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The importance of the capacity and expandability of WAT becomes much more evident in the case of lipodystrophy. Lipodystrophy is a disorder characterized by selective loss of body fat and is accompanied by severe insulin resistance. A series of genetic lipodystrophies has been reported in humans and reflect mutations in genes such as AGPAT2, BSCL2, CAV1, PTRF, CIDEC, PPARG [4]. These genes are implicated in triglyceride synthesis, fusion of lipid droplets and adipogenesis. Although lipodystrophies are relatively rare diseases, there is an increased interest in the development of mouse models so as to better understand the pathophysiological mechanisms of lipodystrophy and the role of specific genes in adipose tissue functionality.  Current mouse models are genetic knock-outs of C/ebpa, Pparg, Agpat2, Cav1  or transgenic mice such as AZIP/F1 and ap2-Srebp-1c [5]. The usefulness of these mouse models lies not only in the fact that they can be used to understand the functions of specific genes but also can expand our understanding of the pathophysiology of insulin resistance [6]. In the present report, we describe a novel mouse model of lipodystrophy that arises from adipose tissue specific overexpression of the Notch [http://www.selleckchem.com/products/AZD2281(Olaparib).html DNA Damage inhibitor] intracellular domain (NICD). The Notch signaling pathway is highly conserved across species, playing roles in cellular differentiation, proliferation and apoptosis [7]. It consists of intermembrane receptors that can be bound by Notch ligands expressed on the surface of adjacent effector cells. This binding initiates the proteolytic cleavage of Notch by which NICD is released from the membrane, enters the nucleus to drive downstream signaling. Notch targets a number of genes, such as hairy and enhancer of split-1 (Hes-1), a prototypical target gene that encodes a transcriptional repressor [8]. Research on the role of the Notch pathway in the field of metabolism is relatively limited, focusing principally on the role of Notch in adipocyte differentiation using in?vitro adipogenesis models such as  3T3-L1 cells [9,10]. Given that these studies were performed in?vitro and taking into account recent studies on the protective effect of Notch inhibition in hepatocytes against fatty liver and insulin resistance [11,12], we investigated the role of Notch in the adipocyte by using a RosaNICD/NICD::Adipoq-Cre (Ad-NICD) mouse that overexpresses NICD specifically in adipose tissue as driven by the adiponectin promoter. We report herein that adipose-tissue specific overexpression of NICD results in a profound lipodystrophic, insulin resistant phenotype. 2.?Materials and methods 2.1. Mice All mouse experiments were performed at the University of Pittsburgh and were approved by the Institutional Animal Care and Use Committee.