Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats.

Inhibition of acetyl-CoA carboxylases has the potential for modulating long chain fatty acid biosynthesis and mitochondrial fatty acid oxidation. Hybridization of weak inhibitors of ACC2 provided a novel, moderately potent but lipophilic series. Optimization led to compounds 33 and 37, which exhibit potent inhibition of human ACC2, 10-fold selectivity over inhibition of human ACC1, good physical and in vitro ADME properties and good bioavailability. X-ray crystallography has shown this series binding in the CT-domain of ACC2 and revealed two key hydrogen bonding interactions. Both 33 and 37 lower levels of hepatic malonyl-CoA in vivo in obese Zucker rats.

PPARalpha and PPARgamma regulation of liver and adipose proteins in obese and dyslipidemic rodents.

Zucker fatty rats and ob/ob mice are both frequently used hyperlipidemic and insulin-resistant spontaneous genetic models of obesity. We used them to study the effect of PPAR agonists on the protein-expression level in liver and white adipose tissue. PPARalpha-agonist treatments of the rats resulted in that 27% of the quantified hepatic proteins were altered; implicating pronounced peroxisome proliferation and increase in capacity for beta-oxidation of fatty acids although no correction of plasma triglycerides were obtained. On treatment with PPARgamma agonists, adipose proteins were regulated to a much larger extent in the rats compared to mice, 18% and 2%, respectively.

Metabolic flexibility.

Human physiology needs to be well adapted to cope with major discontinuities in both the supply of and demand for energy. This adaptability requires 'a clear capacity to utilize lipid and carbohydrate fuels and to transition between them' (Kelley et al. 2002b). Such capacities characterize the healthy state and can be termed 'metabolic flexibility'. However, increasing evidence points to metabolic inflexibility as a key dysfunction of the cluster of disease states encompassed by the term 'metabolic syndrome'. In obese and diabetic individuals this inflexibility is manifest in a range of metabolic pathways and tissues including: (1) failure of cephalic-phase insulin secretion (impaired early-phase prandial insulin secretion concomitant with failure to suppress hepatic glucose production and NEFA efflux from adipose tissue); (2) failure of skeletal muscle to appropriately move between use of lipid in the fasting state and use of carbohydrate in the insulin-stimulated prandial state; (3) impaired transition from fatty acid efflux to storage in response to a meal. Finally, it is increasingly clear that reduced capacity for fuel usage in, for example, skeletal muscle, as indicated by reduced mitochondrial size and density, is characteristic of the metabolic syndrome state and a fundamental component of metabolic inflexibility. Key questions that remain are how metabolic flexibility is lost in obese and diabetic individuals and by what means it may be regained.

Profile of dyslipidemia in Psammomys obesus, an animal model of the metabolic syndrome.

OBJECTIVE: To investigate lipid profiles in Psammomys obesus and relationships between lipid profile and other components of the Metabolic Syndrome. METHODS: A total number of 49 adults with a wide range of body weight and glucose tolerance were studied in a cross-sectional analysis. Plasma cholesterol distribution profiles were measured by size exclusion lipid chromatography. Blood glucose was measured using an enzymatic glucose analyser, and plasma insulin was determined by radioimmunoassay. RESULTS: Obese diabetic Psammomys obesus had elevated plasma cholesterol (P=0.003) and triglyceride levels (p>0.001) compared to their lean littermates. The hypercholesterolemia was mainly due to increased circulating levels of VLDL-cholesterol (P=0.003) and LDL-cholesterol (P=0.003) in these animals. Multiple linear regression analyses revealed that body weight was independently associated with plasma cholesterol (P=0.011) and LDL concentration (P=0.009), while plasma insulin was associated with VLDL-cholesterol concentration (P=0.005). All of the variables measured exhibited continuous distributions across a wide range of phenotypes, from a normal rodent lipid profile to profound dyslipidemia. CONCLUSIONS: These data suggest that the dyslipidemia in obese, diabetic Psammomys obesus is closely associated with other components of the Metabolic Syndrome, including obesity and insulin resistance.