Jü rgens, Hella S., Annette Schü rmann, Reinhart Kluge, Sylvia Ortmann, Susanne Klaus, Hans-Georg Joost, and Matthias H. Tschöp. Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice. Physiol Genomics 25: 234 -241, 2006; doi:10.1152/physiolgenomics.00252.2005.-Among polygenic mouse models of obesity, the New Zealand obese (NZO) mouse exhibits the most severe phenotype, with fat depots exceeding 40% of total body weight at the age of 6 mo. Here we dissected the components of energy balance including feeding behavior, locomotor activity, energy expenditure, and thermogenesis compared with the related lean New Zealand black (NZB) and obese B6.V-Lep ob /J (ob/ob) strains (11% and 65% fat at 23 wk, respectively). NZO mice exhibited a significant hyperphagia that, when food intake was expressed per metabolic body mass, was less pronounced than that of the ob/ob strain. Compared with NZB, NZO mice exhibited increased meal frequency, meal duration, and meal size. Body temperature as determined by telemetry with implanted sensors was reduced in NZO mice, but again to a lesser extent than in the ob/ob strain. In striking contrast to ob/ob mice, NZO mice were able to maintain a constant body temperature during a 20-h cold exposure, thus exhibiting a functioning cold-induced thermogenesis. No significant differences in spontaneous home cage activity were observed among NZO, NZB, and ob/ob strains. When mice had access to voluntary running wheels, however, running activity was significantly lower in NZO than NZB mice and even lower in ob/ob mice. These data indicate that obesity in NZO mice, just as in humans, is due to a combination of hyperphagia, reduced energy expenditure, and insufficient physical activity. Because NZO mice differ strikingly from the ob/ob strain in their resistance to cold stress, we suggest that the molecular defects causing hyperphagia in NZO mice are located distal from leptin and its receptor. feeding behavior; polygenic obesity; ob/ob mice; thermogenesis; locomotor activity THE NEW ZEALAND OBESE (NZO) mouse strain represents a well-established model of morbid obesity (2). Among all polygenic mouse models of obesity, it exhibits the highest degree of adiposity (14). The development of its obesity is markedly accelerated and enhanced by exposure to a high-fat diet (24). In addition to obesity, the NZO strain presents all other characteristics of the human metabolic syndrome, such as insulin resistance progressing to overt diabetes (2, 6), hypercholesterolemia, and hypertension (23). Thus the NZO strain appears to be a most suitable model for human obesity and its secondary complications, in particular the abnormalities of glucose metabolism.The NZO strain has been used in the search for mouse obesity and diabetes genes, and three different genome-wide scans of outcross populations with lean strains (SJL, SM, and NON) have been performed (19,21,25, 28,33). These scans revealed a very complex picture of the genetic basis...