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Altered insulin secretion associated with reduced lipolytic efficiency in aP2-/- mice
L Scheja1, L Makowski, K T Uysal
1Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
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.
Insights
Genetic deficiency of adipocyte fatty acid-binding protein (aP2) protects against obesity-induced insulin resistance by impairing lipolysis and insulin secretion. This suggests aP2 is crucial for the adipo-pancreatic axis in type 2 diabetes pathogenesis.
Area of Science:
- Metabolic diseases
- Endocrinology
- Molecular biology
Background:
- Adipocyte fatty acid-binding protein (aP2) deficiency offers protection against diet-induced hyperinsulinemia and insulin resistance.
- The underlying mechanisms for this protective phenotype remain to be fully elucidated.
Purpose of the Study:
- To investigate the role of aP2 in lipolysis and insulin secretion.
- To explore the potential mechanisms linking aP2 to insulin resistance and hyperinsulinemia.
Main Methods:
- Examined lipolysis and insulin secretion in aP2 knockout (aP2-/-) mice and wild-type (aP2+/+) littermates.
- Stimulated lipolysis using beta-adrenergic agonists and measured glycerol and free fatty acid (FFA) release.
- Assessed insulin secretion in response to beta-adrenergic stimulation and other secretagogues (arginine, glyburide).
- Analyzed plasma FFA profiles and aP2 expression in pancreatic islets.
Main Results:
- aP2-/- mice exhibited diminished lipolysis, evidenced by blunted glycerol release and reduced FFA release from adipocytes.
- Beta-adrenergic stimulation resulted in profoundly suppressed insulin secretion in aP2-/- mice.
- Specific alterations in plasma fatty acid profiles (reduced stearic and cis-11-eicoseneic acids, increased palmitoleic acid) were observed in aP2-/- mice.
- Pancreatic beta-cell function was not generally impaired, as responses to arginine and glyburide were similar to controls.
- No aP2 expression was detected in isolated pancreatic islet cells.
Conclusions:
- aP2 plays a critical role in regulating both lipolysis and insulin secretion.
- These findings support the existence of an adipo-pancreatic axis that requires aP2 for proper function.
- aP2's involvement in the pathogenesis of type 2 diabetes may be mediated through its influence on hyperinsulinemia and insulin resistance via lipolysis and insulin secretion regulation.