Dietary nitrate attenuates high-fat diet-induced obesity via mechanisms involving higher adipocyte respiration and alterations in inflammatory status

M Peleli,D.M.S Ferreira,L Tarnawski,S Mccann Haworth,L Xuechen,Z Zhuge,P.T Newton,J Massart,A.S Chagin,P.S Olofsson,J.L Ruas,E Weitzberg,J.O Lundberg,M Carlström

doi:10.1016/j.redox.2019.101387

M Peleli, D.M.S Ferreira + Show 12 more

Open Access

https://doi.org/10.1016/j.redox.2019.101387

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Journal: Redox Biology	Publication Date: Nov 18, 2019
Citations: 32	License type: cc-by

Affiliation: Karolinska Institutet, Sechenov University

Abstract

Emerging evidence indicates that dietary nitrate can reverse several features of the metabolic syndrome, but the underlying molecular mechanisms still remain elusive. The aim of the present study was to explore mechanisms involved in the effects of dietary nitrate on the metabolic dysfunctions induced by high-fat diet (HFD) in mice. Four weeks old C57BL/6 male mice, exposed to HFD for ten weeks, were characterised by increased body weight, fat content, increased fasting glucose and impaired glucose clearance. All these metabolic abnormalities were significantly attenuated by dietary nitrate. Mechanistically, subcutaneous primary mouse adipocytes exposed to palmitate (PA) and treated with nitrite exhibited higher mitochondrial respiration, increased protein expression of total mitochondrial complexes and elevated gene expression of the thermogenesis gene UCP-1, as well as of the creatine transporter SLC6A8. Finally, dietary nitrate increased the expression of anti-inflammatory markers in visceral fat, plasma and bone marrow-derived macrophages (Arginase-1, Egr-2, IL-10), which was associated with reduction of NADPH oxidase-derived superoxide production in macrophages. In conclusion, dietary nitrate may have therapeutic utility against obesity and associated metabolic complications possibly by increasing adipocyte mitochondrial respiration and by dampening inflammation and oxidative stress.

Highlights

Metabolic syndrome is a combination of metabolic and biochemical abnormalities, often associated with aging and obesity, which increase the risk of developing of type 2 diabetes and cardiovascular disease [1]
high-fat diet (HFD) progressively increased body weight compared with control mice on normal chow, which was due to accumulation of fat mass (Fig. 2A–C)
HFD-fed mice supplemented with nitrate had no change in response to insulin but had improved glucose homeostasis (Fig. 2D–F), as evident from intraperitoneal insulin and glucose tolerance tests

Summary

Introduction

Metabolic syndrome is a combination of metabolic and biochemical abnormalities, often associated with aging and obesity, which increase the risk of developing of type 2 diabetes and cardiovascular disease [1]. Inorganic nitrate is found in our daily diet and is high in green leafy vegetables, a food group that has been associated with favourable cardiometabolic effects in meta-analyses and systematic reviews [3,4]. Studies conducted over the past couple of decades have shown many favourable cardiovascular effects of dietary nitrate [5,6,7]. Since originally described in 2010 [8], numerous studies have showed that supplementation with inorganic nitrate can reverse many features of the metabolic syndrome by restoring nitric oxide (NO) homeostasis in different animal and cellular models [9]

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