Pathophysiology and Genetics of Obesity and Diabetes in the New Zealand Obese Mouse: A Model of the Human Metabolic Syndrome

The New Zealand Obese (NZO) mouse is one of the most thoroughly investigated polygenic models for the human metabolic syndrome and type 2 diabetes. It presents the main characteristics of the disease complex, including early-onset obesity, insulin resistance, dyslipidemia, and hypertension. As a consequence of this syndrome, a combination of lipotoxicity and glucotoxicity produces beta-cell failure and apoptosis resulting in hypoinsulinemia and diabetic hyperglycemia. With NZO as a breeding partner, several adipogenic and diabetogenic gene variants have been identified by hypothesis-free positional cloning (Tbc1d1 , Zfp69 ) or by combining genetic screens and candidate gene approaches (Pctp , Abcg1 , Nmur2 , Lepr ). This chapter summarizes the present knowledge of the NZO strain and describes its pathophysiology as well as the known underlying genetic defects.