Dietary sodium restriction alters muscle lipidomics that relates to insulin resistance in mice

Abstract

A low-sodium (LS) diet has been shown to reduce blood pressure (BP) and the incidence of cardiovascular diseases. However, severe dietary sodium restriction promotes insulin resistance (IR) and dyslipidemia in animal models and humans. Thus, further clarification of the long-term consequences of LS is needed. Here, we investigated the effects of chronic LS on gastrocnemius gene and protein expression and lipidomics and its association with IR and plasma lipids in LDL receptor knockout mice. Three-month-old male mice were fed a normal sodium diet (NS; 0.5% Na; n = 12–19) or LS (0.06% Na; n = 14–20) over 90 days. Body mass (BM), BP, plasma total cholesterol, triacylglycerol (TG), glucose, hematocrit, and IR were evaluated. LS increased BM (9%), plasma TG (51%), blood glucose (19%), and IR (46%) when compared with the NS. RT-qPCR analysis revealed that genes involved in lipid uptake and oxidation were increased by the LS: Fabp3 (106%), Prkaa1 (46%), and Cpt1 (74%). Genes and proteins (assessed by Western blotting) involved in insulin signaling were not changed by the LS. Similarly, lipid species classically involved in muscle IR, such as diacylglycerols and ceramides detected by ultra-high-performance liquid chromatography coupled to mass spectrometry, were also unchanged by LS. Species of phosphatidylcholines (68%), phosphatidylinositol (90%), and free fatty acids (59%) increased while cardiolipins (41%) and acylcarnitines (9%) decreased in gastrocnemius in response to LS and were associated with glucose disposal rate. Together these results suggest that chronic LS alters glycerophospholipid and fatty acids species in gastrocnemius that may contribute to glucose and lipid homeostasis derangements in mice.

Aerobic Exercise Training Prevents Insulin Resistance and Hepatic Lipid Accumulation in LDL Receptor Knockout Mice Chronically Fed a Low-Sodium Diet

“…In the kITT, a reduced glucose decay rate was observed in the LS-S group as compared to others, as previously reported [4]; however, the impairment in the insulin sensitivity was prevented by AET (Figure 3).…”

“…After intervention, the LS groups showed greater body mass, glycemia, and triglyceridemia compared to NS groups ( Table 2 ). Biochemical data from NS-S and LS-S animals were presented elsewhere as a part of the evaluation of muscle lipidomics in those animals [ 4 ]. Unexpectedly, AET mice presented higher blood glucose compared to sedentary ones.…”

“…Moreover, the increased FFA flux to the peripheral insulin-sensitive organs such as adipose tissue and skeletal muscle impairs insulin signaling. In LDLr-KO mice, the peripheral IR elicited by the LS diet was attributed to alterations in the gastrocnemius lipidomics [ 4 ]. In the liver, the mechanisms that induce IR are less clear and may include inflammation and lipid accumulation that accompany obesity [ 24 ].…”

“…Those events contribute to the increase in plasma lipids, especially triglycerides (TG) and free fatty acids (FFA), enhanced lipid infiltration in the arterial wall, and glycoxidative stress [3]. It was recently demonstrated that LDL receptor knockout (LDLr-KO) mice chronically fed a low-sodium (LS) diet present many alterations Nutrients 2021, 13, 2174 2 of 17 in skeletal muscle lipidomics, namely glycerophospholipid and fatty acid species that relate to the reduced insulin sensitivity observed in those animals [4].…”

High-Salt Attenuates the Efficacy of Dapagliflozin in Tubular Protection by Impairing Fatty Acid Metabolism in Diabetic Kidney Disease

“…The impaired energetics of proximal tubules seems to be the underlying basis of lethal and sublethal tubular epithelial cell injury (Basile et al, 2012;Stadler et al, 2015). However, other studies have also pointed out that dietary sodium restriction can increase Cpt1 expression and the content of free fatty acid (Pinto et al, 2021).…”