Scott Lee

Rapid Development of Non-Alcoholic Steatohepatitis in Psammomys obesus (Israeli Sand Rat)

Background and Aims A major impediment to establishing new treatments for non-alcoholic steatohepatitis is the lack of suitable animal models that accurately mimic the biochemical and metabolic characteristics of the disease. The aim of this study was to explore a unique polygenic animal model of metabolic disease as a model of non-alcoholic steatohepatitis by determining the effects of 2% dietary cholesterol supplementation on metabolic and liver endpoints in Psammomys obesus (Israeli sand rat). Methods P. obesus were provided ad libitum access to either a standard rodent diet (20% kcal/fat) or a standard rodent diet supplemented with 2% cholesterol (w/w) for 4 weeks. Histological sections of liver from animals on both diets were examined for key features of non-alcoholic steatohepatitis. The expression levels of key genes involved in hepatic lipid metabolism were measured by real-time PCR. Results P. obesus fed a cholesterol-supplemented diet exhibited profound hepatomegaly and steatosis, and higher plasma transaminase levels. Histological analysis identified extensive steatosis, inflammation, hepatocyte injury and fibrosis. Hepatic gene expression profiling revealed decreased expression of genes involved in delivery and uptake of lipids, and fatty acid and triglyceride synthesis, and increased expression of genes involved in very low density lipoprotein cholesterol synthesis, triglyceride and cholesterol export. Conclusions P. obesus rapidly develop non-alcoholic steatohepatitis when fed a cholesterol-supplemented diet that appears to be histologically and mechanistically similar to patients.

Effects of beacon administration on energy expenditure and substrate utilisation in Psammomys obesus (Israeli sand rats)

OBJECTIVE: To investigate whether beacon administration affects substrate utilisation, physical activity levels or energy expenditure in Psammomys obesus.DESIGN: Pairs of age- and sex-matched Psammomys obesus were randomly assigned to either beacon-treated (15 μg/day for 7 days (i.c.v.)) or control (i.c.v. saline) groups.MEASUREMENTS: Indirect calorimetry on day 0 and day 7 to measure oxygen consumption and carbon dioxide production, which were used to calculate fat oxidation, carbohydrate oxidation and total energy expenditure. Physical activity in the calorimeter was measured using an infrared beam system. Food intake and body weight were measured daily.RESULTS: The administration of beacon significantly increased body weight compared to saline-treated control animals. This body weight gain was primarily due to increased body fat content. Average daily food intake tended to be higher in beacon-treated Psammomys obesus, but no effect of beacon administration on substrate oxidation, activity or energy expenditure was detected.CONCLUSION: The effects of beacon on body weight are due to increased food intake, with no detectable effect on nutrient partitioning, physical activity or energy expenditure.

Effects of rosiglitazone on intramyocellular lipid accumulation in Psammomys obesus

OBJECTIVE To examine the effects of rosiglitazone in intramyocellular lipid (IMCL) content in diabetic Psammomys obesus using novel electron microscopy technologies. BACKGROUND P. obesus is an unique polygenic model of obesity and type 2 diabetes. Male diabetic P. obesus were treated daily with 5 mg/Kg Rosiglitazone by oral gavage for 14 days. Data were compared with a group of age-matched diabetic P. obesus treated with saline vehicle. METHODS Assessment of insulin resistance and adiposity were determine before and after the treatment period by oral glucose tolerance test (oGTT) and dual energy X-ray absorptiometry (DEXA) analysis. We used a new scanning electron microscopy technology, (WETSEM) to investigate the effects of rosiglitazone administration on IMCL content, size and distribution in red gastrocnemius muscle. RESULTS Rosiglitazone treatment improved glucose tolerance in P. obesus with no difference in the overall body fat content although a significant reduction in subscapular fat mass was observed. Rosiglitazone changed the distribution of lipid droplet size in skeletal muscle. Treated animals tended to have smaller lipid droplets compared with saline-treated controls. CONCLUSIONS Since smaller IMCL droplets are associated with improvements in insulin sensitivity, we propose that this may be an important mechanism by which rosiglitazone affects glucose tolerance.

Dysregulation of Leptin in Response to Fasting in Insulin-Resistant Psammomys Obesus (Israeli sand rats)

Leptin is thought to play a significant role in energy balance as an afferent signal to the hypothalamus that reflects body fat content. In addition, leptin may also act as an acute sensor of energy balance independent of body fat mass, since ob gene expression and plasma leptin concentrations are decreased in lean animals and humans in response to short-term caloric deprivation. However, in obese animals and humans, the acute response of leptin to fasting is less clear. We investigated the effects of a 24-hour fast on circulating plasma leptin concentrations in lean and obese Psammomys obesus (Israeli sand rats). In the lean, insulin-sensitive group (n = 25) a 24-hour fast caused a 44% decrease in plasma leptin, whereas in the obese, insulin-resistant group (n = 24) plasma leptin increased by 18% after fasting (P < .003). There was no difference between the two groups regarding the effect of a 24-hour fast on body weight, blood glucose, or plasma insulin. Within the insulin-resistant group, there was no difference in the response of leptin to fasting between hyperglycemic and normoglycemic animals. We conclude that there is a dysregulation of leptin in response to acute caloric deprivation in obese, insulin-resistant but not in lean, insulin-sensitive P obesus.

AGT-121, a novel hypothalamic gene implicated in the development of obesity

High prevalence of foot ulceration in the Balkan region a multicenter study from the BALKANDIAB network. C. N. Manes1, C. Ionescu-Tirgoviste2, L. Koeva3, D. Koev4, F. Agaci5, P. Djordjevic6, M. Bogoev7; 1Diabetes Unit, „Papageorgiou“ Gen. Hospital, Thessaloniki, Greece, 2N. Paulescu, Bucharest, Romania, 3University of Varna, Varna, Bulgaria, 4Bulgarian Society of Endocrinology, Sofia, Bulgaria, 5“Mother Teresa“, University Hospital Center, Tirana, Albania, 6Diabetes Unit, Institute of Endocrinology, Belgrade, Yugoslavia, 7Clinic of Endocrinology, Skopje, The former Yugoslav Republic of Macedonia.