Features of syndrome X develop in transgenic rats expressing a non-insulin responsive phosphoenolpyruvate carboxykinase gene

Abstract

The term`syndrome X' describes a cluster of abnormalities which include glucose intolerance, obesity (particularly abdominal obesity), hypertension, insulin resistance, and dyslipidaemia characterised by raised and potentially atherogenic concentrations of low-density lipoprotein particles, diminished highdensity lipoprotein concentrations and a raised plasma triglyceride concentration [1,2]. Clinically, syndrome X is also associated with increased plasma uric acid and plasminogen activator inhibitor-1 concentrations, and more recently it has been associated with defects in the innate immune system [3] Abstract Aims/hypothesis. Obesity, glucose intolerance, dyslipidaemia and hypertension are a cluster of disorders (syndrome X) affecting many people. It has been hypothesised that these abnormalities are caused by insulin resistance, but definitive proof is lacking. We have developed transgenic rats in which the rate-limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, is non-insulin responsive. The aim of our study was to investigate whether syndrome X develops in these animals and if a high-fat diet interacts with this genetic defect. Methods. Chow-fed transgenic and control rats aged 1, 3, 6 and 17 months and a subgroup of transgenic and control rats fed chow plus cafeteria foods for 6 months were examined for features of syndrome X. Results. At 3 months, transgenic rats had fasting and postprandial hyperinsulinaemia, mild obesity (in abdominal and, to a lesser extent, peripheral regions) and fasting hypercholesterolaemia. Hypertriglyceridaemia was evident after 6 months while hyperglycaemia was apparent at 17 months. Hypertension had not developed by 17 months. The effect of a high-fat diet on insulin, glucose, body weight and body fat was more dramatic than the effect of the transgene alone while the effect of a high-fat diet on cholesterol and triglyceride was similar to the transgene. This illustrates that a high-fat diet is a potent catalyst for many abnormalities associated with syndrome X. There was no evidence of an additive effect of the high-fat diet plus transgene. Conclusion/interpretation. Therefore rats geneticallyengineered with a non-insulin responsive gluconeogenic enzyme develop several aspects of syndrome X, supporting the hypothesis that insulin resistance initiates this cluster of disorders. [Diabetologia (1999) 42: 419±426]

Increased Fatty Acid Re-esterification by PEPCK Overexpression in Adipose Tissue Leads to Obesity Without Insulin Resistance

“…Thus, obesity in homozygous aP2-PEPCK transgenic mice was due to a primary alteration in fat deposition because glucose homeostasis, whole-body and skeletal muscle insulin sensitivity, or liver glucose and triglyceride metabolism were not altered. In contrast, PEPCK overexpression in the liver leads to increased chronic hepatic glucose production and then to increased insulin secretion, hyperinsulinemia, hyperglycemia, and insulin resistance (12,36,37). Because of the aP2 promoter adipose specificity (11), PEPCK was not overexpressed in the liver of aP2-PEPCK transgenic mice.…”

Obesity-Initiated Metabolic Syndrome and the Kidney

“…The capacity of the insulin-resistant liver to impair secondarily systemic energy homeostasis is illustrated by transgenic studies introducing an insulin-resistant form of the rate-limiting enzyme of liver gluconeogenesis: phosphoenolpyruvate carboxykinase (42). Creating isolated hepatic insulin resistance led to systemic hyperglycemia, hyperinsulinemia, and a moderate increase in fat mass (42).…”

“…Creating isolated hepatic insulin resistance led to systemic hyperglycemia, hyperinsulinemia, and a moderate increase in fat mass (42). The last reflects WAT utilization of surplus circulating glucose for insulin-induced lipogenesis.…”

Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y

“…This procedure was performed as previously described. 33 Body composition Dual-energy X-ray absorptiometry (DEXA, Hologic QDR 2000 W) was used to measure fat mass in abdominal and peripheral regions 34 2 and 7 weeks after the operations. This was performed in a subgroup of animals lightly anesthetized with pentobarbital (55 mg=kg body weight).…”