Insulin resistance and impaired glucose homoeostasis are important indicators of Type 2 diabetes and are early risk factors of AD (Alzheimer's disease). An essential feature of AD pathology is the presence of BACE1 (β-site amyloid precursor protein-cleaving enzyme 1), which regulates production of toxic amyloid peptides. However, whether BACE1 also plays a role in glucose homoeostasis is presently unknown. We have used transgenic mice to analyse the effects of loss of BACE1 on body weight, and lipid and glucose homoeostasis. BACE1−/− mice are lean, with decreased adiposity, higher energy expenditure, and improved glucose disposal and peripheral insulin sensitivity than wild-type littermates. BACE1−/− mice are also protected from diet-induced obesity. BACE1-deficient skeletal muscle and liver exhibit improved insulin sensitivity. In a skeletal muscle cell line, BACE1 inhibition increased glucose uptake and enhanced insulin sensitivity. The loss of BACE1 is associated with increased levels of UCP1 (uncoupling protein 1) in BAT (brown adipose tissue) and UCP2 and UCP3 mRNA in skeletal muscle, indicative of increased uncoupled respiration and metabolic inefficiency. Thus BACE1 levels may play a critical role in glucose and lipid homoeostasis in conditions of chronic nutrient excess. Therefore strategies that ameliorate BACE1 activity may be important novel approaches for the treatment of diabetes.

SUMMARYThe heat dissipation limit theory suggests that heat generated during metabolism limits energy intake and, thus, reproductive output. Experiments in laboratory strains of mice and rats, and also domestic livestock generally support this theory. Selection for many generations in the laboratory and in livestock has increased litter size or productivity in these animals. To test the wider validity of the heat dissipation limit theory, we studied common voles (Microtus arvalis), which have small litter sizes by comparison with mice and rats, and regular addition of wild-caught individuals of this species to our laboratory colony ensures a natural genetic background. A crossover design of ambient temperatures (21 and 30°C) during pregnancy and lactation was used. High ambient temperature during lactation decreased milk production, slowing pup growth. The effect on pup growth was amplified when ambient temperature was also high during pregnancy. Shaving fur off dams at 30°C resulted in faster growth of pups; however, no significant increase in food intake and or milk production was detected. With increasing litter size (natural and enlarged), asymptotic food intake during lactation levelled off in the largest litters at both 21 and 30°C. Interestingly, the effects of lactation temperature on pup growth where also observed at smaller litter sizes. This suggests that vole dams trade-off costs associated with hyperthermia during lactation with the yield from investment in pup growth. Moreover, pup survival was higher at 30°C, despite lower growth, probably owing to thermoregulatory benefits. It remains to be seen how the balance is established between the negative effect of high ambient temperature on maternal milk production and pup growth (and/or future reproduction of the dam) and the positive effect of high temperatures on pup survival. This balance ultimately determines the effect of different ambient temperatures on reproductive success.

SUMMARY Free-living animals must forage for food and hence may face energetic constraints imposed by their natural environmental conditions (e.g. ambient temperature, food availability). Simulating the variation in such constraints,we have experimentally manipulated the rate of work (wheel running) mice must do to obtain their food, and studied the ensuing behavioural and physiological responses. This was done with a line of mice selectively bred for high spontaneous wheel running and a randomly bred control line that vary in the amount of baseline wheel-running activity. We first determined the maximum workload for each individual. The maximum workload animals could engage in was around 23 km d–1 in both control and activity-selected mice,and was not associated with baseline wheel-running activity. We then kept mice at 90% of their individual maximum and measured several physiological and behavioural traits. At this high workload, mice increased wheel-running activity from an average of 10 to 20 km d–1, and decreased food intake and body mass by approximately 20%. Mass-specific resting metabolic rate strongly decreased from 1.43 to 0.98 kJ g–1d–1, whereas daily energy expenditure slightly increased from 2.09 to 2.25 kJ g–1 d–1. Costs of running decreased from 2.3 to 1.6 kJ km–1 between baseline and workload conditions. At high workloads, animals were in a negative energy balance, resulting in a sharp reduction in fat mass as well as a slight decrease in dry lean mass. In addition, corticosterone levels increased, and body temperature was extremely low in some animals at high workloads. When challenged to work for food, mice thus show significant physiological and behavioural adjustments.

Objective: Increased dietary fat intake is a precipitating factor for the development of obesity and associated metabolic disturbances. Physically active individuals generally have a reduced risk of developing these unhealthy states, but the underlying mechanisms are poorly understood. In the present study, we investigated the effects of feeding a high-fat diet (HFD) on obesity development and fuel homeostasis in male and female mice with a trait for increased physical activity and in their controls. Methods: Male and female mice selectively bred for a high level of wheel running behavior over 30 generations and nonselected controls (background strain Hsd:ICR) were maintained on a standard lab chow high-carbohydrate diet (HCD) or on an HFD (60% fat). Food intake, body weight, indirect calorimetry parameters, spontaneous locomotor activity and several hormones relevant to metabolism and energy balance were measured. Results: On HFD, mice reduced food intake and increased body fat mass and plasma leptin levels, with the notable exception of the selected females, which increased their ingested calories without any effects on body mass or plasma leptin levels. In addition, they had an elevated daily energy expenditure (DEE), increased spontaneous cage activity (B700% relative to controls) and higher resting metabolic rate (RMR) on the HFD compared with feeding the HCD. The selected males also had a higher DEE compared with controls, but no interaction with diet was observed. On HCD, adiponectin levels were higher in selected male, but not female, mice relative to controls. A marked increase in the level of plasma adiponectin was observed on the HFD in selected females, an effect of diet that was not observed in selected males. Conclusion: Genetically based high locomotor activity renders female, but not male, mice resistant to HFD-induced obesity by alterations in behavioral, endocrine and metabolic traits that facilitate fat utilization rather than limiting HFD intake. International Journal of Obesity (2008) IntroductionObesity is becoming an increasingly prevalent health problem among individuals in affluent societies, because it is often associated with metabolic derangements such as impaired glucose tolerance, insulin resistance, high blood pressure, dyslipidemia and abdominal obesity. When these metabolic abnormalities are displayed in concert (often referred to as the 'metabolic syndrome'), they have a high risk of developing into life-threatening conditions such as cardiovascular disease and diabetes mellitus type 2 (for review, see Moller and Kaufman 1 ). Consensus exists that increased dietary fat intake in combination with a sedentary lifestyle are precipitating factors (World Health Organization), 2 but the underlying endocrine and metabolic mechanisms are poorly understood.A major part of the current knowledge on the etiology of obesity and the metabolic syndrome has come from studies on rodents subjected to a high-fat diet (HFD). [3][4][5][6][7] In particular, the use of selectively bred and geneticall...