Abstract
Chronic low-grade inflammation in visceral adipose tissues triggers the development of obesity-related insulin resistance, leading to the metabolic syndrome, a serious health condition with higher risk of cardiovascular disease, diabetes, and stroke. In the present study, we investigated whether Sprouty-related EVH1-domain-containing protein 2 (Spred2), a negative regulator of the Ras/Raf/ERK/MAPK pathway, plays a role in the development of high fat diet (HFD)-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance. Spred2 knockout (KO) mice, fed with HFD, exhibited an augmented body weight gain, which was associated with enhanced adipocyte hypertrophy in mesenteric white adipose tissue (mWAT) and deteriorated dyslipidemia, compared with wild-type (WT) controls. The number of infiltrating macrophages with a M1 phenotype, and the crown-like structures, composed of macrophages surrounding dead or dying adipocytes, were more abundant in Spred2 KO-mWAT compared to in WT-mWAT. Exacerbated adipose tissue inflammation in Spred2 KO mice led to aggravated insulin resistance and fatty liver disease. To analyze the mechanism(s) that caused adipose tissue inflammation, cytokine response in mWAT was investigated. Stromal vascular fraction that contained macrophages from Spred2 KO-mWAT showed elevated levels of tumor necrosis factor α (TNFα) and monocyte chemoattractant protein-1 (MCP-1/CCL2) compared with those from WT-mWAT. Upon stimulation with palmitate acid (PA), bone marrow-derived macrophages (BMDMs) derived from Spred2 KO mice secreted higher levels of TNFα and MCP-1 than those from WT mice with enhanced ERK activation. U0126, a MEK inhibitor, reduced the PA-induced cytokine response. Taken together, these results suggested that Spred2, in macrophages, negatively regulates high fat diet-induced obesity, adipose tissue inflammation, metabolic abnormalities, and insulin resistance by inhibiting the ERK/MAPK pathway. Thus, Spred2 represents a potential therapeutic tool for the prevention of insulin resistance and resultant metabolic syndrome.
Highlights
Metabolic syndrome is characterized by abdominal obesity, dyslipidemia, elevated blood pressure, and impaired glucose tolerance
Previous studies have shown that the mitogen-activated protein kinase (MAPK) pathway, especially the extracellular signal-regulated kinase (ERK)/MAPK pathway plays an important role in obesity and obesity-associated insulin resistance [13, 51]
Genomewide association studies have indicated that a genetic variation near the Sprouty homolog 2 (SPRY2) gene, an inhibitor of the Ras/Raf/ERK/MAPK pathway [52], is associated with body fat percentage in human [53, 54]
Summary
Metabolic syndrome is characterized by abdominal obesity, dyslipidemia, elevated blood pressure, and impaired glucose tolerance. The principal determinant and core feature of metabolic syndrome is abdominal obesity [3]; insulin resistance has been recognized as the integral feature of this syndrome [4]. Obesity is associated with a state of chronic, low-grade inflammation in the adipose tissue, which involves adipocyte hypertrophy, macrophage infiltration, and adipocytemacrophage interaction [5]. The absence of TNFα resulted in significantly enhanced insulin sensitivity in both diet-induced and leptin-deficient (ob/ob) mouse models of obesity [7]. The chemokine monocyte chemoattractant protein-1 (MCP-1/CCL2), and its receptor C-C motif chemokine receptor 2 (CCR2) play a critical role in macrophage infiltration and insulin resistance associated with obesity [8, 9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
