Abstract
It is well known that high salt intake is associated with cardiovascular diseases including hypertension. However, the research on the mechanism of obesity due to high salt intake is rare. To evaluate the roles of salt on obesity prevalence, the gene expression of adipogenesis/lipogenesis and adipocytokines secretion according to adipocyte dysfunction were investigated in salt-loading adipocytes. High salt dose-dependently increased the expression of adipogenic/lipogenic genes, such as PPAR-γ, C/EBPα, SREBP1c, ACC, FAS, and aP2, but decreased the gene of lipolysis like AMPK, ultimately resulting in fat accumulation. With SIK-2 and Na+/K+-ATPase activation, salt increased the metabolites involved in the renin-angiotensin-aldosterone system (RAAS) such as ADD1, CYP11β2, and MCR. Increasing insulin dependent insulin receptor substrate (IRS)-signaling, resulting in the insulin resistance, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) and Akt-mTOR were activated but AMPK(Thr172) was depressed in salt-loading adipocytes. The expression of pro-inflammatory adipocytokines, TNFα, MCP-1, COX-2, IL-17A, IL-6, leptin, and leptin to adiponectin ratio (LAR) were dose-dependently increased by salt treatment. Using the inhibitors of MAPK/ERK, U0126, we found that the crosstalk among the signaling pathways of MAPK/ERK, Akt-mTOR, and the inflammatory adipogenesis can be the possible mechanism of salt-linked obesity. The possibilities of whether the defense mechanisms against high dose of intracellular salts provoke signaling for adipocytes differentiation or interact with surrounding tissues through other pathways will be explored in future research.
Highlights
Metabolic dysfunction of adipocytes associated with obesity-linked complications on adipogenesis/lipogenesis and adipocytokines production positively depended on various obesogenic environments such as excessive consumption of fat, salt and alcohol, sedentary lifestyles, stresses, and so on [1,2]
The phosphorylated Akt (Ser473)-mammalian target of rapamycin (mTOR) activation significantly increased the translocation of the active form of SREBP-1c (68 kDa) into the nucleus resulting in increased expression of lipogenesis-related genes in salt-loading adipocytes
We demonstrated for the first time that salt-induced SIK2 activation enhances an mitogen-activated protein kinase (MAPK)/ERK mediated Akt-mTOR–dependent up-regulation of adipogenetic genes expression such as PPARγ, C/EBPα, and SREBP-1c, and down-regulation of AMPK (Thr172)
Summary
Metabolic dysfunction of adipocytes associated with obesity-linked complications on adipogenesis/lipogenesis and adipocytokines production positively depended on various obesogenic environments such as excessive consumption of fat, salt and alcohol, sedentary lifestyles, stresses, and so on [1,2]. MAPK/ERK activated by growth factors, hormones, neurotransmitters, nutrients, and chemokines has been shown to have profound effects on the differentiation of 3T3-L1 preadipocytes or in other cellular models This signaling involved the expression of the crucial adipogenic regulators CCAAT/enhancer binding protein-α/-β/-δ (C/EBP-α, -β, -δ), peroxisome proliferator-activated receptor gamma (PPARγ), and sterol regulatory element-binding protein (SREBP-1c) [12]. Adipose tissue secretes an array of hormones, adipokines, or adipocytokines that signal key organs to maintain metabolic homeostasis Inflammatory cytokines such as tumor necrosis factor alpha (TNF-α), PAI-1, monocyte chemoattractant protein (MCP-1), interleukin-6 (IL-6), IL-1β, IL-18, leptin, and angiopoietin-like protein 2 develop adipogenesis [17]. Adipocytokines, inflammatory cytokines related insulin resistance, and signaling pathways of MAPK/ERK and Akt-mTOR were investigated in salt-loading adipocytes
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