Regulation of food intake is affected by leptin and angiotensin, as well as other known and non-known hormones; TNF-α affects intermediate stages of the inflammatory response.
By Pari Rapti, endocrinologist
Adipose tissue is not just a storehouse of adipocytes but an active organ having endocrinological involvement. It could even be said that it is a very extensive endocrinological organ.
A series of biochemical processes takes place in adipose tissue, which are “critical” for the body’s proper functioning and therefore obesity is a key factor not only as regards our appearance but also our quality of life, since it is well-known to affect health.
Our knowledge concerning the involvement of obesity as a pathological factor to overall survival is constantly updated. A good number of years ago, the World Health Organization had designated obesity as a chronic disease.
It is now known that the reason behind obesity is not only an increase in the size or number of adipocytes which depend directly on diet, lack of physical exercise and type of activity, but there are also genetic, hormonal, immune and environmental factors and local inflammatory processes of the adipose tissue, known as “metabolic inflammations”.
As regards the implication of various substances in subclinical inflammation that occurs in obesity, such as chemokines, cytokines, growth factors, lipokines, angiotensinogen, interleukin 6, interleukin 8, interleukin 10, TNF-α, MIF, I and others, there is a plethora of information in international literature.
What could be the association between obesity and the new coronavirus as regards the severity and progression of COVID-19?
We already know that various cardiovascular diseases, neoplasms (e.g. breast cancer), metabolic diseases, diabetes mellitus, the metabolic syndrome and many other diseases are linked to obesity, but also to the “topography” of adipose tissue deposition, gender and age. Furthermore, the distribution of adipose tissue between sexes seems to be a determining factor for phenotype (different body type), but also a “natural” necessity.
Adipose tissue deposition, e.g. in the abdominal region, has been linked to body burden and the occurrence of cardiovascular diseases. In addition, centripetal obesity is associated with the clinical aspect of certain diseases, such as e.g. Cushing’s syndrome, in which case it is described as a shift of adipose tissue with the patient having thinned extremities, abdominal fat deposition (central obesity), and hump, while the presence of adipose tissue in the gluteal region in women seems to be associated to fetal survival in pregnant women during periods of famine. This is because the deposition of adipose tissue in the gluteal region does not seem to burden women’s health and may not be associated with cardiovascular problems.
The importance of sex hormones in differing function through differentiated topography of fat deposition between men and women at certain stages of the reproductive age could be a determining factor.
Insulin resistance also seems to be associated with weight gain and this, in turn, is associated with various factors some of which are the peptides produced by adipocytes, such as lipokines, liponectin, resistin, as well as various cytokines such as interleukin 6, interleukin 8 and TNF-α, the expression of which differs in obese persons.
Diseases linked to a generalized or abdominal increase in adipose tissue, such as in the case of Cushing’s syndrome but also in various other syndromes affecting the reproductive system or thyroid function, are due to different hormonal factors. Insulin resistance is also seen in polycystic ovary syndrome which is characterized by a disturbance of androgen secretion. Obesity is also associated with various hormone-dependent malignancies.
The association of cardiovascular diseases with obesity, not only generalized obesity but also in relation to waist-hip ratio, can be a predictor of cardiovascular risk. The same applies to abdominal deposition and increased visceral adipose tissue, meaning that it is necessary to take into account the Body Mass Index (BMI).
Adipose tissue is not composed only of adipocytes, but also of other tissues and cells, which constitute the circulatory organs for attracting various types of cells, such as immune cells and various substances, as well as carrying oxygen into the smallest blood vessels, and consequently are necessary for the existence of endothelium, smooth muscle fibers of the vessels and various other anatomical components that are described below. It is, therefore, a biochemical powerhouse of exceptional importance for our welfare and well-being.
The study of changes that occur either through diet or physical exercise, or in relation to circadian rhythm and length of sleep are of great interest because they are modifying factors of appearance and body type, but most importantly they are linked to various diseases which affect both the quality of life and duration of disease.
Adipose tissue deposition results from an imbalance between lipogenesis and lipolysis. It is now clear that adipose tissue is not an inactive organ. It is an endocrinology organ which is responsible for the synthesis and secretion of various hormones that have multiple effects either locally or in the whole body.
Among the hormones that affect body weight either through appetite increase or locally we note leptin, insulin, cortisol, ghrelin and various other substances such as cholecystokinin, peptide YY, intestinal peptides, which act locally, substances that transmit their messages to the hypothalamic centers of hunger and satiety in the brain or through the vagus.
The various hormonal, nervous and metabolic signals affect the expression and secretion of other hypothalamic peptides, thus reducing or increasing hunger.
The previously prevalent belief that adipocytes are fat storehouses has now changed following the realization that adipocytes also function as endocrine cells that produce TNF-α, leptin, plasminogen activator inhibitor-1 (prothrombogenic agents), angiotensinogen, antiponectin and other factors, such as complement factors, factor D (adipsin), interleukin 6, TNF, interleukin 8. It is clear that there are also other factors that have not been identified yet.
Regulation of food intake is affected by leptin and angiotensin, as well as other known and non-known hormones; TNF-α affects intermediate stages of the inflammatory response but also insulin sensitivity, since it is involved in insulin resistance; pathways such as those of PAI-1 (Plasminogene Activator Inhibitor 1) and other hormones such as adiponectin and resistin are involved in various biochemical processes, however in this analysis we are going to focus on interleukin 6, interleukin 8 and interleukin 18 which seem to affect the pathophysiology of COVID-19.
Adipose tissue comes into two forms, white and brown, each with different functions. Let’s have a look into the secretory potential of this “organ”. It seems that adipocytes have multiple effects, which is owned to their ability to secrete enzymes, proteins, growth factors, supplements and hormones, to express receptors, as well as to activate various pathways involved in homeostasis, metabolism, food intake and energy consumption processes, with immune response, blood pressure, etc.
Adipocytes provide a network of signaling pathways through autocrine, paracrine, and endocrine functions and secretions that affect responses in many cells, such as endothelial cells, smooth muscle fibers, immune cells, and cells also found in other tissues, but they also affect the function of various organs, such as the pancreas, the hypothalamus, the kidneys, the musculoskeletal system, the bone system and the immune system. A brief reference to the immune system is made next.
It also seems that the processes taking place in white and brown adipose tissue are differentiated. It is known that the ratio of these tissues subcutaneously or viscerally is different. Both of these adipocyte types produce different substances as mentioned above, but they may do so in different quantities. For example, visceral fat probably produces higher quantities of interleukin 6 and PAI-1 (Plasminogene Activator Inhibitor 1).
As a secretory organ, it is obviously under the control of gene expression, just like the other organs, which affects the secretory hormonal and chemical mechanisms and the secretory capacity of adipocytes and other adipose tissue components.
What is the role of adrenal-produced cortisol in adipose tissue?
What is the role of interleukin 6 and other interleukins in adipose tissue and what is the possible implication of interleukin 6 in the pathophysiology of diseases such as COVID-19 or conditions with interleukin 6 hypersecretion syndrome in obese patients?
What is the role of adipose tissue and increased body weight in people infected with the new coronavirus since it is known that other cytokines and molecules increase with obesity, stimulated by TNF-a and interleukin 6 and interleukin 8, while there seem to be concomitant inflammatory cells, such as monocytes and macrophages, that are known to also produce interleukin 6?
What is the role of interleukins in inviting immune cells, monocytes, macrophages, dendritic cells, T-lymphocytes and what is the action of CD-T lymphocytes which seem to have a determinant role in COVID-19?
In the international literature, high levels of interleukin 6 seem to be associated with cardiovascular diseases, atherosclerosis and myocardial infarction. Interleukin 6 and TNF-α seem to be produced by both adipocytes and vascular wall cells, as well as macrophages. It should be noted that interleukin 6 is possibly implicated by blocking the insulin signaling pathway.
Reference has been made to interleukin 6 in many articles emphasizing its pleiotropic actions. It is extremely interesting to also emphasize the type of cells that secrete it, such as immature immune cells, adipocytes, muscle cells, fibroblasts and immune cells such as monocytes and macrophages.
Extensive reference should also be made to how interleukin 6 is involved in the mechanisms of stress, sepsis and inflammatory processes. Furthermore, the amount of visceral adipose tissue participation in the production of interleukin 6 is also extremely important, as it seems that interleukin 6 is produced in larger quantities in visceral adipose tissue than in subcutaneous adipose tissue.
In patients with obesity and an elevated BMI (body mass index), mainly in men but also in postmenopausal women, higher levels of interleukin 6 seem to be recorded. C-reactive protein (CRP) is known to be elevated in the biological markers of various inflammations. In the case of metabolic inflammation, interleukin 6 also seems to be involved in this increase. It is also known that interleukin 6 stimulates fibrinogen production in the liver but also causes the liver to oversecrete triglycerides, especially when insulin resistance is impaired.
What are the effects of sex hormones, catecholamines, glucocorticoids on the production of interleukin 6 and what is the effect of interleukin 6 on axis stimulation in the presence of inflammation (COVID-19 in this case)?
International literature shows that the production of interleukin 6 is stimulated by catecholamines and reduced by estrogens and glucocorticoids. Its action on the vascular endothelium seems also involve it in the production of atherosclerotic plaques. It is affected and stimulated even in sleep deprivation since it seems to exhibit a circadian rhythm of secretion. Nonetheless, these are not all the effects of interleukin 6.
Angiotensin II and adipose tissue
In previous articles we looked into the action of angiotensin II in COVID-19 patients, which seems to be overproduced by an alternative pathway, that between ACE stimulation and the AT1 receptor as a result of depleted transmembrane ACE2 receptor, which causes the binding of this receptor to the Spike protein of the new coronavirus. A prerequisite for the ability of the Spike (S) protein to bind to ACE2 is the presence of serine protein.
In describing the mechanisms that enhance immune response, emphasis should be placed on the observation by some researchers that the action of serine protease may activate alternative pathways for the production of angiotensin II with the known effects mentioned above. And that may be very important.
The renin-angiotensin-aldosterone system seems to be fully expressed in adipose tissue. Angiotensinogen mRNA and protein levels in adipose tissue are possibly affected and regulated by both diet and physical exercise. Some scientific papers in international literature suggest that angiotensin produced in adipose tissue can affect the growth and differentiation of adipocytes and cells of other tissues through the secretion of substances which affect tissues such, as cardiovascular issue and others, through circulation. It is noted that human platelets also express the AT1 receptors of angiotensin II.
The existence of a local RAAS system in various organs seems to necessitate further investigation in the context of COVID-19 of the hypothetical expansion of chemical processes that we inadvertently liken to “a pebble in the sea”.
What other factor is involved at the vascular level and in the wall of small vessels located in adipose tissue?
The PAI-1 gene is located on a known chromosome. In international literature it is mentioned that sources for the secretion of this factor, besides the endothelium and vascular smooth muscle fibers, are also other cells such as adipocytes, adipose tissue stromal cells, hepatocytes, fibroblasts, monocytes and macrophages.
In obesity, where an increase in these cells is observed, is this production modified and in what direction?
What is the role of angiotensin II, glucocorticoids, insulin, catecholamines, TNF-α and others as regards adipose tissue involvement in obese persons?
Answers to these questions are found in international literature.
It seems that this protein factor, which is involved in fibrinolysis, is differentiated by obesity and the ratio between subcutaneous and visceral white and brown fat.
Considering that thrombotic episodes are encountered in a number of COVID-19 cases, what is the role of these substances in obese people, e.g. in cases of metabolic syndrome, as regards the progression and severity of the disease in genetically determined patients?
Of course, the expression of certain obesity genes, many of which have already been studied, should not be overlooked.
So perhaps obesity is an additional factor to investigate other biochemical phenomena and processes seen in COVID-19.
The production and secretion of inflammation modifiers is influenced by genetic factors through genes encoding pro-inflammatory or anti-inflammatory substances. Even small changes in the genes encoding cytokines seems to affect the body’s ability to synthesize and secrete these substances and may be the cause of cytokine polymorphism (TNF-α, lymphotoxin alpha, interleukin 6, interleukin 8 and interleukin 1) and any disturbance in the production of cytokines seems to be involved with various diseases, including autoimmune diseases, other pathologies and inflammations.
In the presence of impaired immune response to COVID-19, the possible involvement of the production and secretion of cytokines and other substances produced in adipose tissue, perhaps in larger quantities in obese people, should be considered for certain patients. If this is happening, it may be down to genetic factors.