Obesity is one of the fastest growing major diseases in developed and developing countries [1]. Modifying fat balance is a key to therapy for obesity [2]. Triglyceride is an important carrier of blood lipid and lipoprotein lipase (LPL) strongly controls triglyceride metabolism. Lipoprotein lipase is an enzyme that hydrolyses triglycerides of triglyceride-rich lipoproteins into non-esterified fatty acids (NEFA) and glycerol. The NEFA generated as a result of these enzymatic reactions can be used for metabolic fuel in tissues such as muscle but also serve as substrate for re-esterification to triglyceride in adipose tissue. The balance of these competing effects could determine whether increased LPL activity will lead to reduced rate of weight gain (through greater disposal of ingested fats as metabolic fuel) or increased adiposity through increased rates of adipose tissue storage of triglycer- Diabetologia (2000) Abstract Aims/hypothesis. Fat balance is critical in the aetiology of obesity and related diseases. Lipoprotein lipase is of major importance in lipid metabolism. The aim of this study was to investigate the long-term effects of the lipoprotein lipase activator, NO-1886, on substrate utilisation, adiposity and insulin action in rats fed a high-fat diet. Methods. Male, Sprague-Dawley rats were fed for 10 weeks on a chow diet or a high-fat diet with, or without, NO-1886 (50 mg × kg ±1 × day
±1). Weight gain, fat accumulation and both hormone-sensitive and lipoprotein, lipase activities were measured. Insulin action was assessed by the euglycaemic hyperinsulinaemic clamp and metabolic rate/substrate utilisation by open-circuit respirometry. Results. Compared with chow-fed controls, a high-fat diet increased weight gain, an effect lessened by NO-1886 [weight gain (g): chow, 37 ± 3, high-fat, 222 ± 9; high-fat + NO-1886, 109 ± 6, all groups differed p < 0.001]. A similar pattern existed for fat accumulation [visceral fat (g): chow, 35.9 ± 3.2; high-fat, 81.9 ± 6.6; high-fat + NO-1886, 52.3 ± 4.7, p < 0.01 high-fat vs the other groups]. A high-fat diet induced wholebody insulin resistance (clamp glucose infusion rate: 4.8 ± 1.3 mg × kg ±1 × min ±1 vs 10.6 ± 1.1 for the chow group, p < 0.01) with NO-1886 lessening this effect (8.3 ± 0.5, p < 0.05 vs high-fat). The 24-h respiratory quotient was lower in the high-fat + NO-1886 group (0.825 ± 0.010) compared with high-fat alone (0.849 ± 0.004, p < 0.05). A high-fat diet increased lipoprotein and hormone-sensitive, lipase activities in epididymal fat, an effect not altered by NO-1886. In myocardium and skeletal muscle a high-fat diet lowered lipoprotein lipase activity, an effect lessened by NO-1886. Conclusion/interpretation: Lipoprotein lipase activators could have potential benefits for the treatment of obesity by increasing fat utilisation. [Diabetologia (2000) 43: 875±880]
