Time to Consider the "Exposome Hypothesis" in the Development of the Obesity Pandemic

The obesity epidemic shows no signs of abatement. Genetics and overnutrition together with a dramatic decline in physical activity are the alleged main causes for this pandemic. While they undoubtedly represent the main contributors to the obesity problem, they are not able to fully explain all cases and current trends. In this context, a body of knowledge related to exposure to as yet underappreciated obesogenic factors, which can be referred to as the "exposome", merits detailed analysis. Contrarily to the genome, the "exposome" is subject to a great dynamism and variability, which unfolds throughout the individual's lifetime. The development of precise ways of capturing the full exposure spectrum of a person is extraordinarily demanding. Data derived from epidemiological studies linking excess weight with elevated ambient temperatures, in utero, and intergenerational effects as well as epigenetics, microorganisms, microbiota, sleep curtailment, and endocrine disruptors, among others, suggests the possibility that they may work alone or synergistically as several alternative putative contributors to this global epidemic. This narrative review reports the available evidence on as yet underappreciated drivers of the obesity epidemic. Broadly based interventions are needed to better identify these drivers at the same time as stimulating reflection on the potential relevance of the "exposome" in the development and perpetuation of the obesity epidemic

Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I₂ Receptor Ligands

The imidazoline I₂ receptors (I₂-IRs) are widely distributed in the brain, and I₂-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I₂-IR remains unknown, the discovery of selective I₂-IR ligands devoid of α₂-adrenoceptor (α₂-AR) affinity is likely to provide valuable tools in defining the pharmacological characterization of these receptors. We report the pharmacological characterization of a new family of (2-imidazolin-4-yl)­phosphonates. Radioligand binding studies showed that they displayed a higher affinity for I₂-IRs than idazoxan, and high I₂/α₂ selectivity. In vivo studies in mice showed that acute treatments with <b>1b</b> and <b>2c</b> significantly increased p-FADD/FADD ratio (an index of cell survival) in the hippocampus when compared with vehicle-treated controls. Additionally, acute and repeated treatments with <b>2c</b>, but not with <b>1b</b>, markedly reduced hippocampal p35 cleavage into neurotoxic p25. The present results indicate a neuroprotective potential of (2-imidazolin-4-yl)­phosphonates acting at I₂-IRs