Obesity and COVID-19: what makes obese host so vulnerable?

The disease (COVID-19) novel coronavirus pandemic has so far infected millions resulting in the death of over a million people as of Oct 2020. More than 90% of those infected with COVID-19 show mild or no symptoms but the rest of the infected cases show severe symptoms resulting in significant mortality. Age has emerged as a major factor to predict the severity of the disease and mortality rates are significantly higher in elderly patients. Besides, patients with underlying conditions like Type 2 diabetes, cardiovascular diseases, hypertension, and cancer have an increased risk of severe disease and death due to COVID-19 infection. Obesity has emerged as a novel risk factor for hospitalization and death due to COVID-19. Several independent studies have observed that people with obesity are at a greater risk of severe disease and death due to COVID-19. Here we review the published data related to obesity and overweight to assess the possible risk and outcome in Covid-19 patients based on their body weight. Besides, we explore how the obese host provides a unique microenvironment for disease pathogenesis, resulting in increased severity of the disease and poor outcome.

Functional Characterization of the Obesity-Linked Variant of the ß3-Adrenergic Receptor.

Adrenergic receptor ß3 (ADRß3) is a member of the rhodopsin-like G protein-coupled receptor family. The binding of the ligand to ADRß3 activates adenylate cyclase and increases cAMP in the cells. ADRß3 is highly expressed in white and brown adipocytes and controls key regulatory pathways of lipid metabolism. Trp64Arg (W64R) polymorphism in the ADRß3 is associated with the early development of type 2 diabetes mellitus, lower resting metabolic rate, abdominal obesity, and insulin resistance. It is unclear how the substitution of W64R affects the functioning of ADRß3. This study was initiated to functionally characterize this obesity-linked variant of ADRß3. We evaluated in detail the expression, subcellular distribution, and post-activation behavior of the WT and W64R ADRß3 using single cell quantitative fluorescence microscopy. When expressed in HEK 293 cells, ADRß3 shows a typical distribution displayed by other GPCRs with a predominant localization at the cell surface. Unlike adrenergic receptor ß2 (ADRß2), agonist-induced desensitization of ADRß3 does not involve loss of cell surface expression. WT and W64R variant of ADRß3 displayed comparable biochemical properties, and there was no significant impact of the substitution of tryptophan with arginine on the expression, cellular distribution, signaling, and post-activation behavior of ADRß3. The obesity-linked W64R variant of ADRß3 is indistinguishable from the WT ADRß3 in terms of expression, cellular distribution, signaling, and post-activation behavior.

Free Fatty Acid Receptors (FFARs) in Adipose: Physiological Role and Therapeutic Outlook.

Fatty acids (FFAs) are important biological molecules that serve as a major energy source and are key components of biological membranes. In addition, FFAs play important roles in metabolic regulation and contribute to the development and progression of metabolic disorders like diabetes. Recent studies have shown that FFAs can act as important ligands of G-protein-coupled receptors (GPCRs) on the surface of cells and impact key physiological processes. Free fatty acid-activated receptors include FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), and FFAR4 (GPR120). FFAR2 and FFAR3 are activated by short-chain fatty acids like acetate, propionate, and butyrate, whereas FFAR1 and FFAR4 are activated by medium- and long-chain fatty acids like palmitate, oleate, linoleate, and others. FFARs have attracted considerable attention over the last few years and have become attractive pharmacological targets in the treatment of type 2 diabetes and metabolic syndrome. Several lines of evidence point to their importance in the regulation of whole-body metabolic homeostasis including adipose metabolism. Here, we summarize our current understanding of the physiological functions of FFAR isoforms in adipose biology and explore the prospect of FFAR-based therapies to treat patients with obesity and Type 2 diabetes.

Single-cell Analysis of ß2-Adrenergic Receptor Dynamics by Quantitative Fluorescence Microscopy.

BACKGROUND: G protein-coupled receptors (GPCRs) represent the largest family of surface proteins and are involved in the regulation of key physiological processes. GPCRs are characterized by seven transmembrane domains, an extracellular N-terminus and an intracellular C-terminus. Cellular response of these receptors to their ligands is largely determined by their surface expression and postactivation behavior including expression, desensitization and resensitization. OBJECTIVE: To develop a quantitative fluorescence Microscopy assay to study ß2- Adrenergic receptor expression and desensitization. METHOD: ß2-Adrenergic receptor cDNA was engineered to put an HA tag at the extracellular N-terminus and GFP Tag at the intracellular C-terminus. GFP fluorescence serves as a measure of total cellular expression; whereas staining with CY3 conjugated anti-HA antibodies without permeabilizing the cells represents the surface expression of ß2-AR. The images are quantified and amount of CY3 (surface) and GFP (total) fluorescence for each cell determined using image processing software. RESULTS: The method is sensitive and allows for the simultaneous measurement of surface and total expression of ß2-AR. CONCLUSION: A highly accurate method is described for measuring ß2-AR surface and total expression based on single-cell quantitative immunofluorescence. The method can be used to determine agonist-induced desensitization and resensitization process as well as receptor kinetics like endocytosis and exocytosis of ß2-Adrenergic receptor and can be applied to essentially any other GPCR.