Mast Cell-Derived Histamine Regulates Liver Ketogenesis via Oleoylethanolamide Signaling.

The conversion of lipolysis-derived fatty acids into ketone bodies (ketogenesis) is a crucial metabolic adaptation to prolonged periods of food scarcity. The process occurs primarily in liver mitochondria and is initiated by fatty-acid-mediated stimulation of the ligand-operated transcription factor, peroxisome proliferator-activated receptor-α (PPAR-α). Here, we present evidence that mast cells contribute to the control of fasting-induced ketogenesis via a paracrine mechanism that involves secretion of histamine into the hepatic portal circulation, stimulation of liver H1 receptors, and local biosynthesis of the high-affinity PPAR-α agonist, oleoylethanolamide (OEA). Genetic or pharmacological interventions that disable any one of these events, including mast cell elimination, deletion of histamine- or OEA-synthesizing enzymes, and H1 blockade, blunt ketogenesis without affecting lipolysis. The results reveal an unexpected role for mast cells in the regulation of systemic fatty-acid homeostasis, and suggest that OEA may act in concert with lipolysis-derived fatty acids to activate liver PPAR-α and promote ketogenesis.

Systemic and vascular inflammation in an in-vitro model of central obesity.

Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models. Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload.