Page 40 - CIBERDEM-2015-eng

Research groups
Laboratory of molecular endocrinology
Programme: P2
Lead Researcher: Burks, Deborah
Group members
STAFF MEMBERS: Acosta Umanzor, Carlos René | Manzano Núñez, Fátima | Noon, Luke. ASSOCIATED MEMBERS: González Navarro, Herminia | Leal Tassias, Aranzazu | Moreno Gimeno,
Inmaculada | Sánchez Pérez, Ana María | Sanz González, Silvia María.
Main lines of research
Our research focuses on insulin receptor substrate (IRS) proteins which are the major intracellular tar- gets of the activated insulin receptor. Loss of Irs2 in both mice and humans is associated with a reduced mass of pancreatic beta cells and peripheral insulin resistance, hallmarks of diabetes.
Our core research consists of 4 major lines: 1) Regu- lation of beta cell compensation and pancreas regen- eration. Given that proliferation of existing beta cells represents the fundamental mechanism for beta cell compensation, it is important to precisely define the signals which govern cell-cycle machinery in the en- docrine pancreas. Recently, we have observed that IRS2 signals are essential for the regulation of the cyclin kinase CDK4 in beta cells. 2) The role of IRS2 signals in obesity-induced inflammation. Female Irs2-deficient mice display a dysregulation of appetite due to the role of IRS2 signals in the hypothalamus and thus, develop moderate obesity. We are current- ly characterizing the inflammation components that are regulated directly by the insulin resistance result-
ing from loss of Irs2. Also, Irs2-deficient mice have more adipose progenitors but these fail to differen- tiate to mature adipocytes. 3) Hepatic insulin resist- ance, liver regeneration, and mechanisms of NAFLD. Throughout the lifetime of an individual, adult stem cells represent a mechanism for the maintenance and regeneration of tissues. One of our objectives is to identify the molecular mechanisms by which in- sulin signaling modulates proliferation and differen- tiation of progenitor cells in insulin-sensitive tissues. These results may provide tools for maintaining stem cell function in the presence of aging-related and pathologic changes in metabolism. 4) Mechanisms of insulin resistance in the CNS. Aged Irs2-deficient mice present various manifestations of neurodegen- eration including neuronal loss and deposits of hy- perphosphorylated tau. Through the use of genomics and proteomics, we hope to identify new markers of neurodegeneration that are regulated by insulin sig- naling. Given that we seek to identify the molecular basis of obesity and insulin resistance, our research
40 I Annual report 2015 I CIBERDEM