- The concept proposing a major role for interorgan crosstalk as a link between dysmetabolism and inflammation largely builds on two major conceptual advances that developed mainly in the last two decades. The first one is the recognition that endocrine-type crosstalk exists between virtually all organs and tissues, extending way beyond very specific, “classical” endocrine glands. This has relied on various lines of experimental approaches, including “omics” types of data, revealing that a large fraction of the expressed genome of many tissues encodes known and predicted secreted proteins. Complementarily, tissue-specific genetic manipulations provided in vivo evidence for the ability to alter the function of a tissue distant from the site directly affected by the genetic intervention. The second conceptual advance is the huge expansion in our understanding of the homeostatic-physiological roles, as well as the pathophysiological involvement, of the immune system in diverse types of diseases. In this context, two decades ago, the finding that tumour necrosis factor-α (TNF-α) is overexpressed in adipose tissue of obese mice provided the first clear link between obesity and chronic inflammation . Almost at the same time, the discovery of leptin, the first adipokine that signals through a cytokine receptor family member, sparked the understanding that inflammatory changes within adipose tissue may alter the way this tissue communicates with various organs, even the brain . More recently, a wealth of data established the concept that obesity is associated with systemic and tissue-level low-grade chronic inflammation, initially recognized by adipose tissue infiltration with inflammatory cells in response to an excessive energetic nutrient load [3, 4]. The concept of “metabolic inflammation” or “metaflammation” was eventually formulated and fueled by examples of specific mechanisms tying metabolic mediators to inflammatory cascades and inflammatory mediators to alterations in metabolic regulation . The metabolic inflammation, possibly initiated in response to excess calories/high fat feeding in the adipose tissue, may subsequently involve other metabolic organs such as the liver, skeletal muscle, and pancreas, contributing to metabolic dysfunction and insulin resistance. This multiorgan involvement of obesity-associated inflammation presents a challenge to researchers attempting to clarify the complex signaling mechanisms of the interorgan crosstalk leading to metabolic dysfunction. Alongside inflammation pertaining to “metabolic” organs, studies published during the past decade have convincingly demonstrated a pathophysiological role for the inflammatory response in the development of cardiovascular disease (CVD), the most important complication of the metabolic syndrome and diabetes . In addition, a multitude of mediators of metabolic inflammation have been found to modulate vascular homeostasis, suggesting further mechanisms of interorgan crosstalk between metabolic tissues and the vasculature. Therefore, the low chronic inflammatory state may be responsible for both insulin resistance and endothelial dysfunction, providing deleterious connections between inflammation and metabolic/CVD processes.