Hepatocyte Growth Factor Prevented High-Fat Diet-Induced Obesity and Improved Insulin Resistance in Mice

Abstract

Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4–5 times higher serum HGF levels than wild-type mice were used. While body weight in wild-type mice fed with high fat diet (HFD) for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

Anti-inflammatory effect of HGF responses to traumatic oral ulcers using an HGF-Tg mouse model

“…inhibiting immune cell infiltration and inflammation in tissues [8,26]. We found that HGF-Tg mice presented less weight loss, less epithelial ulceration and less infiltration of Ly6G+ neutrophils as shown by histological and immunohistochemical observation on day 5.…”

“…Inflammation cytokines mediate complex functions in traumatic ulcers, depending on their proportional concentrations [15,30,31]. HGF maybe a new drug target to treat metabolic disease by inhibiting the inflammation cytokines in adipose tissue in HGF-Tg mice [26]. Anti-inflammatory roles of HGF have been described, including inhibiting pro-and inflammatory cytokines such as TNF-ɑ, IFNγ,TGF-βand iNOS.…”

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

“…In addition, cardiacspecific overexpression of HGF resulting in a fourfold increase in circulating HGF levels is sufficient to protect mice from highfat diet-induced body weight gain and insulin resistance. These mice also demonstrate reduced accumulation of macrophages and reduced levels of inflammatory factors in white adipose tissue compared to wild-type mice (Muratsu et al, 2017). Consistent with the improved glucose tolerance when overexpressed, a HGF-neutralizing antibody in wild-type mice exacerbated the symptoms of diet-induced obesity and impaired glucose clearance ability, but the tissues responsible for this phenotype were not identified (Muratsu et al, 2017).…”

“…These mice also demonstrate reduced accumulation of macrophages and reduced levels of inflammatory factors in white adipose tissue compared to wild-type mice (Muratsu et al, 2017). Consistent with the improved glucose tolerance when overexpressed, a HGF-neutralizing antibody in wild-type mice exacerbated the symptoms of diet-induced obesity and impaired glucose clearance ability, but the tissues responsible for this phenotype were not identified (Muratsu et al, 2017). Mechanistically, activation of the HGF/MET pathway increases glucose uptake in peripheral metabolic organs and stimulates insulin secretion in pancreatic β-cells.…”

“…The MET kinase inhibitor SU11274 has been studied in non-small cell lung cancer xenografts resulting in inhibition of tumor growth (Tang et al, 2008), but whether pharmacological administration of HGF can lead to cancer development in the absence of oncogene or tumor suppressor alterations is unclear. It is also possible that the mitogenic properties of HGF could be uncoupled from the metabolic effects, as previously shown to be possible with FGF1 (Muratsu et al, 2017). In addition, the metabolic effects of highly selective MET inhibitors such as capmatinib in regulating glucose or lipid metabolism have not been shown in either animal models or in humans.…”