In vivo Effects of Adipose‐Specific Deletion of Jagged 1 in Mice Administered a High Fat Diet

Abstract

Adipose tissue is a major site of lipid metabolism that works synergistically with other organs to regulate whole body energy homeostasis. Adipose tissue also modulates metabolism by secretion of adipokines such as leptin and adiponectin. Abnormalities in the differentiation and function of mature fat cells (adipocytes) are linked to metabolic disease. The evolutionarily‐conserved Notch signaling pathway is necessary for the differentiation of all cell types including adipocytes. Both inhibition and activation of Notch 1 interfere with adipose remodeling in response to nutritional stress. Although activation of the canonical Notch pathway requires binding to one of its transmembrane ligands such as Jagged‐1, the importance of the ligand itself in regulating adipose development and function has been poorly studied. Furthermore, the ability of the Jagged1 ligand to regulate adipocyte cell fate decisions directly through translocation of its intracellular domain (ICD) into the nucleus is unknown. To address these questions regarding the role of Jagged1 in maintaining metabolically healthy adipose, we generated a novel Cre‐mediated conditional knockout murine strain (ap2‐Jag1tm2Grid) to study the impact that jagged1 gene dosage has on visceral adipose depots under conditions of dietary stress. The ap2‐Jag1tm2Grid line produces progeny with three possible Jagged‐1 genotypes that result in either wild type, haploinsufficient or complete loss of Jagged1 expression in mature adipocytes. Physiological and biochemical measurements conducted on young mice representing all three genotypes after administration of either a high fat (“Western”) or standard diet for 5 weeks support our hypothesis that complete or partial loss of Jagged1 in adipocytes is detrimental to the ability of adipose to remodel and function normally in response to the intake of dietary lipids. Differences among the cohorts regarding weight gain, % visceral fat mass, fasting blood glucose, serum lipids and expression of adipokines leptin and adiponectin support a role for Jagged‐1 in maintaining proper adipose growth and metabolism. Data from this study may lead to a better understanding of how the expression level of Jagged1 influences an individual's susceptibility to obesity and metabolic disease.Support or Funding InformationDeena J. Small, University of New England Department of Chemistry & PhysicsWoon Yuen Koh, University of New England Department of Mathematical SciencesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.