overeating in many cases is a symptom, reflecting a dysregulation of the control of satiety and basal metabolism, basically controlled by the brain, and is therefore a disease rather than a pure whim of culinary delight.

What is meant by “gut-brain axis”?

As for the gut-brain axis, it involves bidirectional communication between various cognitive centres in the brain and gut function. In recent decades, the importance of the microbiota as a key factor in modulating this interaction has become clear and has become a real therapeutic target.

How is the current development of gene therapies for the treatment of diabetes?

The purpose of gene therapy is to transfer genetic material into an individual’s cells to restore a function that was abolished or defective, to introduce a new function, or to interfere with an existing function. The various gene therapy strategies are based on a combination of three key elements: the genetic material to be transferred, the method of transfer, and the cell type that will incorporate the genetic material. In the case of type 1 diabetes mellitus, the aim will be to suppress the autoimmune component (e.g. autoreactive T cells) to  prevent the destruction of the insulin-producing pancreatic islets, or to generate insulin once the disease is already established. Among the prevention strategies, the use of CAR (Chimeric Antigen Receptor) technology has been successful at the experimental level, while pluripotent stem cells have also succeeded in experimental models in “regenerating” the insulin-producing capacity of the beta cells that constitute the pancreatic islets. However, although these advances in basic research are very important and highly promising, we must still be cautious about their applicability in clinical practice. With respect to type 2 diabetes, as it is a more complex disease than type 1 diabetes (combining tissue resistance to insulin action with a relative deficit in the insulin secretion capacity of the pancreas), gene therapy is seen more as a palliative or adjuvant treatment than a true cure. In this type of diabetes, the potential use of microRNAs to regulate insulin and incretin production seems promising.
In short, gene therapy, although making important qualitative leaps, is a milestone that needs more research to be transferred to everyday clinical practice.

The use of Ozempic or other similar GLP-1/GIP agonist drugs are indicated for the treatment of type 2 diabetes, but their off-label use for weight loss is currently widespread, should they be regulated for this indication?

The “problem” with GLP-1 receptor agonists, which are the most widely used today, is that they were originally designed for the treatment of type 2 diabetes mellitus. However, in addition to increasing insulin production through the incretin effect, they achieved a clear and sustained weight loss, which was fundamental to explain their success in metabolic control of the disease. In addition, there was a marked decrease in cardiovascular risk and virtually no hypoglycaemia. All of this was a major claim to fame when translated from clinical trials to the real world. Thus, a patient without diabetes could safely take a GLP-1 agonist without hypoglycaemia, with significant weight loss as a key effect. Therefore, off-label use for weight loss was to be expected and, in fact, has contributed to the fact that there is currently a significant shortage of these compounds due to lack of stock. Clearly, all medication must be regulated and, in fact, specific compounds for the treatment of obesity already exist and more will soon follow, although most are based on the same principle as those initially designed for the treatment of type 2 diabetes mellitus.

One of the factors that is implicated in the pathology of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is the excess accumulation of lipids in the liver. What weight does obesity have in this pathology?

Most MASLD occurs in patients who are obese or overweight. However, between 10%-15% of patients with MASLD have a normal weight and body mass index (BMI). In this regard, it is important to mention that the BMI classification is imperfect in terms of assessing the accumulation and distribution of adipose tissue. Thus, obesity is currently defined by an “excess accumulation of dysfunctional adipose tissue that negatively impacts on health”, rather than a BMI>30kg/m². Therefore, methods to study and quantify the distribution of adipose tissue and its functionality will be essential for good phenotyping of the obese patient.

You are co-founder of the company Endolipid Therapeutics, which is developing, among other products, a peptidomimetic SHBG (sex hormone binding globulin) for the indication MASLD. What stage of development is the product currently at?

The best-known function of SHBG is to act as a transporter of sex steroids (estrogen and testosterone). However, our research group has shown that SHBG has other important functions such as an anti-lipogenic, lipolytic, anti-inflammatory and antifibrotic action. These actions are preserved in some SHBG-derived peptides, which we have had the opportunity to generate and test both in vitro and in vivo. The advantage of these peptides, apart from their small size which reduces production costs, is that they do not have the capacity to bind to sex hormones and therefore have no effect on this sphere, nor have we observed any other adverse effects in the experiments carried out. It is clear to everyone that the above actions directly target the main pathogenic mechanisms of MASLD and, in fact, we have observed a clear preventive and therapeutic action on hepatic steatosis, inflammation and even a significant anti-fibrotic effect in various experimental models. Currently, under a well-protected patent with a wide international diffusion, we are making firm preclinical regulatory steps, and we believe that in about a year we will be able to initiate the clinical development phases.