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GLP-2 Regulation of Dietary Fat Absorption and Intestinal Chylomicron Production via Neuronal Nitric Oxide Synthase (nNOS) Signaling

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posted on 27.04.2022, 20:00 by Elisabeth M. Grande, Fitore Raka, Simon Hoffman, Khosrow Adeli

Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes (T2D). It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide-2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. Here, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters, after intraduodenal and oral fat administration. GLP-2 treatment in WT mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and PKG inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicates an nNOS-PKG mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production. 


This study was supported by a Canadian Institutes of Health Research (CIHR) Foundation grant to KA. EMG is supported by a Physiology Graduate Fellowship award from the University of Toronto. FR is supported by a CIHR doctoral award.