The lipoprotein lipase activator, NO-1886, suppresses fat accumulation and insulin resistance in rats fed a high-fat diet

Abstract

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]

Overexpression of lipoprotein lipase improves insulin resistance induced by a high-fat diet in transgenic rabbits

“…Therefore, it is not clear whether rabbits are different from mice in terms of LPL effects on glucose metabolism and insulin resistance. In spite of this, our results favour the notion of the elevation of LPL activity, such as by the compound NO-1886 [8,9,10,11] or by LPL gene therapy [12,33], for therapeutic treatments of hypertriglyceridaemia, obesity and related disorders. Compound NO-1886 has been shown to increase LPL mRNA in adipose tissue, myocardium and skeletal muscle, resulting in an elevation of postheparin plasma LPL activity and a decrease in serum TG.…”

“…Patients deficient in LPL have hypertriglyceridaemia and high levels of NEFA, which is associated with insulin-resistant diabetes and can be ameliorated by lowering concentrations of TG [7]. Administration of the compound NO-1886, an LPL-promoting agent in rats [8], rabbits [9] and pigs [10] fed a high-fat diet (HFD) suppresses fat accumulation and insulin resistance. Therefore, it is not clear, when within a physiological range, whether "the higher, the better" or "the lower, the better" is a more accurate description in terms of LPL activity in glucose tolerance and adipose tissue.…”

Preventive effect of Ibrolipim on suppressing lipid accumulation and increasing lipoprotein lipase in the kidneys of diet-induced diabetic minipigs

“…Adipose tissue LPL activity rises rapidly after feeding by a post-transcriptional mechanism in guinea pigs and mice [36,37]. In SD rats, a high-fat diet differentially affects LPL activity in muscle and adipose tissue, reducing the former and greatly increasing the latter, which tends to induce fat storage and insulin resistance [22]. It is, therefore, speculated that HFSD seems to promote the release of LPL from peripheral tissues such as adipose tissue to blood.…”

“…Firstly, Ibrolipim reduces ectopic lipid deposition in the heart, skeletal muscle, liver and pancreas in diet-induced diabetic animal model [22,23] through increasing LPL activity in soleus skeletal muscle and myocardium with an increase in fat oxidation [22]. Therefore, it is possible that the increase of renal LPL expression and activity can also lead to an increase of triglyceride utilization in kidney.…”

“…Furthermore, Ibrolipim decreases visceral and subcutaneous fat accumulation and ectopic lipid deposition in the heart, skeletal muscle, liver and pancreas in diet-induced diabetic animal models [7,22,23]. In rat model of nephrotic syndrome induced by adriamycin and a high-protein diet, Ibrolipim reduces plasma creatinine (Cr), blood urea nitrogen and proteinuria, and ameliorates tubulointerstitial lesions [24].…”