World J Mens Health.  2018 Jan;36(1):41-49. 10.5534/wjmh.17028.

Udenafil, a Phosphodiesterase 5 Inhibitor, Reduces Body Weight in High-Fat-Fed Mice

• Ryu SY
• Choi YJ
• Park SY
• Kim JY
• Kim YD
• Kim YW

• KMID: 2399170
• DOI: http://doi.org/10.5534/wjmh.17028

Abstract

PURPOSE
High-fat (HF) feeding induces hypothalamic leptin resistance via the activation of toll-like receptor 4 (TLR4). TLR4 deficiency confers resistance to diet-induced obesity. Udenafil, an anti-impotence drug, inhibits TLR4 in airway epithelial cells in vitro. In this study, we evaluated whether udenafil suppressed the hypothalamic expression of TLR4 and reduced body weight.
MATERIALS AND METHODS
The hypothalamic expression of TLR4, phosphodiesterase 5 (PDE5), nuclear factor-κB (NF-κB), and myeloid differentiation primary response gene 88 (Myd88) was analyzed by real-time polymerase chain reaction after treating mice for 2 days with udenafil (0, 12, 120, or 600 µg/d). Furthermore, the hypothalamic expression of TLR4, pro-opiomelanocortin (POMC), and neuropeptide Y (NPY) was analyzed after 9 days' treatment with udenafil and/or leptin. We also measured body weight and food intake following 9 days of udenafil and/or leptin treatment in control- and HF-fed mice.
RESULTS
Udenafil suppressed hypothalamic TLR4 mRNA expression dose-dependently. The changes were associated with decreased PDE5, NF-κB, and Myd88 expression. Udenafil treatment for 9 days reduced body weight and caloric intake in HF-fed mice. This may have been associated with the suppression of NPY expression that was elevated by HF feeding. POMC expression was not affected by udenafil. However, udenafil did not augment the effects of leptin on the reduction of body weight and caloric intake in HF-fed mice.
CONCLUSIONS
These results suggested that udenafil reduced body weight by suppressing hypothalamic TLR4 mRNA expression in HF-fed mice and the combination effect of udenafil and leptin was additive rather than synergistic.

Keyword

Body weight; Hypothalamus; Leptin; Toll-like receptors; Udenafil

MeSH Terms

Animals
Body Weight*
Cyclic Nucleotide Phosphodiesterases, Type 5*
Eating
Energy Intake
Epithelial Cells
Hypothalamus
In Vitro Techniques
Leptin
Mice*
Neuropeptide Y
Obesity
Pro-Opiomelanocortin
Real-Time Polymerase Chain Reaction
RNA, Messenger
Toll-Like Receptor 4
Toll-Like Receptors
Cyclic Nucleotide Phosphodiesterases, Type 5
Leptin
Neuropeptide Y
Pro-Opiomelanocortin
RNA, Messenger
Toll-Like Receptor 4
Toll-Like Receptors

Figure

• 

  Fig. 1 The effect of udenafil on toll-like receptor 4 (TLR4) mRNA expression in the hypothalamus. Udenafil (500 µg) was dissolved in 10 µL saline. Udenafil or an equal volume of saline were injected into the lateral ventricle in rats. Data are expressed as mean±standard error of 3 experimental rats. *p<0.05 vs. control.

• 

  Fig. 2 The effects of different dosages (0, 12, 120, 600 µg) of udenafil on the expression of toll-like receptor 4 (TLR4) (A), phosphodiesterase 5 (PD5E) (B), myeloid differentiation primary response gene 88 (Myd88) (C), and nuclear factor-κB (NF-κB) (D) mRNA in the hypothalamus in mice. Udenafil was administered via gavage for 2 consecutive days. Data are expressed as mean±standard error of 6 mice in each experimental group. Values that do not share a common superscript letters are significantly different at p<0.05.

• 

  Fig. 3 Hypothalamic mRNA levels of toll-like receptor 4 (TLR4) (A), pro-opiomelanocortin (POMC) (B), and neuropeptide Y (NPY) (C) after treatment with udenafil and/or leptin for 9 days. The mRNA levels were analyzed using real-time polymerase chain reaction. A-: AIN-93G diet, H-: high-fat diet with 60% of the calories from fat, CON: control, LEP: leptin, UDE: udenafil. Data are expressed as mean±standard error of 7 mice in each experimental group. *p<0.05, vs. A-control. Values that do not share a common superscript letters are significantly different at p<0.05 in the control- or high-fat-fed mice.

Reference

1. Mozumdar A, Liguori G. Persistent increase of prevalence of metabolic syndrome among U.S. adults: NHANES III to NHANES 1999-2006. Diabetes Care. 2011; 34:216–219. PMID: 20889854.

2. Wisse BE, Schwartz MW. Does hypothalamic inflammation cause obesity? Cell Metab. 2009; 10:241–242. PMID: 19808014.

3. Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, et al. Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J Neurosci. 2009; 29:359–370. PMID: 19144836.

4. De Souza CT, Araujo EP, Bordin S, Ashimine R, Zollner RL, Boschero AC, et al. Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology. 2005; 146:4192–4199. PMID: 16002529.

5. Medzhitov R, Janeway C Jr. The Toll receptor family and microbial recognition. Trends Microbiol. 2000; 8:452–456. PMID: 11044679.

6. Aderem A. Role of Toll-like receptors in inflammatory response in macrophages. Crit Care Med. 2001; 29:S16–S18. PMID: 11445728.

7. Poulain-Godefroy O, Le Bacquer O, Plancq P, Lecoeur C, Pattou F, Frühbeck G, et al. Inflammatory role of Toll-like receptors in human and murine adipose tissue. Mediators Inflamm. 2010; DOI: 10.1155/2010/823486.

8. Scholtes VP, Versteeg D, de Vries JP, Hoefer IE, Schoneveld AH, Stella PR, et al. Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis. Clin Sci (Lond). 2011; 121:205–214. PMID: 21446916.

9. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest. 2006; 116:3015–3025. PMID: 17053832.

10. Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, et al. Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver. Diabetes. 2012; 61:1455–1462. PMID: 22522614.

11. Siriwardhana N, Kalupahana NS, Fletcher S, Xin W, Claycombe KJ, Quignard-Boulange A, et al. n-3 and n-6 polyunsaturated fatty acids differentially regulate adipose angiotensinogen and other inflammatory adipokines in part via NF-κB-dependent mechanisms. J Nutr Biochem. 2012; 23:1661–1667. PMID: 22475809.

12. Liu HQ, Qiu Y, Mu Y, Zhang XJ, Liu L, Hou XH, et al. A high ratio of dietary n-3/n-6 polyunsaturated fatty acids improves obesity-linked inflammation and insulin resistance through suppressing activation of TLR4 in SD rats. Nutr Res. 2013; 33:849–858. PMID: 24074743.

13. Park NK, Choi YS, Lee JH, Kim HS, Kim JK, Ahn JH, et al. Effect of udenafil on MUC5B expression in human airway epithelial cells. Korean J Otorhinolaryngol-Head Neck Surg. 2013; 56:501–505.

14. Bacon CG, Mittleman MA, Kawachi I, Giovannucci E, Glasser DB, Rimm EB. A prospective study of risk factors for erectile dysfunction. J Urol. 2006; 176:217–221. PMID: 16753404.

15. Yu JY, Kang KK, Yoo M. Erectile potentials of a new phosphodiesterase type 5 inhibitor, DA-8159, in diet-induced obese rats. Asian J Androl. 2006; 8:325–329. PMID: 16625282.

16. Aleid M, Muneer A, Renshaw S, George J, Jenkinson AD, Adamo M, et al. Early effect of bariatric surgery on urogenital function in morbidly obese men. J Sex Med. 2017; 14:205–214. PMID: 28087357.

17. Moon KH, Ko YH, Kim SW, Moon du G, Kim JJ, Park NC, et al. Efficacy of once-daily administration of udenafil for 24 weeks on erectile dysfunction: results from a randomized multicenter placebo-controlled clinical trial. J Sex Med. 2015; 12:1194–1201. PMID: 25736397.

18. Kim YW, Kim JY, Park YH, Park SY, Won KC, Choi KH, et al. Metformin restores leptin sensitivity in high-fat-fed obese rats with leptin resistance. Diabetes. 2006; 55:716–724. PMID: 16505235.

19. Shim HJ, Kim YC, Jang JM, Park KJ, Kim DH, Kang KK, et al. Subacute toxicities and toxicokinetics of DA-8159, a new phosphodiesterase type V inhibitor, after single and 4-week repeated oral administration in rats. Biopharm Drug Dispos. 2003; 24:409–418. PMID: 14689469.

20. Kim DS, Cha HN, Jo HJ, Song IH, Baek SH, Dan JM, et al. TLR2 deficiency attenuates skeletal muscle atrophy in mice. Biochem Biophys Res Commun. 2015; 459:534–540. PMID: 25749338.

21. Rocha DM, Caldas AP, Oliveira LL, Bressan J, Hermsdorff HH. Saturated fatty acids trigger TLR4-mediated inflammatory response. Atherosclerosis. 2016; 244:211–215. PMID: 26687466.

22. Sharma R. Novel phosphodiesterase-5 inhibitors: current indications and future directions. Indian J Med Sci. 2007; 61:667–679. PMID: 18174638.

23. Handa P, Tateya S, Rizzo NO, Cheng AM, Morgan-Stevenson V, Han CY, et al. Reduced vascular nitric oxide-cGMP signaling contributes to adipose tissue inflammation during high-fat feeding. Arterioscler Thromb Vasc Biol. 2011; 31:2827–2835. PMID: 21903940.

24. Varma A, Das A, Hoke NN, Durrant DE, Salloum FN, Kukreja RC. Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice. PLoS One. 2012; 7:e45243. PMID: 23028874.

25. Ayala JE, Bracy DP, Julien BM, Rottman JN, Fueger PT, Wasserman DH. Chronic treatment with sildenafil improves energy balance and insulin action in high fat-fed conscious mice. Diabetes. 2007; 56:1025–1033. PMID: 17229936.

26. Kim ED, Seftel AD, Goldfischer ER, Ni X, Burns PR. A return to normal erectile function with tadalafil once daily after an incomplete response to as-needed PDE5 inhibitor therapy. J Sex Med. 2014; 11:820–830. PMID: 23841532.

27. Burns PR, Rosen RC, Dunn M, Baygani SK, Perelman MA. Treatment satisfaction of men and partners following switch from on-demand phosphodiesterase type 5 inhibitor therapy to tadalafil 5 mg once daily. J Sex Med. 2015; 12:720–727. PMID: 25615445.

28. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000; 404:661–671. PMID: 10766253.

29. Harrold JA. Hypothalamic control of energy balance. Curr Drug Targets. 2004; 5:207–219. PMID: 15058308.

30. Shim YS, Pae CU, Cho KJ, Kim SW, Kim JC, Koh JS. Effects of daily low-dose treatment with phosphodiesterase type 5 inhibitor on cognition, depression, somatization and erectile function in patients with erectile dysfunction: a double-blind, placebo-controlled study. Int J Impot Res. 2014; 26:76–80. PMID: 24285284.