Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice.

Abstract

Recent studies have shown that genetic deficiency of the adipocyte fatty acid-binding protein (aP2) results in minor alterations of plasma lipids and adipocyte development but provides significant protection from dietary obesity-induced hyperinsulinemia and insulin resistance. To identify potential mechanisms responsible for this phenotype, we examined lipolysis and insulin secretion in aP2-/- mice. Beta-adrenergic stimulation resulted in a blunted rise of blood glycerol levels in aP2-/- compared with aP2+/+ mice, suggesting diminished lipolysis in aP2-/- adipocytes. Confirming this, primary adipocytes isolated from aP2-/- mice showed attenuated glycerol and free fatty acid (FFA) release in response to dibutyryl cAMP. The decreased lipolytic response seen in the aP2-/- mice was not associated with altered expression levels of hormone-sensitive lipase or perilipin. The acute insulin secretory response to beta-adrenergic stimulation was also profoundly suppressed in aP2-/- mice despite comparable total concentrations and only minor changes in the composition of systemic FFAs. To address whether levels of specific fatty acids are different in aP2-/- mice, the plasma FFA profile after beta-adrenergic stimulation was determined. Significant reduction in both stearic and cis-11-eicoseneic acids and an increase in palmitoleic acid were observed. The response of aP2-/- mice to other insulin secretagogues such as arginine and glyburide was similar to that of aP2+/+ mice, arguing against generally impaired function of pancreatic beta-cells. Finally, no aP2 expression was detected in isolated pancreatic islet cells. These results provide support for the existence of an adipo-pancreatic axis, the proper action of which relies on the presence of aP2. Consequently, aP2's role in the pathogenesis of type 2 diabetes might involve regulation of both hyperinsulinemia and insulin resistance through its impact on both lipolysis and insulin secretion.

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

“…These findings are in agreement with results from two independent studies obtained in Afabp −/− mice [28,34]. Reduced β-adrenoceptor-stimulated lipolysis translates into significantly reduced lipolysis-associated insulin secretion from beta cells in both ob/ob-Afabp −/− mice [31] and Afabp −/− mice [34]. However, loss of AFABP does not generally impair beta cell function.…”

“…Thus, the lipolytic response to β-adrenergic stimulation is significantly reduced in ob/ob-Afabp −/− animals [31]. These findings are in agreement with results from two independent studies obtained in Afabp −/− mice [28,34]. Reduced β-adrenoceptor-stimulated lipolysis translates into significantly reduced lipolysis-associated insulin secretion from beta cells in both ob/ob-Afabp −/− mice [31] and Afabp −/− mice [34].…”

“…Thus, glucose-stimulated insulin secretion is significantly improved in ob/ob-Afabp −/− mice compared with controls [31]. Furthermore, other insulin secretagogues such as arginine and glibenclamide (known as glyburide in the USA and Canada) are as effective in stimulating an insulin secretory response in Afabp −/− mice as in controls [34]. No apparent morphological differences in the structure or size of the pancreatic islets are detectable between ob/obAfabp −/− animals and ob/ob controls [31].…”

Effects of obesity and weight loss on the expression of proteins involved in fatty acid metabolism in human adipose tissue

“…11 In wild-type mice, mal1 protein is expressed at levels approximately 1 -5% of that of aP2. 12,13 Interestingly, adipocytes from aP2 knock-out mice have a strong induction of mal1 expression and exhibit diminished lipolysis compared to wild-type adipocytes. 12,13 These data suggest that aP2=ALBP and possibly mal1=KLBP could be of importance for the non-hormonal regulation of adipose tissue lipolysis and insulin resistance.…”

“…12,13 Interestingly, adipocytes from aP2 knock-out mice have a strong induction of mal1 expression and exhibit diminished lipolysis compared to wild-type adipocytes. 12,13 These data suggest that aP2=ALBP and possibly mal1=KLBP could be of importance for the non-hormonal regulation of adipose tissue lipolysis and insulin resistance. Furthermore, some FABPs can localize to the nucleus and may modulate the activity of transcription factors such as peroxisome proliferator-activated receptors (PPARs).…”