QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Serisier, S. Articles by Nguyen, P. Search for Related Content PubMed PubMed Citation Articles by Serisier, S. Articles by Nguyen, P.

---

Supplement: The WALTHAM International Sciences Symposia Innovations in Companion Animal Nutrition: Poster Presentations

Fenofibrate Lowers Lipid Parameters in Obese Dogs^1,2

Samuel Serisier^*,,**, François Briand^*,,**, Khadija Ouguerram^,**, Brigitte Siliart^*,**, Thierry Magot^,** and Patrick Nguyen^*,**,3

^* Endocrinology and Nutrition Unit, National Veterinary School of Nantes, France; INSERM U539, University Hospital, Nantes, France; and ^** Human Nutrition Research Center of Nantes, France

³ To whom correspondence should be addressed. E-Mail: pnguyen{at}vet-nantes.fr.

KEY WORDS: • obese dog • dyslipidemia • fenofibrate

Various surveys and cross-sectional epidemiologic studies have attempted to estimate the prevalence of overweight and obesity of dogs in industrialized societies. About 25% of dogs receiving veterinary care in Western countries are overweight to obese (1). Data from 52 private practices across the United States collected as part of the 1995 National Companion Animal Study (NCAS) indicated that 28.3% of 27,415 dogs of all ages were overweight or obese (2). Thus, obesity has become the most common nutritionally related health problem in companion animals (3).

In humans, it has been established that obesity is closely associated with insulin resistance, type 2 diabetes, and other chronic diseases such as hypertension and dyslipidemia consisting of elevations of very-low-density lipoprotein (VLDL)⁴ triglycerides (TG) and low-density lipoprotein (LDL) cholesterol and low concentrations of high-density lipoprotein (HDL) cholesterol (4). Canine hypertriglyceridemia can be associated with abdominal pain, seizures, diarrhea, vomiting, paralysis, hepatomegaly, splenomegaly, pancreatitis, ocular troubles, cardiovascular dysfunctions, lethargy, and anorexia (5). Hypercholesterolemic clinical signs are more discreet. Moreover, hyperlipidemia produced intimal fatty lesions in the abdominal aorta and many of its branches and in large and small coronary arteries (6). At postmortem examinations of a dog with diabetes mellitus, atherosclerotic plaques were observed in the terminal aorta and in medium-sized arteries including the coronary arteries, renal and arcuate arteries, and arteries of the brain (7). However, atherosclerosis occurs more rarely than in humans because, in dogs, the HDL/LDL ratio is the inverse of that in humans (8). Hypertriglyceridemia is one of the most common abnormalities reported in obesity as a result of a VLDL-TG overproduction that could be caused by an increased supply of substrates to the liver, particularly free fatty acids (FFA) (9).

Fenofibrate is a member of the fibrate class that mainly exerts hypolipidemic actions (10). In humans, fibrates effectively lower plasma TG concentrations. LDL cholesterol, which is associated with increased risk of atherosclerosis, is also reduced by these drugs but to a lesser extent. The TG-lowering activity of fibrates has been attributed to both inhibition of hepatic fatty acid synthesis and increased catabolism of VLDL-TG (11). The lipid-modulating effects of fibrates appear to be mediated through the peroxisome proliferator-activated receptor- (PPAR), a member of the nuclear hormone receptor superfamily known to induce changes in the transcription of genes encoding enzymes involved in lipid and lipoprotein metabolism (12).

In dogs, the disease severity is directly related to circulating lipid concentrations (5,6). Thus, interventions aimed at correcting dyslipidemia and particularly hypertriglyceridemia should be a priority in the prevention of obesity-related diseases in dogs as it is in humans. Moreover, postprandial state is a critical point. Indeed, the postprandial lipemia, characterized by a rise in TG-rich lipoproteins after eating, is a non-steady-state condition in which animals spend a lot of time. In humans, there are several lines of evidence suggesting that postprandial lipemia increases the risk of atherogenesis. Clinical data show a correlation between postprandial lipoprotein levels and the presence of coronary artery disease (13) and carotid intimal thickness (14). Thus, lipid-lowering medications should affect variables related to postprandial lipemia.

Because the effects of fibrates on serum lipid concentrations in dogs have been poorly characterized, the aims of this study were 1) to examine whether fenofibrate was effective in decreasing the plasma lipid in obese dogs at a dose weaker than those usually used in other animal studies (15–19), and 2) to see whether fenofibrate is as effective on lipid parameters in the fasting state as in the postprandial state.

	MATERIALS AND METHODS

TOP MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Animals and diet

Six adult obese beagle dogs (spayed females) were included in the study. Mean body weight (BW) was 15.7 ± 0.9 kg (ideal BW was 10.0 ± 0.4 kg), and age was 6 y. The body condition score was 7 or 8 on the 9-point scale (20). Before the initiation of the study, dogs were fed daily 300 g of a hyperenergetic dry commercial food (18 MJ/kg, 320 g crude protein/kg) in a single meal. Animals were housed at the National Veterinary School of Nantes according to the regulations for animal welfare of the French Ministry of Agriculture and Fisheries. The experimental protocol adhered to European Union guidelines and was approved by the Animal Use and Care Advisory Committee of the University of Nantes. Clinical examinations, blood cell counts, and biochemistry were performed before the study to ensure that all animals were in good health. Dogs were administered fenofibrate, 10 mg/kg each day just before their meal, for 15 d. Jugular vein blood samples were collected on d 0, d 8, and d 15 and after a washout period of 4 wk, in a fasting state (24-h unfed) and 6 h after feeding. These samples were placed in EDTA tubes. Blood was immediately centrifuged at 5000 x g for10 min and stored at –80°C until further analysis of triglycerides, total cholesterol (TC), FFA, and phospholipids (PL).

Chemical analysis

TG, TC, PL, and FFA were analyzed in plasma using enzymatic methods (Triglycérides enzymatiques PAP 150, BioMérieux; Cholesterol RTU, Biomérieux; Phospholipids B, NEFA C, WAKO).

Statistical analysis

The results of this study are expressed as means ± SEM. The statistical analysis was made using Stat View 5.0 software (SAS Institute). An ANOVA with repeated measures was used to compare the 3 d of blood collection. When significant (F-test, P < 0.05), the differences between mean values were assessed by the Fisher's protected least significant difference test (PLSD). A P-value of <0.05 was considered to be significant for all analyses.

	RESULTS

TOP MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Treatment for 2 wk with 10 mg·kg^–1· d^–1 of fenofibrate significantly reduced plasma lipid concentrations. Fasting triglycerides, total cholesterol, free fatty acids, and phospholipids concentrations significantly decreased by 29 ± 9, 30 ± 7, 30 ± 5, and 25 ± 3%, respectively. In the postprandial state, fenofibrate was also efficient in approximately the same proportions because lipid concentrations significantly decreased by 33 ± 8, 25 ± 4, 30 ± 7, and 15 ± 3%, respectively (Table 1). These effects were observed, as expected, as early as wk 1 and were maintained until the end of treatment; indeed, values between d 8 and d 15 were not significantly different. After a 4-wk washout period, lipids returned to baseline.

	DISCUSSION

TOP MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 
Fenofibrate treatment improved lipid parameters in obese dogs. Obesity is commonly associated with dyslipidemia and type 2 diabetes and subsequent hyperinsulinemia and hyperglycemia. Indeed, increased circulating free fatty acids lead to insulin resistance (21). Furthermore, hypertriglyceridemia, especially when severe, may place dogs at risk for developing several problems such as abdominal pain, seizures, vomiting, diarrhea, hepatomegaly, splenomegaly, cardiovascular compromise, lethargy, anorexia, lipemia retinalis, and pancreatitis. Hypercholesterolemia, of great concern in human medicine because of its role in the development of atherosclerosis, generally does not cause severe clinical problems in dogs, although in dogs it has been associated with lipemia retinalis, lipid opacifications in the cornea, and, rarely, atherosclerosis (5–7). It was reasonable to suggest that lowering FFA would improve insulin sensitivity and would lower hyperglycemia in insulin-resistant obese dogs. Moreover, dyslipidemia is involved in many serious diseases, and the degree of pathogenesis is directly related to circulating lipid levels (5,6). Thus, interventions aimed at correcting dyslipidemia should be a priority in the prevention of pathogenesis in the obese dog.

In humans, and possibly in animals, severe hyperlipidemia can result from hereditary factors working in concert with one or more acquired conditions. Ultimately, hyperlipidemia results from excessive dietary intake of lipids, excessive endogenous production or mobilization of lipids, ineffective clearance of lipids from the blood, or combinations of these (9). Because VLDL-TG synthesis is stimulated by the influx of fatty acids into the liver, the mobilization of body fat stores can cause hypertriglyceridemia. Furthermore, because normal clearance of VLDL triglycerides from the blood requires the action of lipoprotein lipase, a decreased activity of this enzyme may also be responsible for hypertriglyceridemia (5).

To avoid clinical complications, it seems important to treat hypertriglyceridemia and hypercholesterolemia as efficiently as possible without adverse effects. Fenofibrate is a member of the fibrates, which are hypolipidemic drugs currently used in the treatment of human dyslipidemia (10). PPAR, the first identified PPAR family member, mediates the hypolipidemic action of fibrates in the treatment of hypertriglyceridemia and hypercholesterolemia with 4 major metabolic pathways: 1) induction of peripheral lipoprotein lipolysis as a result of an increase in intrinsic lipoprotein lipase activity; 2) limitation of hepatic TG synthesis and VLDL production through enhanced FFA catabolism and reduced FFA synthesis; 3) increase in LDL particle removal as a result of changes in plasma LDL composition and subsequent increase in LDL affinity for its liver receptor leading to LDL catabolism; and 4) increase in HDL production and stimulation of reverse cholesterol transport (12).

The amino acid sequence of dog PPAR was found to be 97% identical to that of human PPAR (22); thus, it has been hypothesized that the effectiveness of PPAR agonist in human treatment could be similar in dogs. Similar to the effects observed in humans (23), treatment of obese dogs with fenofibrate markedly lowered serum TG and TC. There are a few reports describing the effects of fenofibrate on serum FFA and PL, and we showed that fenofibrate also decreased plasma FFA and PL concentrations. When we considered the results for each dog, fenofibrate was most effective when baseline lipid levels were high. Moreover, fenofibrate was effective in the fasting state as well as in the postprandial state; effects were seen during wk 1 of treatment, and, as in previous studies (15,19), lipid concentrations remained constant throughout the treatment period, indicating that a steady state was obtained within 7 d of fenofibrate treatment. However, after the end of treatment, lipid concentrations returned to baseline so fenofibrate treatment would need to be long term. The duration of treatment has been selected based on the pharmacokinetic properties of fenofibrate in humans. Indeed, steady-state plasma levels have been reached within 5 d in a healthy volunteer (23). We have measured acute effects of fenofibrate and not the possible harmful secondary effects, but chronic toxicity studies in dogs failed to show any adverse effects (24). Nevertheless, in chronic human treatment, fenofibrate showed a few adverse effects such as digestive or skin problems (10); thus, a clinical surveillance would be advised in dog treatment.

In our study, body weight decreased significantly but very slightly (3 ± 1%). Several primate studies have not reported any change in body weight with fenofibrate treatment, but it seemed to act as a weight stabilizer through PPAR (15,21). In contrast, fibrates have been shown to reduce body weight gain and white adipose tissue in several rodent models of obesity, diabetes, and insulin resistance (16–18,25). These effects are thought to be mediated through the coupling of an increased flux of FFA from peripheral tissues to the liver with enhanced hepatic FFA catabolism mediated by PPARs, mainly through the induction of target enzymes involved in hepatic lipid metabolism. Indeed, fatty acid oxidation is significantly elevated in fenofibrate-treated animals, as evidenced by marked upregulation of hepatic acyl CoA oxidase and carnitine palmitoyl transferase expression (17).

In conclusion, we have shown in this study that fenofibrate is effective in improving dyslipidemia as early as wk 1 of treatment in the fasting state as well as in the postprandial state. Because fenofibrate is involved in lipoprotein metabolism, further work is required to study the effect of fenofibrate on lipid concentrations in the different lipoprotein fractions and the mechanisms explaining enhancement of plasma lipid levels.

	ACKNOWLEDGMENTS

 
The authors are grateful to Samuel Ninet and Gérald Pondevie for technical assistance and Sophie Le Trionnaire for performing the serum chemistry analyses.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented as part of The WALTHAM International Nutritional Sciences Symposium: Innovations in Companion Animal Nutrition held in Washington, DC, September 15–18, 2005. This conference was supported by The WALTHAM Centre for Pet Nutrition and organized in collaboration with the University of California, Davis, and Cornell University. This publication was supported by The WALTHAM Centre for Pet Nutrition. Guest editors for this symposium were D'Ann Finley, Francis A. Kallfelz, James G. Morris, and Quinton R. Rogers. Guest editor disclosure: expenses for the editors to travel to the symposium and honoraria were paid by The WALTHAM Centre for Pet Nutrition.

² Author disclosure: Expenses for authors (F.B. and P.N.) to travel to the symposium were paid by Royal Canin.

⁴ Abbreviations used: PL, phospholipids; PPAR, peroxisome proliferator-activated receptor; TC, total cholesterol; TG, triglycerides; VLDL, very-low-density lipoprotein.

	LITERATURE CITED

TOP MATERIALS AND METHODS RESULTS DISCUSSION LITERATURE CITED

 

1. Edney AT, Smith PM. Study of obesity in dogs visiting veterinary practices in the United Kingdom. Vet Rec. 1986;118:391–6.[Abstract]

2. Lund EM, Armstrong PJ, Kirk CA, Kolar LM, Klausner JS. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J Am Vet Med Assoc. 1999;214:1336–41.[Medline]

3. Sloth C. Practical management of obesity in dogs and cats. J Small Anim Pract. 1992;33:178–82.

4. Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414:782–7.[Medline]

5. Whitney MS. Evaluation of hyperlipidemias in dogs and cats. Semin Vet Med Surg (Small Anim). 1992;7:292–300.

6. Nandan R, Fisher JD, Towery EP, Brown DR, Ganote E, Jennings RB. Effects of dextrothyroxine on hyperlipidemia and experimental atherosclerosis in beagle dogs. Atherosclerosis. 1975;22:299–311.[Medline]

7. Sottiaux J. Atherosclerosis in a dog with diabetes mellitus. J Small Anim Pract. 1999;40:581–4.[Medline]

8. Bailhache E, Nguyen P, Krempf M, Siliart B, Magot T, Ouguerram K. Lipoproteins abnormalities in obese insulin-resistant dogs. Metabolism. 2003;52:559–64.[Medline]

9. Grundy SM, Barnett JP. Metabolic and health complications of obesity. Dis Mon. 1990;36:641–731.[Medline]

10. Adkins JC, Faulds D. Micronised fenofibrate: a review of its pharmacodynamic properties and clinical efficacy in the management of dyslipidaemia. Drugs. 1997;54:615–33.[Medline]

11. Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–93.[Abstract/Free Full Text]

12. Gervois P, Torra IP, Fruchart JC, Staels B. Regulation of lipid and lipoprotein metabolism by PPAR activators. Clin Chem Lab Med. 2000;38:3–11.[Medline]

13. Hyson D, Rutledge JC, Berglund L. Postprandial lipemia and cardiovascular disease. Curr Atheroscler Rep. 2003;5:437–44.[Medline]

14. Boquist S, Ruotolo G, Tang R, Bjorkegren J, Bond MG, de Faire U, Karpe F, Hamsten A. Alimentary lipemia, postprandial triglyceride-rich lipoproteins, and common carotid intima-media thickness in healthy, middle-aged men. Circulation. 1999;100:723–8.[Abstract/Free Full Text]

15. Winegar DA, Brown PJ, Wilkison WO, Lewis MC, Ott RJ, Tong WQ, Brown HR, Lehmann JM, Kliewer SA, et al. Effects of fenofibrate on lipid parameters in obese rhesus monkeys. J Lipid Res. 2001;42:1543–51.[Abstract/Free Full Text]

16. Larsen PJ, Jensen PB, Sorensen RV, Larsen LK, Vrang N, Wulff EM, Wassermann K. Differential influences of peroxisome proliferator-activated receptors gamma and alpha on food intake and energy homeostasis. Diabetes. 2003;52:2249–59.[Abstract/Free Full Text]

17. Chaput E, Saladin R, Silvestre M, Edgar AD. Fenofibrate and rosiglitazone lower serum triglycerides with opposing effects on body weight. Biochem Biophys Res Commun. 2000;271:445–50.[Medline]

18. Mancini FP, Lanni A, Sabatino L, Moreno M, Giannino A, Contaldo F, Colantuoni V, Goglia F. Fenofibrate prevents and reduces body weight gain and adiposity in diet-induced obese rats. FEBS Lett. 2001;491:154–8.[Medline]

19. Hennuyer N, Poulain P, Madsen L, Berge RK, Houdebine LM, Branellec D, Fruchart JC, Fievet C, Duverger N, et al. Beneficial effects of fibrates on apolipoprotein A-I metabolism occur independently of any peroxisome proliferative response. Circulation. 1999;99:2445–51.[Abstract/Free Full Text]

20. Laflamme DP, Kuhlman G, Lawler DF, Kealy RD, Schmidt DA. Obesity management in dogs. Vet Clin Nutr. 1994;1:59–65.

21. Damci T, Tatliagac S, Osar Z, Ilkova H. Fenofibrate treatment is associated with better glycemic control and lower serum leptin and insulin levels in type 2 diabetic patients with hypertriglyceridemia. Eur J Intern Med. 2003;14:357–60.[Medline]

22. Nagasawa M, Ide T, Suzuki M, Tsunoda M, Akasaka Y, Okazaki T, Mochizuki T, Murakami K. Pharmacological characterization of a human-specific peroxisome proliferater-activated receptor alpha (PPARalpha) agonist in dogs. Biochem Pharmacol. 2004;67:2057–69.[Medline]

23. Najib J. Fenofibrate in the treatment of dyslipidemia: a review of the data as they relate to the new suprabioavailable tablet formulation. Clin Ther. 2002;24:2022–50.[Medline]

24. Blane GF, Pinaroli F. [Fenofibrate: animal toxicology in relation to side-effects in man (author's transl).] Nouv Presse Med. 1980;9:3737–46.[Medline]

25. Jeong S, Han M, Lee H, Kim M, Kim J, Nicol CJ, Kim BH, Choi JH, Nam KH, et al. Effects of fenofibrate on high-fat diet-induced body weight gain and adiposity in female C57BL/6J mice. Metabolism. 2004;53:1284–9.[Medline]

This article has been cited by other articles:

				M. Tsunoda, N. Kobayashi, T. Ide, M. Utsumi, M. Nagasawa, and K. Murakami A novel PPAR{alpha} agonist ameliorates insulin resistance in dogs fed a high-fat diet Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E833 - E840. [Abstract] [Full Text] [PDF]

				V. Labinskyy, M. Bellomo, M. P. Chandler, M. E. Young, V. Lionetti, K. Qanud, F. Bigazzi, T. Sampietro, W. C. Stanley, and F. A. Recchia Chronic Activation of Peroxisome Proliferator-Activated Receptor-{alpha} with Fenofibrate Prevents Alterations in Cardiac Metabolic Phenotype without Changing the Onset of Decompensation in Pacing-Induced Heart Failure J. Pharmacol. Exp. Ther., April 1, 2007; 321(1): 165 - 171. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Serisier, S. Articles by Nguyen, P. Search for Related Content PubMed PubMed Citation Articles by Serisier, S. Articles by Nguyen, P.