HGF-INSR

Hepatocyte Growth Factor and Insulin Resistance

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 Obiettivo del progetto (Objective)

'Insulin resistance is a hallmark of human diseases, including diabetes and obesity, which lead to abnormal glucose and lipid metabolism as a result of impaired metabolic response to insulin. The mechanism underlying the development of insulin resistance remains incompletely understood. Excessive production of pro-inflammatory cytokines by the adipose tissue is linked to insulin resistance. Hepatocyte Growth Factor (HGF) is an adipocytokine elevated in obese subjects, which strongly correlated with the metabolic syndrome. However the role of HGF in the etiology of the insulin resistance remains unknown. Recently, we have demonstrated that HGF is a potent activator of glucose transport and metabolism, and also a strong inhibitor of fatty acid oxidation in rodent myotubes (Perdomo et al., J. Biol. Chem., 2008). In addition, we have generated (i) a conditional transgenic mouse of HGF in the skeletal muscle, and (ii) a conditional knockout mouse of the HGF receptor (c-met) in skeletal muscle. We hypothesized that HGF ameliorates skeletal muscle insulin resistance in vivo. To test this hypothesis, we propose two aims: 1) To investigate the relationship between plasma HGF levels and insulin resistance in humans. 2) To investigate the role of HGF in the insulin-resistant skeletal muscle. Accomplishing this project will elucidate the relationship between plasma HGF levels and insulin resistance in humans and determine its contribution to the etiology and pathophysiology of insulin resistance. A mechanistic understanding of insulin resistance will facilitate the development of therapeutic strategies and identification of new drug targets in the prevention and treatment of diabetes and obesity. Finally, my preliminary data have provided feasibility for the project.'

Introduzione (Teaser)

Obesity is considered the epidemic of the 21st century. Understanding the aetiology and pathophysiology of obesity should facilitate its prevention, diagnosis and treatment.

Descrizione progetto (Article)

Insulin resistance is a common denominator in many metabolic-related diseases and obesity. However, the mechanism that causes insulin resistance is not completely understood. Emerging evidence indicates that the presence of certain pro-inflammatory cytokines such as hepatocyte growth factor (HGF) in adipose tissue is tightly associated with obese subjects and the development of metabolic disease.

Although the role of HGF in the activation of glucose metabolism and in the inhibition of fatty acid oxidation is well established, little is known about its role in insulin resistance. Seeking to address this, the EU-funded 'Hepatocyte growth factor and insulin resistance' (HGF-INSR) consortium generated transgenic mice expressing HGF in skeletal muscle and mice lacking the HGF receptor in skeletal muscle.

Looking at the impact of HGF in these mice, they observed reduced plasma insulin levels and improved glucose tolerance, despite similar body weight. The results were even more striking when HGF was overexpressed in the muscle of obese mice, with improved total body glucose metabolism and insulin sensitivity.

The consortium worked under the hypothesis that HGF improves insulin sensitivity. They also performed anthropometric measurements in normal and obese children to find an association between plasma HGF levels and insulin resistance in obese children. HGF levels were also higher in pre-term neonates, suggesting a potential role in foetal maturity.

To understand the association between maternal obesity and foetal metabolism, scientists measured the levels of HGF in amniotic fluid. Their findings clearly supported a mechanistic link between HGF with glucose and lipid metabolism in neonates. They suggest that HGF modifies the availability of nutrients to the foetus, thereby increasing the risk of metabolic diseases such as obesity and diabetes later in life.

Taken together, the results of the HGF-INSR study underscore the importance of HGF in insulin resistance and the development of metabolic diseases. Furthermore, they indicate that HGF could be reliably used as a diagnostic marker for predicting obesity or diabetes.