Effect of blockade of neuropeptide Y receptor on aortic intima-media thickness and adipose tissue characteristics in normal and obese mice

Document Type: Original Article


1 Department of Physiology, Isfahan University of Medical Sciences, Isfahan, Iran

2 Department of Anatomy, Isfahan University of Medical Sciences, Isfahan, Iran

3 Department of Physiology, Applied Physiology research center, Isfahan University of Medical Sciences, Isfahan, Iran

4 Neurogenic Inflammation Research Center and Department of Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Atherosclerosis is an important risk factor for coronary heart disease. Neuropeptide Y (NPY) and its receptors, located in peripheral tissue such as white adipose tissue, have been linked to obesity and fat storage. The role of NPY in atherosclerosis has not yet been fully studied, so this study was conducted to further investigate the effect of BIIE 0246, an NPY receptor antagonist, on aortic intima-media thickness and size and number of adipocyte cells in normal and obese mice.
Materials and Methods: Tests were performed on 24 male C57BL/6 mice. The animals were divided into four groups as follows: control (normal), obese (high-fat diet), normal+NPY receptor antagonist (1 μM, 100 µl/Kg BIIE0246 intraperitoneally) and obese+NPY receptor antagonist (n=6 each). After 14 days, the animals were sacrificed and epididymal adipose tissue and thoracic aorta were removed. Evaluations were made for adipocyte cell number and size and for aortic intima-media thickness.
Results: The group on a high-fat diet showed a significantly decreased number of adipocyte cells and increased cell size (P<0.05). BIIE0246 application changed the cell number of adipocyte in normal mice (P=0.05); however, it did not change adipocyte cell size and aortic intima-media thickness in obese and normal mice (P>0.05).
Conclusion: NPY receptor antagonist had no effect on adipocyte cell size and aortic intima-media thickness; however, it decreased cell number in the normal group indicating likely involvement in the progression of obesity


1. Wong JP, Wijaya S, Ting KN, Wiart C, Shipton F, Khoo TJ. Crude ethanol extract of Pithecellobium ellipticum as a potential lipid-lowering treatment for Hypercholesterolaemia. Evid Based Complemant Alternat Med 2014; 2014:492703.

2. Pignoli P, Tremoli E, Poli A, Oreste P, Paoletti R. Intimal plus medial thickness of the arterial wall: a direct measurement with ultrasound imaging. Circulation 1986; 74:1399-1406.

3. Cupini LM, Pasqualetti P, Diomedi M, Vernieri F, Silvestrini M, Rizzato B, et al. Carotid artery intima-media thickness and lacunar versus nonlacunar infarcts. Stroke 2002; 33:689-694.

4. Chugh P, Sharma S. Recent advances in the pathophysiology and pharmacological treatment of obesity. J cli Pharm Ther 2012; 37:525-535.

5. Grobbee DE, Bots ML. Carotid artery intima‐media thickness as an indicator of generalized atherosclerosis. J Intern Med 1994; 236:567-573.

6. Billington CJ, Briggs JE, Grace M, Levine AS. Effects of intracerebroventricular injection of neuropeptide Y on energy metabolism. Am J Physiol 1991; 260:321-327.

7. Billington CJ, Briggs JE, Harker S, Grace M, Levine AS. Neuropeptide Y in hypothalamic paraventricular nucleus: a center coordinating energy metabolism. Am J Physiol 1994; 266:1765-1770.

8. Nguyen AD, Herzog H, Sainsbury A. Neuropeptide Y and peptide YY: important regulators of energy metabolism. Curr Opin Endocrinol Diabetes Obes 2011; 18:56-60.

9. Toyoshima M, Asakawa A, Fujimiya M, Inoue K, Inoue S, Kinboshi M, et al. Dimorphic gene expression patterns of anorexigenic and orexigenic peptides in hypothalamus account male and female hyperphagia in Akita type 1 diabetic mice. Biochem Biophys Res commun 2007; 352:703-708.

10. Lin S, Boey D, Herzog H. NPY and Y receptors: lessons from transgenic and knockout models. Neuropeptides 2004; 38:189-200.

11. Chambers AP, Woods SC. The role of neuropeptide Y in energy homeostasis.  Handb Exp Pharmacol 2012; 209:23-45.

12. Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, Lussier R, et al. β-cell failure in diet-induced obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced β-cell mass. Diabetes 2010; 59:2178-2187.

13. Dileepan KN, Johnston TP, Li Y, Tawfik O, Stechschulte DJ. Deranged aortic intima-media thickness, plasma triglycerides and granulopoiesis in Sl/Sl d mice. Mediators inflamm 2004; 13:335-341.

14. Neuhofer A, Wernly B, Leitner L, Sarabi A, Sommer NG, Staffler G, et al. An accelerated mouse model for atherosclerosis and adipose tissue inflammation. Cardiovasc Diabetol 2014; 13:23.

15. Hajer GR, van Haeften TW, Visseren FL. Adipose tissue dysfunction in obesity, diabetes, and vascular diseases. Eur Heart J 2008; 29:2959-2971.

16. Zhang L, Bijker MS, Herzog H. The neuropeptide Y system: pathophysiological and therapeutic implications in obesity and cancer. Pharmacol Ther 2011; 131:91-113.

17. Shi YC, Lin S, Wong IP, Baldock PA, Aljanova A, Enriquez RF,  et al. NPY neuron-specific Y2 receptors regulate adipose tissue and trabecular bone but not cortical bone homeostasis in mice. PLoS One 2010; 5:e11361.

18. Comuzzie AG, Allison DB. The search for human obesity genes. Science 1998; 280:1374-1377.

19. Faust IM, Johnson PR, Stern JS, Hirsch J. Diet-induced adipocyte number increase in adult rats: a new model of obesity. Am J Physiol 1978; 235:279-286.

20. Tschöp M, Castaneda T, Joost HG, Thöne-Reineke C, Ortmann S, Klaus S, et al. Physiology: does gut hormone PYY3–36 decrease food intake in rodents? Nature 2004; 430:1-165.

21. Koegler FH, Enriori PJ, Billes SK, Takahashi DL, Martin MS, Clark RL, et al. Peptide YY (3–36) inhibits morning, but not evening, food intake and decreases body weight in rhesus macaques. Diabetes 2005; 54:3198-3204.

22. Naveilhan P, Neveu I, Arenas E, Ernfors P. Complementary and overlapping expression of Y1, Y2 and Y5 receptors in the developing and adult mouse nervous system. Neuroscience 1998; 87:289-302.

23. Sainsbury A, Zhang L. Role of the arcuate nucleus of the hypothalamus in regulation of body weight during energy deficit. Mol cell Endocrinol 2010; 316:109-119.

24. Zhang L, Riepler SJ, Turner N, Enriquez RF, Lee IC, Baldock PA, et al. Y2 and Y4 receptor signaling synergistically act on energy expenditure and physical activity. Am J Physiol Integr Comp Physiol 2010; 299:R1618-1628.

25. Ortiz AA, Milardo LF, DeCarr LB, Buckholz TM, Mays MR, Claus TH, et al. A novel long-acting selective neuropeptide Y2 receptor polyethylene glycol-conjugated peptide agonist reduces food intake and body weight and improves glucose metabolism in rodents. J Pharmacol Exp Ther 2007; 323:692-700.

26. Kuo LE, Kitlinska JB, Tilan JU, Li L, Baker SB, Johnson MD, et al. Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome. Nat Med 2007; 13:803-811.

27. Rosmaninho-Salgado J, Cortez V, Estrada M, Santana MM, Gonçalves A, Marques AP, et al. Intracellular mechanisms coupled to NPY Y 2 and Y 5 receptor activation and lipid accumulation in murine adipocytes. Neuropeptides 2012; 46:359-366.