Obesity and its associated inflammatory cytokines pose significant risk factors for COVID-19 outcomes

Abstract

The incidence of overweight, obesity and non-alcoholic fatty liver disease (NAFLD) in Western society have increased to epidemic proportions in the past decade and are now recognized as significant progressive comorbidities contributing to complications of COVID-19. Adiposity reflects an imbalance in energy homeostasis, where cumulative energy intake chronically exceeds net energy expenditure often associated with Insulin resistance (IR) and other endocrinopathies which further impairs parameters of energy balance and expenditure. A primary function of white adipose tissues (WAT) is nutritionally and hormonally mediated lipogenesis and lipid storage in the form of triglycerides, derived from dietary or de novo substrates. Central adiposity, including visceral adipose depots is typically associated with chronic inflammation and endocrine dysregulation including elevations in plasma insulin, amylin, and hyperlipidemia, a suppressed immune response, and elevations in markers of inflammation in peripheral tissues, which are contributory to the progression of the cardiovascular, renal, and other significant comorbid sequela that often follow. Multiple mechanisms are operative in obesity that contribute to the magnitude of severity of COVID-19 illness. 1: The SARS-CoV-1 can infect multiple organ systems that contain ACE2 receptors, including WAT; 2. The SARS-CoV-2 virus contains abundant viral spike proteins compatible with the ACE2 receptors of WAT, enabling the efficient uptake of COVID-19 viral particles; 3: WAT secretes the inflammatory cytokines TNF, IL-6, and others, augmented by adipocytokines leptin and resistin, which together facilitate the creation of an enhanced inflammatory state combined in concert with the suppressed immune state; 4: WAT secretes leptin, TNFα, CXCL-10 and other inflammatory adipokines that are common factors in central obesity have been correlated with the severity of COVID-19 in obese individuals, and 5: the cytokine IL-6 from WAT acts as a primary mediator of the cytokine storm inflammatory response which typically leads to the development of an acute respiratory distress syndrome (ARDS) often with dire consequences in later stages of COVID-19. NAFLD also correlates with hyperlipidemia and the severity of COVID-19 in a similar manner. Thus, the inflammatory markers and the lipogenic characteristics of IR, excess adiposity, chronic inflammation, and related sequelae are significant opportunistic contributors to the magnitude of severity and outcome of the morbidity and mortality observed in COVID-19 illness. The purpose of this editorial review is to present an overview of the contributions of obesity and its endocrinologic and inflammatory pathophysiologic sequelae on COVID-19 illness.

The role of adiposity, body mass index, aging and chronic comorbidities on the progression of COVID-19 illness. Is a ‘long COVID’ syndrome inevitable?

“…The SARS-Cov-2 virus can easily infect adipose tissue due to the presence of ACE2 receptors on adipocyte plasma membranes, with an apparent greater affinity for visceral than for subcutaneous adipose tissue. 3,10,11 Adipose tissue is now regarded as an endocrine organ by many researchers, as it has the capacity to secrete a number of hormonal substances including leptin, IL-6, TNFα, resistin and CXCL-10. 12,13 The secretory capacity for leptin as well as other secretory products increases in proportion to the mass of adipose tissue, leading the hyperleptinemia, and disordered energy homeostasis via its negative effects on appetite and satiation control mechanisms.…”

“…The proinflammatory cytokine CLCX-10 is also secreted by adipose tissue and appears to become upregulated during covid-19 infection, and along with IL-6 and others has been attributed to be an element in the cytokine contributions to the cytokine storm phenomena and to the severity of covid-19 symptoms. 3,10,11 The hormonally active peptide resistin can also become elevated in obesity and overweight conditions, and functions as an immunodulatory adipokine that is believed to contribute to renal injury during covid infection. In obese patients diagnosed with chronic kidney disease and covid-19, plasma resistin concentrations were found to be more closely correlated with IL-6 and with the chemoattractant MCP-1 transmembrane proteins, and associated with generalized states of oxidative stress in addition to insulin resistance, also common among the overweight and obese.…”

“…Multiple pathophysiologic factors have been associated with the symptoms and severity of covid-19 illness, including obesity and overweight conditions, diabetes, especially non-insulin dependent diabetes (NIDDM or T2DM), hypertension, the disordered bioenergetics of metabolic syndrome, and respiratory diseases, among others which when prevalent represent highly significant and complicating risk factors for infected individuals. 3,[8][9][10][16][17][18] Since the incidence of obesity and overweight conditions now approach epidemic proportions across much of the age spectrum often commencing from early childhood onward in Westernized nations, a large proportion of the populations is at potential risk, including those who may have an otherwise healthy lifestyle. 6,7 The mechanisms that contribute to the underlying risks of obesity and adiposity to the resulting magnitude of SARS-CoV-2 infections remain incompletely defined, but are likely related to the physiology and anatomic distribution of adipose tissue with particular reference to the visceral adipose tissue depot which has been more highly associated with adiposity related disorders than at least some subcutaneous depots although a comprehensive evaluations and correlations with all primary fat depots and covid-19 illness have yet to be determined and would be of clinical interest.…”

“…6,7 The mechanisms that contribute to the underlying risks of obesity and adiposity to the resulting magnitude of SARS-CoV-2 infections remain incompletely defined, but are likely related to the physiology and anatomic distribution of adipose tissue with particular reference to the visceral adipose tissue depot which has been more highly associated with adiposity related disorders than at least some subcutaneous depots although a comprehensive evaluations and correlations with all primary fat depots and covid-19 illness have yet to be determined and would be of clinical interest. 1,3,[16][17][18][19][20]…”

“…risk of cytokine mediated COVID-19 complications than which occurs in non-obese individuals where the relative BMI is less than 25 kg/m 2 .and remains at that level. 3 Once receptive tissues become infected with the virus, the intracellular viral replication occurs rapidly and may spread to other receptive tissues including other adipose depots and other organs. In severe cases, death may occur due to a combination of the additive impact of the virus and comorbidities, and the more advanced the obese state in concert with additional individual or multiple comorbidities, the more severe illness and most dire consequences may occur.…”