Effect of high fat diet on gene expression in pancreatic islet associated macrophages. Effect of high fat diet on gene expression in pancreatic islet associated macrophages

We have exploited islet-associated macrophages (IAMs) as a model of resident macrophage function, focusing on more physiological conditions than the commonly used extremes of M1 (inflammation) versus M2 (tissue-remodelling) polarization. Under steady-state, murine IAMs are metabolically poised between aerobic glycolysis and oxidative phosphorylation, and thereby exert a brake on glucose-stimulated insulin secretion (GSIS). This is underpinned by epigenetic remodelling via the metabolically-regulated histone demethylase Kdm5a. Conversely, GSIS is enhanced by engaging Axl receptors on IAMs, or by augmenting their oxidation of glucose. Following high-fat feeding, efferocytosis is stimulated in IAMs in conjunction with Mertk and Tgfb receptor signalling. This impairs GSIS and potentially contributes to b-cell failure in pre-diabetes. Thus, IAMs serve as relays in many more settings than currently appreciated, fine-tuning insulin secretion in response to dynamic changes in the external environment. Intervening in this nexus might represent a means of preserving b-cell function during metabolic disease. Overall design: Mice were maintained from 8 weeks of age for an additional 8 weeks on either standard chow diet (10.88 kJ/g; 8% fat, 21% protein, and 71% carbohydrate) or a high fat diet (19.67kJ/g; 45% fat, 20% protein, 35% carbohydrate). RNA was extracted from CD11b+, F4/80+ cells prepared from pancreatic islets isolated from C57BL/6J. A total of 4 replicates per diet condition were analysed, each comprising extracts pooled from two mice.