Implication of neuronal calcium sensor protein 1 (NCS-1) in metabolic stress and obesity

• Applicant: Professor Dr. Olaf Pongs
• Subject Area: Anatomy and Physiology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 269219700

Obesity, a spreading worldwide health problem, represents a major risk factor for the development of type 2 diabetes. Increased levels of saturated free fatty acid in the blood causes metabolic stress and insulin resistance. The mixed lineage protein kinase (MLK) pathway plays a critical role for diet-induced insulin resistance and obesity. An understanding of the mechanisms that regulate the activity of this pathway is therefore important for the development of therapeutic interventions in the treatment of obesity-related metabolic stress. This proposal focuses on the activity of neuronal calcium sensor protein-1 (NCS-1) in adipose tissue of the mouse and the role of NCS-1 in the metabolic stress response to obesity. It involves the mixed-lineage kinase (MLK) pathway that activates c-Jun NH2-terminal kinase (JNK). Using NCS-1 knock-out (NCS-1-/-) mice, which possess an elevated JNK activity, and a combination of NCS-1-/- with MLK2/MLK3 deficient (Map3k10-/- Map3k11-/- compound) mice, the proposal has three major objectives: i) unravel the physiological role of NCS-1 in relation to the obese phenotype of NCS-1-/- mice; ii) further characterize the type 2 diabetes phenotype of NCS-1-/- mice, which is associated with alterations in the metabolic stress response observed under a high-fat diet; iii) explore the role of NCS-1 in the mixed-lineage protein kinase pathway leading to increased JNK activity in NCS-1-/- mice. We expect that the results of our studies contribute to a better understanding of the regulation of the metabolic stress response to obesity.

• DFG Programme: Research Grants