Hyperphagia, lower body temperature, and reduced running wheel activity precede development of morbid obesity in New Zealand obese mice

Abstract

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...

Development of diabetes in obese, insulin-resistant mice: essential role of dietary carbohydrate in beta cell destruction

“…Conscious mice were placed in an applied static magnetic field for 0.9 min as described previously [9,14] and duplicate measurements of fat mass and lean mass were recorded for each time point and used for the data analysis.…”

“…The NZO mouse is an optimal model for the study of obesityassociated diabetes ('diabesity'). It presents morbid obesity associated with hyperphagia and reduced energy expenditure [9], rapidly developing a form of diabetes that is characterised by marked hyperglycaemia and hypoinsulinaemia associated with beta cell destruction [10][11][12][13]. Exposure to a 'cafeteria-type' high-fat diet (HFD) accelerated that process, apparently supporting the concept of lipotoxicity.…”

Stimulation of fat accumulation in hepatocytes by PGE2-dependent repression of hepatic lipolysis, β-oxidation and VLDL-synthesis

“…15 C57BL/6J, ob/ob (B6.V-Lep ob /J) (Charles River, Sulzfeld, Germany) and NZO mice (NZO/HIBomDife: Dr R Kluge, German Institute of Human Nutrition, Nuthetal, Germany) were kept on standard diet containing or high-fat diet (Altromin, Lage, Germany), as described previously, 16,17 8 or 22 weeks at a temperature of 22 1C with a 12-h light/dark cycle. Mice were killed and portions of liver were snapfrozen.…”

“…In all these models development of obesity is accompanied by severe hepatic steatosis. [15][16][17] The respective controls are lean and devoid of hepatic pathology. In C3H/HouJ-mice fed with standard diet and tap water containing 30% fructose (the pathological model), mRNA expression of mPGES1 was 17-fold induced and expression of COX2 and mPGES2 were moderately increased by factor 1.5 in comparison with control mice fed with plain tap water ( Figure 1).…”

Skeletal muscle mitochondrial uncoupling prevents diabetes but not obesity in NZO mice, a model for polygenic diabesity

“…On a high-fat diet NZO mice exhibit hypertension and hypercholesterolemia in addition to obesity, hyperinsulinemia and hyperglycemia (Joost and Schurmann 2014;Ortlepp et al 2000). The development of obesity in NZO mice was found to be caused by hyperphagia combined with reduced energy expenditure and impaired voluntary physical activity (Jurgens et al 2006). Development of diabetes and beta-cell failure in NZO mice is linked to the development of obesity and is also dependent on the presence of dietary carbohydrates (Jurgens et al 2007;Kluth et al 2011).…”