Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity

• Published in: Diabetologia Vol. 54; no. 1; pp. 180 - 189
• Main Authors: Jager, J, Corcelle, V, Grémeaux, T, Laurent, K, Waget, A, Pagès, G, Binétruy, B, Le Marchand-Brustel, Y, Burcelin, R, Bost, F, Tanti, J. F
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Berlin/Heidelberg : Springer-Verlag 01.01.2011; Springer-Verlag; Springer; Springer Nature B.V; Springer Verlag
• Subjects: adipose tissue; Animals; Biological and medical sciences; Development Biology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - physiopathology; Female; Gastroenterology. Liver. Pancreas. Abdomen; Human Physiology; inflammation; Insulin resistance; Insulin Resistance - genetics; Insulin Resistance - physiology; Internal Medicine; Kinases; Leptin - deficiency; Leptin - genetics; Life Sciences; Liver. Biliary tract. Portal circulation. Exocrine pancreas; macrophages; Male; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metabolites; Mice; Mice, Knockout; Mice, Obese; Mitogen-Activated Protein Kinase 3 - deficiency; Mitogen-Activated Protein Kinase 3 - genetics; muscles; ob/ob mice; Obesity; Obesity - genetics; Obesity - physiopathology; Other diseases. Semiology; T-lymphocytes; France; T lymphocytes; Adipose tissue; Fatty liver; Muscles; Insulin resistance; Inflammation; Macrophages; mice; /; Endocrinopathy; Extracellular signal-regulated protein kinase; Hepatic disease; ob/ob mice; T-Lymphocyte; Muscle; Nutritional status; Obesity; Enzyme; Diabetes mellitus; Deficiency; Rodentia; Nutrition disorder; Metabolic diseases; Adipokine; Target tissue resistance; Vertebrata; Mammalia; Mouse; Animal; Leptin; Digestive diseases; Macrophage
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-010-1944-0

Aims/hypothesis Extracellular signal-regulated kinase (ERK) activity is increased in adipose tissue in obesity and type 2 diabetes mellitus and strong evidences suggests that it is implicated in the downregulation of insulin signalling and action in the insulin-resistant state. To determine the role of ERK1 in obesity-associated insulin resistance in vivo, we inactivated Erk1 (also known as Mapk3) in obese leptin-deficient mice (ob/ob). Methods Mice of genotype ob/ob-Erk1 ⁻/⁻ were obtained by crossing Erk1 ⁻/⁻ mice with ob/ob mice. Glucose tolerance and insulin sensitivity were studied in 12-week-old mice. Tissue-specific insulin sensitivity, insulin signalling, liver steatosis and adipose tissue inflammation were determined. Results While ob/ob-Erk1 ⁻/⁻ and ob/ob mice exhibited comparable body weight and adiposity, ob/ob-Erk1 ⁻/⁻ mice did not develop hyperglycaemia and their glucose tolerance was improved. Hyperinsulinaemic-euglycaemic clamp studies demonstrated an increase in whole-body insulin sensitivity in the ob/ob-Erk1 ⁻/⁻ mice associated with an increase in both insulin-stimulated glucose disposal in skeletal muscles and adipose tissue insulin sensitivity. This occurred in parallel with improved insulin signalling in both tissues. The ob/ob-Erk1 ⁻/⁻ mice were also partially protected against hepatic steatosis with a strong reduction in acetyl-CoA carboxylase level. These metabolic improvements were associated with reduced expression of mRNA encoding inflammatory cytokine and T lymphocyte markers in the adipose tissue. Conclusions/interpretation Our results demonstrate that the targeting of ERK1 could partially protect obese mice against insulin resistance and liver steatosis by decreasing adipose tissue inflammation and by increasing muscle glucose uptake. Our results indicate that deregulation of the ERK1 pathway could be an important component in obesity-associated metabolic disorders.