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

Abstract

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 leptindeficient 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.

Photoactivation of Dok1/ERK/PPARγ signaling axis inhibits excessive lipolysis in insulin-resistant adipocytes

“…ERK is an important component in obesity-associated metabolic disorders [32,33]. Based on the increased phosphorylation of ERK in adipose tissues of patients with type 2 diabetes, we next investigated whether activated ERK is involved in Dex-induced insulin-resistant.…”

Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

“…In particular, the mitogen-activated protein kinase (MAPK) pathway is an established regulator of hepatic metabolism (7)(8)(9)(10). The stressresponsive MAPK c-Jun NH 2 -terminal kinase 1 (JNK1), when deleted specifically in the liver, results in the development of hepatosteatosis, enhanced hepatic glucose production, and insulin resistance (11).…”

Improved insulin sensitivity with calorie restriction does not require reduced JNK1/2, p38, or ERK1/2 phosphorylation in skeletal muscle of 9-month-old rats

“…Excessive JNK activation has been frequently implicated in the development of insulin resistance (32,34). There are also multiple lines of evidence linking greater stimulation of ERK1/2 to insulin resistance (11,28,35,72,73). Some studies have suggested that p38 can play a positive role in insulin-mediated glucose transport (24,37), but other studies have provided evidence linking activation of p38 to insulin resistance (15,18,32).…”