Osteopontin Deletion Prevents the Development of Obesity and Hepatic Steatosis via Impaired Adipose Tissue Matrix Remodeling and Reduced Inflammation and Fibrosis in Adipose Tissue and Liver in Mice

Abstract

Osteopontin (OPN) is a multifunctional extracellular matrix (ECM) protein involved in multiple physiological processes. OPN expression is dramatically increased in visceral adipose tissue in obesity and the lack of OPN protects against the development of insulin resistance and inflammation in mice. We sought to unravel the potential mechanisms involved in the beneficial effects of the absence of OPN. We analyzed the effect of the lack of OPN in the development of obesity and hepatic steatosis induced by a high-fat diet (HFD) using OPN-KO mice. OPN expression was upregulated in epididymal white adipose tissue (EWAT) and liver in wild type (WT) mice with HFD. OPN-KO mice had higher insulin sensitivity, lower body weight and fat mass with reduced adipose tissue ECM remodeling and reduced adipocyte size than WT mice under a HFD. Reduced MMP2 and MMP9 activity was involved in the decreased ECM remodeling. Crown-like structure number in EWAT as well as F4/80-positive cells and Emr1 expression in EWAT and liver increased with HFD, while OPN-deficiency blunted the increase. Moreover, our data show for the first time that OPN-KO under a HFD mice display reduced fibrosis in adipose tissue and liver, as well as reduced oxidative stress in adipose tissue. Gene expression of collagens Col1a1, Col6a1 and Col6a3 in EWAT and liver, as well as the profibrotic cytokine Tgfb1 in EWAT were increased with HFD, while OPN-deficiency prevented this increase. OPN deficiency prevented hepatic steatosis via reduction in the expression of molecules involved in the onset of fat accumulation such as Pparg, Srebf1, Fasn, Mogat1, Dgat2 and Cidec. Furthermore, OPN-KO mice exhibited higher body temperature and improved BAT function. The present data reveal novel mechanisms of OPN in the development of obesity, pointing out the inhibition of OPN as a promising target for the treatment of obesity and fatty liver.

Peripheral mononuclear blood cells contribute to the obesity-associated inflammatory state independently of glycemic status: involvement of the novel proinflammatory adipokines chemerin, chitinase-3-like protein 1, lipocalin-2 and osteopontin

“…Therefore, our findings may also be relevant with respect to migration of PBMC to sites of inflammation such as adipose tissue or liver. OPN deficiency has been described to improve glucose tolerance (Kiefer et al 2010;Lancha et al 2014). In this regard, a positive association of mRNA levels of SPP1 in PBMC with insulin resistance has been shown in the present study, suggesting the involvement of PBMC in glucose homeostasis in obesity.…”

“…OPN regulates a great variety of cellular processes including tissue remodeling and immune regulation through its interactions with multiple cell surface receptors (Kahles Lancha et al 2014). This observation is in line with our results, where elevated circulating levels of OPN and its gene expression in PBMC in obesity have been observed.…”

“…The family of adipokines is highly diverse in structure and function. Whereas LCN-2 seems to act as an antagonist to the effect of inflammatory molecules (Guo et al 2014;Zhang et al 2008), OPN and YKL-40 are directly related to increased inflammation and insulin resistance via impaired extracellular matrix remodeling (Johansen et al 2000;Lancha et al 2014).…”

Revisiting the adipocyte: a model for integration of cytokine signaling in the regulation of energy metabolism

“…In this regard, OPN expression can be induced by proinflammatory cytokines such as TNF␣ and TGF␤, hypoxia and hyperglycemia, all wellknown factors of obesity-related inflammation (282). Moreover, OPN deletion prevents the development of obesity and hepatic steatosis via impaired adipose tissue matrix remodeling and reduced inflammation and fibrosis in adipose tissue and liver in mice (159,177). Interestingly, diet-induced weight loss is associated with a reduction in plasmatic and gene expression levels of OPN in visceral fat in obese animals and humans (99, 176,177,224), which may reflect an improvement in systemic and local inflammation.…”

Chitinase 3 Like-1: An Emerging Molecule Involved in Diabetes and Diabetic Complications

“…PBMCs from obese individuals produce elevated levels of TNF-α, IFN-γ and IL-2, whereas the production of the anti-inflammatory cytokine IL-10 is reduced [65]. New factors secreted by adipose tissue promoting inflammatory responses and metabolic dysfunction that have recently been identified include CHI3L1, chemerin, LCN-2 (lipocalin-2) and OPN (osteopontin) [66,67]. These factors are highly diverse in structure and function.…”