{"id":56078,"date":"2024-03-20T11:46:21","date_gmt":"2024-03-20T11:46:21","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=56078"},"modified":"2024-04-01T19:00:55","modified_gmt":"2024-04-01T19:00:55","slug":"the-impact-of-administration-of-fenofibrate-during-suckling-on-glucose-homeostasis-and-programming-of-metabolic-function-in-adolescent-sprague-dawley-rats","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol17no1\/the-impact-of-administration-of-fenofibrate-during-suckling-on-glucose-homeostasis-and-programming-of-metabolic-function-in-adolescent-sprague-dawley-rats\/","title":{"rendered":"The Impact of Administration of Fenofibrate During Suckling on Glucose Homeostasis and Programming of Metabolic Function in Adolescent Sprague Dawley Rats"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Fenofibrate belongs to the class of drugs called fibrates 1<\/sup> and is a peroxisome\nproliferator-activated receptor-alpha (PPAR-\u03b1) agonist used as an\nantihyperlipidaemic agent 2, 3<\/sup>.\nIts main biological action is reducing the levels of blood triglyceride in both\nfasting and postprandial states 4<\/sup>.<\/p>\n\n\n\n

However, in addition to its primary antihyperlipidaemic\nactivity, it has shown additional benefits when used in patients with metabolic\nsyndrome by significantly reducing the likelihood of having serious\ncardiovascular problems such as incident coronary heart disease, cardiac ischaemia\nand mortality when used in combination with statins 5<\/sup>. Fenofibrate is also known to protect\nagainst diabetes mellitus (DM) and related pathologies 6<\/sup>. By its action of regulating the\nmetabolism of sphingolipid, fenofibrate was shown to protect against the\ndevelopment of DM by modifying the lipids in the pancreas to a less toxic state 7<\/sup>. It also, probably through its\nanti-inflammatory effect, prevents the development of diabetes-related pathologies such as the\nprogression of retinopathy 8, 9<\/sup>,\nnephropathy\n10, 11<\/sup> and cardiopathy 12<\/sup>. Fenofibrate also protects against liver\ndiseases including non-alcoholic fatty liver\ndisease 13, 14<\/sup>.\n<\/p>\n\n\n\n

The prevalence of DM and non-alcoholic fatty liver disease (NAFLD)\nare on the rise globally, driven by environmental factors such as endocrine disrupting\nchemicals, epigenetics and poor dietary choices\nespecially increased dietary intake of fructose and\nfat, and physical inactivity 15, 16<\/sup>.\nMoreover, fructose rich diets have been shown to cause metabolic syndrome,\nthereby predisposing individuals to insulin resistance (IR) and type II diabetes\nmellitus (T2DM) 17<\/sup>. The cost\nof managing diabetes mellitus and NAFLD is\nhuge 18, 19<\/sup>, making it more\nprudent to prevent their occurrence. Unfortunately, the increased consumption\nof fruit juices, beverages and confectionaries usually loaded with high\nfructose, in children and adolescents 20-22<\/sup>\nhas led to an equally increased incidence of metabolic diseases in those age\ngroups 23<\/sup>. <\/p>\n\n\n\n

Studies have shown that the early critical periods of life (when\nthe tissues are highly developmentally plastic) can be epigenetically impacted\nby the application of stressors like nutritional interventions 24<\/sup>. These interventions then subsequently\ndetermine the expression of genes associated with metabolism, and whether these\nchanges will protect or make vulnerable, the individual to developing metabolic\nderangements in future 25<\/sup>.\nThis is a concept called developmental programming, a central idea in the \u201cdevelopmental\norigins of health and disease (DOHaD)\u201d hypothesis 26<\/sup>.  In rodents, the\nperiod of suckling provides a window of opportunity for targeted interventions\nseeking to induce neonatal metabolic programming 27, 28<\/sup>.<\/p>\n\n\n\n

The broad spectrum of metabolic effects exhibited by fenofibrate\nmakes it an ideal choice for use in programming against metabolic dysfunction.\nHowever, its use in children, especially neonates is not without concern.\nCurrently, there is limited data on safety, efficacy and dosing of fenofibrate\nin the paediatric age group 29, 30<\/sup>.\nMoreover, there is conflicting data on its ability to cross the placenta as\nshown in a study involving virgin and pregnant rats 31<\/sup>, as well as the fear that it could be\nboth embryotoxic and teratogenic 32-34<\/sup>.<\/p>\n\n\n\n

Despite the above concerns, neonates are still exposed to\nfenofibrate. As a pregnancy class C drug, fenofibrate is prescribed with\ncaution for the treatment of pregnant women with hyperlipidaemia 35, 36<\/sup>, as it may cross the placenta and cause\nharm to the developing embryo 37<\/sup>.\nIn neonatology, fenofibrate is now being used to boost the effectiveness of\nphototherapy in clinical management of unconjugated hyperbilirubinemia as a\nsingle or twice only oral dose 38, 39<\/sup>\nwith resultant improvement of symptoms, reduction in hospitalization and no\nreported side effects after 48 hours 40<\/sup>.\n However, the extended consequences of\nthis early life exposure to fenofibrate requires further exploration.<\/p>\n\n\n\n

In view of the use of fenofibrate in neonates, we investigated\nthe long-term health impact of administering fenofibrate to neonate male and\nfemale pups and whether it would affect their response to a postweaning diet high\nin fructose, in late adolescence. <\/p>\n\n\n\n

Materials\nand methods<\/strong><\/p>\n\n\n\n

Study Site <\/strong><\/p>\n\n\n\n

The research on animals was carried out in the Wits Research Animal Facility (WRAF), while the various assays were done in the laboratories of the Nutrition and Metabolism team of the School of Physiology, University of the Witwatersrand, Johannesburg, South Africa. <\/p>\n\n\n\n

Ethical clearance\/approval  <\/strong><\/p>\n\n\n\n

The conduct and reporting\nof the research were aligned to the ARRIVE guidelines 41<\/sup>. Ethical approval (Certificate number:\nAESC2016\/04\/18\/B) for the study protocols was issued by the Animal Ethics\nScreening Committee of the University of the Witwatersrand. Additionally,\nstrict adherence to international ethical guidelines and standards for the use and\nwelfare of laboratory rodents was ensured in the\nstudy. <\/p>\n\n\n\n

Chemicals and reagents  <\/strong><\/p>\n\n\n\n

The chemical agents for\nthis research were sourced as follows: Dimethyl sulfoxide, DMSO; was from\nSigma-Aldrich, Missouri, USA. It was prepared as a 0.5% solution in distilled\nwater. Fenofibrate was from Sigma-Aldrich, Missouri, USA and was dissolved in the\nvehicle solution and administered as 100mg.kg-1<\/sup> body mass. Food-grade\nfructose was purchased from Nature’s Choice (Randvaal, Republic of South Africa).\nThe fructose solution was prepared to a concentration of 20% using distilled\nwater (0.5% DMSO) in the suckling phase of the rats and then in tap water\n(without DMSO) post-weaning. The chow fed to the rats was sourced from Epol\u00ae in\nCenturion, South Africa.<\/p>\n\n\n\n

General care<\/strong>\nof the study animals<\/strong><\/p>\n\n\n\n

In\nthis study, 6-day old nursing male and female rat pups (Sprague Dawley) were\nused. The pups were litter mates from fourteen dams obtained from the WRAF.  We ensured that the litter size for each dam\nwas between 8-10 pups to avoid the impact of litter size (under- or\nover-nutrition) on the study 42, 43<\/sup>.\nThere was no intervention in the dams but the pups nursed freely with their own\ndams in the first phase of the study. The temperature in the allocated room at\nthe WRAF was kept at 26 \u00b1 2\u00baC (each room had its own separate temperature\ncontrol) with provision of adequate through and through ventilation. A 12-hour\nlight\/dark cycle (lights on at 0700hrs, off at 1900hrs) was used. <\/p>\n\n\n\n

At\nweaning, 21 days after birth (PND 21), the pups were separated from their dams and\nkept in individually labelled perspex cages, with wire mesh lids and fed standard\nrat cubes with either plain tap water or a 20% fructose solution. The design of\nthe cages enabled the rats to see each other for welfare socialisation. The dams\nnot used for any further studies.<\/p>\n\n\n\n

Study design<\/strong><\/p>\n\n\n\n

This\nprospective, randomized intervention study was performed in two distinct phases\n(see Figure 1). Phase one (pre-weaning) of the study extended from postnatal\nday (PND) 6 to PND 21 during suckling, with the dual aim of inducing metabolic programming\nwith fenofibrate and fructose, and also providing neonatal exposure to\nfenofibrate in order to monitor any adverse effects either immediately or later\nin life. The phase two (post-weaning) of the study which lasted for six weeks, commenced\non PND 22 until PND 63. The rationale for the post-weaning intervention was to explore\nthe potential impact (increased predisposition or protection) of the initial\ntreatments on how the rats would respond to the post-weaning high fructose. <\/p>\n\n\n\n

A\ntotal of 119 pups of both sexes (61 males and 58 females) were initially\ngrouped randomly using a split-litter pattern into four and administered with\nthe following treatments per Kg of their body mass (BM):<\/p>\n\n\n\n

C – 0.5% DMSO solution <\/p>\n\n\n\n

F – fenofibrate, 100mg.kg-1 <\/sup>BM. <\/p>\n\n\n\n

FD – 20% fructose solution <\/p>\n\n\n\n

FFD- combination of fenofibrate and fructose solution<\/p>\n\n\n\n

The\ntreatments were dispensed to the pups once daily through oral gavage, between 9\nam and 11 am, using a 10ml.kg-1<\/sup> BM volume to prevent over-filling of\nthe stomach. <\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 1: <\/strong>A schema of the study design.<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

C= 0.5% dimethyl\nsulfoxide; F=fenofibrate,100mg.kg-1<\/sup>BM; FD=20% fructose solution; FFD=fenofibrate\nand fructose; TW= tap water; M= males; F= females.<\/p>\n\n\n\n

In\nstudy phase two (post-weaning) which started on PND 22, the weanling rats from\neach of the initial four treatment groups were randomly allocated to two equally\nsized sub-groups which were all fed with normal rat chow. The sub grouping was\nbased on the drinking fluid of the rats, either tap water or a 20% fructose\nsolution provided ad libitum<\/em>.  These phase two interventions were continued\nfor six weeks and ended on PND 63. Therefore, during the second phase, there\nwere eight groups of rats (Fig 1). <\/p>\n\n\n\n

Measurement of the body mass\nof the rats <\/strong><\/strong><\/p>\n\n\n\n

The rat body masses were recorded every day during the pre-weaning phase in order to ensure correct dosing by making the necessary adjustments to their administered treatments. Post-weaning, the body masses were determined twice weekly for the purpose of growth and general health monitoring. However, only the induction weight at the beginning of the study, the weight at weaning and the terminal weight of the rats are specifically reported on in this manuscript. <\/p>\n\n\n\n

Euthanasia\nand sample preparation <\/strong><\/p>\n\n\n\n

The night prior to the termination of the rats (PND62), they were deprived of food overnight (12h) and their body masses measured and recorded in the morning of PND 63.  Before euthanasia, the rats fasting blood glucose (FBG) concentration was determined with a glucometer (Contour Plus \u2122, Bayer Corporation, Mishawaka, USA) using blood obtained from the tail vein through a pin prick.  <\/p>\n\n\n\n

Euthanasia was done using sodium pentobarbitone (Euthapent; Kyron Laboratories, South Africa) administered at a dose of 150mg.kg-1<\/sup> BM intraperitoneally. The thorax of each of the rats was cut open to expose the heart from where about 5-7ml of blood was drawn using a 10ml syringe and emptied gently into tubes for blood collection  (Becton Dickinson Vacutainer Systems Europe, Meylan Cedex, France) containing heparin. Plasma was harvested for hormonal analysis by centrifuging the blood in a centrifuge (Hermle Z 230A, B Hermle AG, Germany) for `15 minutes at 4000 x g at 4\u00baC. The abdomen was incised and the liver, kidneys, pancreas, and visceral fat pad removed and weighed. The hepatic samples were kept in a freezer  at -20\u00baC and susbequently processed for the deremination of its lipid content. <\/p>\n\n\n\n

Plasma\nadiponectin and insulin concentration assays,\nand calculation of HOMA-IR<\/strong> <\/strong><\/p>\n\n\n\n

Two\nrat enzyme-linked immunosorbent assay (ELISA) kits specific for adiponectin (Elabscience\n\u00ae Rat ADP\/Acrp30 ELISA kit, Houston, TX, USA) and insulin [Elabscience \u00ae INS\n(Insulin) ELISA kit, Houston, TX, USA] respectively were used for the quantification\nof plasma adiponectin and insulin, according to the instructions of the\nmanufacturer. We then calculated the homeostatic model of insulin resistance\nusing the formula proposed by 44<\/sup>:\n<\/p>\n\n\n\n

HOMA-IR = [fasting insulin concentration (ng.dL-1<\/sup>) x fasting glucose concentration (mg.dl-1<\/sup>)]\/405 .<\/a><\/p>\n\n\n\n

Hepatic lipid content\nquantification<\/strong><\/p>\n\n\n\n

The hepatic lipid content\nof the rats was assayed gravimetrically using solvent (chloroform and methanol)\nextraction methods 45<\/sup>. The\nhepatic fat content was then computed as a percentage of the liver weight.<\/p>\n\n\n\n

Statistical analyses<\/strong><\/p>\n\n\n\n

Data\nanalysis was done using the statistical software GraphPad Prism version 9.0\n(GraphPad Software Inc., San Diego, CA,\nUSA). Data are presented as mean \u00b1 standard error of the mean (SEM). Body mass\ndata was analysed by a repeated measure analysis of variance (ANOVA) while all\nother data was analysed using a one-way ANOVA for comparison of the means of\nthe treatment groups. A Bonferroni post\nhoc <\/em>test to identify\nsignificant differences across the groups. Statistical significance was accepted\nat p<0.05.
\n<\/strong><\/p>\n\n\n\n

Results<\/strong><\/p>\n\n\n\n

Tables\n1a and 1b display the rats\u2019 body masses at induction, weaning and termination following\na pre-weaning administration of fenofibrate and a postweaning high fructose\ndiet. Rats of both sexes gained significant (p<0.0001) body masses through\nthe three time points across all the treatment groups.<\/p>\n\n\n\n

Table 1a: Impact of post-weaning diet high in fructose on the body masses of male adolescent rats which had been administered fenofibrate in the suckling phase<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

Induction mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Weaning mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Terminal mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

13 \u00b1 1.00a<\/sup><\/p>\n<\/td>\n

\n

45 \u00b1 1.40b<\/sup><\/p>\n<\/td>\n

\n

276 \u00b1 12.00c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

14 \u00b1 0.48 a<\/sup><\/p>\n<\/td>\n

\n

44 \u00b1 1.10 b<\/sup><\/p>\n<\/td>\n

\n

276 \u00b1 5.20 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

13 \u00b1 0.68 a<\/sup><\/p>\n<\/td>\n

\n

39 \u00b1 1.10 b<\/sup><\/p>\n<\/td>\n

\n

286 \u00b1 11.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

14 \u00b1 0.46 a<\/sup><\/p>\n<\/td>\n

\n

41 \u00b1 2.00 b<\/sup><\/p>\n<\/td>\n

\n

238 \u00b1 13.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

15 \u00b1 0.60 a<\/sup><\/p>\n<\/td>\n

\n

45 \u00b1 2.90 b<\/sup><\/p>\n<\/td>\n

\n

303 \u00b1 14.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

15 \u00b1 0.46 a<\/sup><\/p>\n<\/td>\n

\n

45 \u00b1 1.80 b<\/sup><\/p>\n<\/td>\n

\n

259 \u00b1 11.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

13 \u00b1 0.53 a<\/sup><\/p>\n<\/td>\n

\n

39 \u00b1 1.10 b<\/sup><\/p>\n<\/td>\n

\n

272 \u00b1 16.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

14 \u00b1 0.49 a<\/sup><\/p>\n<\/td>\n

\n

40 \u00b1 1.60 b<\/sup><\/p>\n<\/td>\n

\n

263 \u00b1 9.10 c<\/sup><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

a,b\n,c<\/sup> = Means with different superscripts\nacross rows are significantly different at p< 0.0001 using repeated measures\nANOVA. C= 10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare expressed as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

Table 1b: Impact of a diet high in fructose post-weaning on the body masses of female adolescent rats which had been administered fenofibrate in the suckling phase<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

Induction mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Weaning mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Terminal mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

12 \u00b1 0.45 a<\/sup><\/p>\n<\/td>\n

\n

43 \u00b1 1.10 b<\/sup><\/p>\n<\/td>\n

\n

206 \u00b1 7.10 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

14 \u00b1 0.38 a<\/sup><\/p>\n<\/td>\n

\n

41 \u00b1 1.50 b<\/sup><\/p>\n<\/td>\n

\n

203 \u00b1 5.80 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

13 \u00b1 0.40 a<\/sup><\/p>\n<\/td>\n

\n

38 \u00b1 1.40 b<\/sup><\/p>\n<\/td>\n

\n

208 \u00b1 7.20 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

13 \u00b1 0.40 a<\/sup><\/p>\n<\/td>\n

\n

36 \u00b1 1.70 b<\/sup><\/p>\n<\/td>\n

\n

192 \u00b1 6.50 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

13 \u00b1 0.20 a<\/sup><\/p>\n<\/td>\n

\n

45 \u00b1 2.00 b<\/sup><\/p>\n<\/td>\n

\n

211 \u00b1 5.90 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

13 \u00b1 0.36 a<\/sup><\/p>\n<\/td>\n

\n

42 \u00b1 1.10 b<\/sup><\/p>\n<\/td>\n

\n

215 \u00b1 4.00 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

12 \u00b1 0.60 a<\/sup><\/p>\n<\/td>\n

\n

38 \u00b1 1.40 b<\/sup><\/p>\n<\/td>\n

\n

202 \u00b1 6.40 c<\/sup><\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

12 \u00b1 0.50 a<\/sup><\/p>\n<\/td>\n

\n

37 \u00b1 2.00 b<\/sup><\/p>\n<\/td>\n

\n

198 \u00b1 4.80 c<\/sup><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

a,b\n,c<\/sup> = Means with different superscripts\nacross rows are significantly different at p< 0.0001 using repeated measures\nANOVA. C= 10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20%\nfructose drink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare expressed as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

Tables\n2a and 2b show fasting circulating glucose and insulin\nconcentration and the computed HOMA-IR of rats of male and female which\nreceived fenofibrate during the pre-weaning phase followed by a high fructose solution\nas drinking fluid postweaning. <\/p>\n\n\n\n

Circulating\nfasting glucose and insulin concentrations, and HOMA-IR were not significantly\ndifferent (p>0.05, ANOVA) amongst the treatment groups in both males and\nfemales. <\/p>\n\n\n\n

Table 2a: Impact of a post-weaning high fructose diet on concentrations of fasting blood glucose and insulin, and the computed HOMA-IR of male adolescent rats administered fenofibrate in the pre-weaning phase<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

FBG<\/strong><\/p>\n

mg\/dl<\/strong><\/p>\n<\/td>\n

\n

Insulin<\/strong><\/p>\n

ng\/ml<\/strong><\/p>\n<\/td>\n

\n

HOMA-IR<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

74 \u00b1 3.40<\/p>\n<\/td>\n

\n

4.8 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.89 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

81 \u00b1 4.00<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.06<\/p>\n<\/td>\n

\n

0.97 \u00b1 0.05<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

81 \u00b1 5.70<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.07<\/p>\n<\/td>\n

\n

0.99 \u00b1 0.07<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

70 \u00b1 2.10<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.07<\/p>\n<\/td>\n

\n

0.87 \u00b1 0.04<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

81 \u00b1 4.50<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.98 \u00b1 0.06<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

73 \u00b1 2.00<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.90 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

77 \u00b1 4.60<\/p>\n<\/td>\n

\n

4.4 \u00b1 0.55<\/p>\n<\/td>\n

\n

0.83 \u00b1 0.12<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

73 \u00b1 2.10<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.88 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats.<\/p>\n\n\n\n

Table 2b: Impact of a post-weaning diet high in fructose on the concentration of fasting blood glucose and insulin, and the computed HOMA-IR of female adolescent rats administered fenofibrate during the pre-weaning phase<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

FBG<\/strong><\/p>\n

mg\/dl<\/strong><\/p>\n<\/td>\n

\n

Insulin<\/strong><\/p>\n

ng\/ml<\/strong><\/p>\n<\/td>\n

\n

HOMA-IR<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

78 \u00b1 3.50<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.94 \u00b1 0.04<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

78 \u00b1 2.90<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.94 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

72 \u00b1 1.70<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.90 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

71 \u00b1 2.30<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.87 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

73 \u00b1 5.20<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.06<\/p>\n<\/td>\n

\n

0.88 \u00b1 0.07<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

72 \u00b1 1.80<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.87 \u00b1 0.02<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

74 \u00b1 2.70<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.90 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

76 \u00b1 2.60<\/p>\n<\/td>\n

\n

4.9 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.92 \u00b1 0.03<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

The\nimpact of a diet high in fructose post-weaning on the liver masses,\nhepato-somatic indices and hepatic percentage lipid content of adolescent rats gavaged\nwith fenofibrate when they were neonates are presented in Tables 3a and 3b. <\/p>\n\n\n\n

The\nliver masses, hepatosomatic indices and liver lipid content of female and male\nrats in the different groups were similar (p>0.05, ANOVA) in both sexes.<\/p>\n\n\n\n

Table 3a: Impact of a post-weaning diet high in fructose on liver masses, hepatosomatic index and lipid content of adolescent male rats were gavaged with fenofibrate during the neonatal phase<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

Liver mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Hepatosomatic index <\/strong><\/p>\n<\/td>\n

\n

Liver lipids<\/strong><\/p>\n

(%)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

9.6 \u00b1 0.44<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.08<\/p>\n<\/td>\n

\n

7.5 \u00b1 0.06<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

9.6 \u00b1 0.28<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.07<\/p>\n<\/td>\n

\n

6.4 \u00b1 1.10<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

11 \u00b1 0.69<\/p>\n<\/td>\n

\n

3.7 \u00b1 0.19<\/p>\n<\/td>\n

\n

4.7 \u00b1 0.21<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

8.4 \u00b1 0.48<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.11<\/p>\n<\/td>\n

\n

6.9 \u00b1 0.66<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

11 \u00b1 0.50<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.18<\/p>\n<\/td>\n

\n

6.8 \u00b1 0.58<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

9.1 \u00b1 0.42<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.05<\/p>\n<\/td>\n

\n

8.5 \u00b1 0.27<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

9.8 \u00b1 0.78<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.20<\/p>\n<\/td>\n

\n

7.7 \u00b1 1.00<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

9.1 \u00b1 0.34<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.05<\/p>\n<\/td>\n

\n

8.4 \u00b1 0.63<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented  as mean \u00b1 SEM, n= 7-8 rats\nin each group.<\/p>\n\n\n\n

Table 3b: Impact of a post-weaning diet high fructose on the liver masses, hepatosomatic index and hepatic lipid content of female adolescent rats which received fenofibrate during the neonatal phase<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

Liver mass<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Hepatosomatic index<\/strong><\/p>\n<\/td>\n

\n

Liver lipids <\/strong><\/p>\n

(%)<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

7.4 \u00b1 0.53<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.18<\/p>\n<\/td>\n

\n

9.5 \u00b1 0.39<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

7.4 \u00b1 0.26<\/p>\n<\/td>\n

\n

3.7 \u00b1 0.08<\/p>\n<\/td>\n

\n

7.5 \u00b1 0.60<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

7.2 \u00b1 0.32<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.09<\/p>\n<\/td>\n

\n

8.7 \u00b1 1.10<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

7.3 \u00b1 0.33<\/p>\n<\/td>\n

\n

3.8 \u00b1 0.11<\/p>\n<\/td>\n

\n

8.7 \u00b1 1.10<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

7.6 \u00b1 0.62<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.20<\/p>\n<\/td>\n

\n

10 \u00b1 1.00<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

7.8 \u00b1 0.19<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.06<\/p>\n<\/td>\n

\n

7.5 \u00b1 0.06<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

7.2 \u00b1 0.31<\/p>\n<\/td>\n

\n

3.6 \u00b1 0.12<\/p>\n<\/td>\n

\n

12 \u00b1 0.91<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

7.5 \u00b1 0.27<\/p>\n<\/td>\n

\n

3.8 \u00b1 0.09<\/p>\n<\/td>\n

\n

12 \u00b1 1.50<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

 <\/p>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

Tables\n4a and 4b show the effect of a post-weaning high fructose diet on the absolute\n(g) and relative (% body mass) masses of the kidneys, pancreas and abdominal visceral\nfat mass of male and female adolescent rats that were administered with\nfenofibrate as neonates. <\/p>\n\n\n\n

In both sexes, there was no significant difference (p>0.05) seen in the above parameters of the different intervention groups.<\/p>\n\n\n\n

Table 4a: Effect of a post-weaning high fructose diet on `masses of the kidneys, pancreata and abdominal visceral fat masses of adolescent male Sprague Dawley rats administered with fenofibrate as neonates<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment groups<\/strong><\/p>\n<\/td>\n

\n

Kidneys<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Kidneys<\/strong><\/p>\n

%body mass<\/strong><\/p>\n<\/td>\n

\n

Pancreas<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Pancreas<\/strong><\/p>\n

% body mass<\/strong><\/p>\n<\/td>\n

\n

Visceral fat pad<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Visceral Fat Pad<\/strong><\/p>\n

% body mass<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

2.0 \u00b1 0.08<\/p>\n<\/td>\n

\n

0.72 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.96 \u00b1 0.08<\/p>\n<\/td>\n

\n

0.35 \u00b1 0.04<\/p>\n<\/td>\n

\n

3.0 \u00b1 0.22<\/p>\n<\/td>\n

\n

1.10 \u00b1 0.11<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

1.9 \u00b1 0.06<\/p>\n<\/td>\n

\n

0.71 \u00b1 0.02<\/p>\n<\/td>\n

\n

1.0 \u00b1 0.06<\/p>\n<\/td>\n

\n

0.36 \u00b1 0.02<\/p>\n<\/td>\n

\n

2.9 \u00b1 0.19<\/p>\n<\/td>\n

\n

1.00 \u00b1 0.02<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

2.2 \u00b1 0.06<\/p>\n<\/td>\n

\n

0.71 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.93 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.40 \u00b1 0.04<\/p>\n<\/td>\n

\n

3.2 \u00b1 0.30<\/p>\n<\/td>\n

\n

1.10 \u00b1 0.13<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

2.2 \u00b1 0.14<\/p>\n<\/td>\n

\n

0.77 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.91 \u00b1 0.07<\/p>\n<\/td>\n

\n

0.35 \u00b1 0.02<\/p>\n<\/td>\n

\n

2.1 \u00b1 0.37<\/p>\n<\/td>\n

\n

0.86 \u00b1 0.12<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

2.2 \u00b1 0.07<\/p>\n<\/td>\n

\n

0.72 \u00b1 0.02<\/p>\n<\/td>\n

\n

1.2 \u00b1 0.13<\/p>\n<\/td>\n

\n

0.40 \u00b1 0.02<\/p>\n<\/td>\n

\n

3.2 \u00b1 0.55<\/p>\n<\/td>\n

\n

1.10 \u00b1 0.22<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

2.2 \u00b1 0.14<\/p>\n<\/td>\n

\n

0.86 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.92 \u00b1 0.08<\/p>\n<\/td>\n

\n

0.35 \u00b1 0.04<\/p>\n<\/td>\n

\n

2.6 \u00b1 0.34<\/p>\n<\/td>\n

\n

1.00 \u00b1 0.10<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

1.9 \u00b1 0.11<\/p>\n<\/td>\n

\n

0.72 \u00b1 0.02<\/p>\n<\/td>\n

\n

1.0 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.38 \u00b1 0.03<\/p>\n<\/td>\n

\n

3.5 \u00b1 0.44<\/p>\n<\/td>\n

\n

1.30 \u00b1 0.19<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

1.9 \u00b1 0.07<\/p>\n<\/td>\n

\n

0.71 \u00b1 0.02<\/p>\n<\/td>\n

\n

1.0 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.40  \u00b1 0.02<\/p>\n<\/td>\n

\n

3.0 \u00b1 0.38<\/p>\n<\/td>\n

\n

1.10 \u00b1 0.12<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

C= 10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose drink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD= fenofibrate and fructose. The first letters before the addition sign in the designation of the treatment groups indicate the pre-weaning treatment while the letters after the addition sign indicate the post-weaning treatments. Data are presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

Table 4b: Impact of a post-weaning diet high in fructose on the masses of the kidneys, pancreata and abdominal visceral fat masses of adolescent female Sprague Dawley rats administered with fenofibrate as neonates<\/strong>.<\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Treatment
groups<\/strong><\/p>\n<\/td>\n

\n

Kidneys<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Kidneys<\/strong><\/p>\n

% body mass<\/strong><\/p>\n<\/td>\n

\n

Pancreas<\/strong><\/p>\n

(g)<\/strong><\/p>\n<\/td>\n

\n

Pancreas<\/strong><\/p>\n

% body mass<\/strong><\/p>\n<\/td>\n

\n

Visceral fat pad<\/strong><\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n

Visceral fat pad<\/strong><\/p>\n

% Body mass<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

C + TW<\/p>\n<\/td>\n

\n

1.5 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.71 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.77 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.38 \u00b1 0.02<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.47<\/p>\n<\/td>\n

\n

2.4 \u00b1 0.22<\/p>\n<\/td>\n<\/tr>\n

\n

C + FD<\/p>\n<\/td>\n

\n

1.5 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.74 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.89 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.44 \u00b1 0.03<\/p>\n<\/td>\n

\n

4.4 \u00b1 0.58<\/p>\n<\/td>\n

\n

2.1 \u00b1 0.24<\/p>\n<\/td>\n<\/tr>\n

\n

F + TW<\/p>\n<\/td>\n

\n

1.5 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.73 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.84 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.47 \u00b1 0.01<\/p>\n<\/td>\n

\n

3.7 \u00b1 0.37<\/p>\n<\/td>\n

\n

2.1 \u00b1 0.32<\/p>\n<\/td>\n<\/tr>\n

\n

F + FD<\/p>\n<\/td>\n

\n

1.6 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.78 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.88 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.41 \u00b1 0.03<\/p>\n<\/td>\n

\n

4.2 \u00b1 0.29<\/p>\n<\/td>\n

\n

1.9 \u00b1 0.20<\/p>\n<\/td>\n<\/tr>\n

\n

 FD + TW<\/p>\n<\/td>\n

\n

1.5 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.72 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.94 \u00b1 0.08<\/p>\n<\/td>\n

\n

0.44 \u00b1 0.03<\/p>\n<\/td>\n

\n

4.2 \u00b1 0.54<\/p>\n<\/td>\n

\n

2.0 \u00b1 0.31<\/p>\n<\/td>\n<\/tr>\n

\n

FD + FD<\/p>\n<\/td>\n

\n

1.6 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.74 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.88 \u00b1 0.04<\/p>\n<\/td>\n

\n

0.41 \u00b1 0.02<\/p>\n<\/td>\n

\n

5.1 \u00b1 0.23<\/p>\n<\/td>\n

\n

2.4 \u00b1 0.10<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + TW<\/p>\n<\/td>\n

\n

1.5 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.72 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.85 \u00b1 0.03<\/p>\n<\/td>\n

\n

0.38 \u00b1  0.02<\/p>\n<\/td>\n

\n

4.3 \u00b1 0.49<\/p>\n<\/td>\n

\n

2.1 \u00b1 0.15<\/p>\n<\/td>\n<\/tr>\n

\n

FFD + FD<\/p>\n<\/td>\n

\n

1.6 \u00b1 0.05<\/p>\n<\/td>\n

\n

0.75 \u00b1 0.01<\/p>\n<\/td>\n

\n

0.94 \u00b1 0.08<\/p>\n<\/td>\n

\n

0.49 \u00b1 0.01<\/p>\n<\/td>\n

\n

5.0 \u00b1 0.50<\/p>\n<\/td>\n

\n

2.0 \u00b1 0.21<\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

The\nimpact of a post-weaning diet high in fructose on the fasting plasma levels of\nadiponectin in male and female rats which received fenofibrate during the suckling\nphase are displayed in Figures 2a and 2b.<\/p>\n\n\n\n

The\nfasting plasma concentration of adiponectin not significantly different (p>0.05)\nin both sexes of the different treatment groups.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 2a<\/strong>: Effect of post-weaning high fructose diet on the fasting plasma concentration of adiponectin in adolescent male rats administered with fenofibrate as neonates<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure 2b<\/strong>: Effect of post-weaning high fructose diet on the fasting plasma concentration of adiponectin in adolescent female rats administered with fenofibrate as neonates<\/strong><\/p>\n

<\/p>\n

Click here to view Figure<\/a><\/p>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

C=\n10ml.kg-1<\/sup> of a 0.5% dimethyl sulfoxide solution, FD= 20% fructose\ndrink, F= fenofibrate, 100mg.kg-1<\/sup> BM, TW= tap water, FFD=\nfenofibrate and fructose. The first letters before the addition sign in the\ndesignation of the treatment groups indicate the pre-weaning treatment while\nthe letters after the addition sign indicate the post-weaning treatments. Data\nare presented as mean \u00b1 SEM, n= 7-8 rats in each group.<\/p>\n\n\n\n

Discussion<\/strong><\/p>\n\n\n\n

Currently,\nthe global epidemic of metabolic syndrome affects all age groups 46<\/sup> and is partially driven by an\nincreased consumption of fructose rich diets 47, 48<\/sup>. However, in this our current study, our postweaning\nhigh fructose intervention failed to produce metabolic dysfunction in the\nadolescent rats.  All the metabolic\nparameters we measured were similar in both sexes regardless of the treatment.\nA number of factors which we will discuss shortly could be responsible for this\nfinding. However, of significance, is the fact that the administration of\nfenofibrate to suckling rats did not produce any overt side effects in the rats,\nat least until late adolescence when they were terminated. <\/p>\n\n\n\n

We\nconsider this as a significant finding because it adds to the evidence that\nsupports the safe use of fenofibrate in the neonatal and young age groups. Even\nthough, fenofibrate is currently used with caution together with phototherapy as\na therapeutic approach for management of neonatal hyperbilirubinaemia 38-40<\/sup>, there is always the fear of its\nembryotoxic and teratogenic potential 32-34<\/sup>.\nIt is therefore used as a single or at most twice-only dosage. <\/p>\n\n\n\n

In\nour study, we administered 100mg of fenofibrate per kg body mass to the\nsuckling pups daily for 15 days starting from PND6 to PND 21. It has been shown\nthat the early postnatal days in rats correspond to the last trimester of gestation\nin humans 49, 50<\/sup>. The period\nwithin which we administered our pre-weaning treatments is a period of\ndevelopmental plasticity that is similar to the last pregnancy trimester and\nthe early postnatal years (approximately three years old) in humans. Interestingly,\nwe did not observe any overt or biochemical adverse effects in the adolescent rats.\nThis finding can be interpreted to suggest that fenofibrate may actually be\nsafe and could therefore be used with more confidence in pregnant women with\ndyslipidaemia and in neonates for the treatment of hyperbilirubinaemia and\nother conditions. However, it is notable that the study did not use pregnant\nrats and hence the transplacental pharmacodynamics and maternal metabolism of\nfenofibrate would need to also be taken into consideration.<\/p>\n\n\n\n

In\nthe present study, we fed weanling rats with fructose (20%) solution for 6\nweeks without any resultant induction of metabolic dysfunction. In both sexes\nof rats, the measured metabolic parameters including the body masses, visceral\nfat pads, fasting blood glucose and insulin concentrations, computed HOMA-IR, plasma\nconcentration of adiponectin and liver lipid content were similarly comparable between\nthe different treatment groups. This finding is at variance with that of several\nstudies where in rats, the administration of a 20% fructose caused metabolic\nsyndrome. Feeding Sprague Dawley rats with 20% fructose water has previously\nbeen shown to cause increased blood lipids and glucose concentrations, visceral\nfat mass, hypoinsulinaemia and insulin resistance 51<\/sup> and increased liver lipids content 52<\/sup>. In another study, 20% fructose solution\nadministered for 60 days to Sprague Dawley rats produced\nhyperinsulinemia, insulin resistance, and an increase in low-density\nlipoprotein (LDL), visceral fat, and significantly increased the liver weights\nof the rats 53<\/sup>. <\/p>\n\n\n\n

Adiponectin, a circulating hormone secreted by the adipose\ntissue exerts protective effects against inflammation and modulates the endocrine\nsystem, by enhancing insulin sensitivity in obese animals as well as in humans 54<\/sup>. Disruption of glucose homeostasis by\na high fructose diet has been shown to decrease the concentration of\nadiponectin 55<\/sup>. However, in\nour study there were no differences in adiponectin concentrations of the rats\nacross the different groups suggesting that the fenofibrate and high fructose\ndid not impair adiponectin homeostasis and function. <\/p>\n\n\n\n

 In the current study, we targeted the late adolescent\nand early adulthood group to enable us to explore the programming outcomes of\nneonatal administration of both fructose and fenofibrate when accompanied by a\npostweaning fructose diet.  Accordingly, the\nrats were placed on fructose in the active growth phase of their lives. The metabolic\nrate of nursing rat pups and weanling\/growing rats is greater compared to adult\nrats because of their higher ratio of body surface area to volume, which leads\nto oxidation of the excess consumed fructose and utilization for growth and\nmaintenance of homeostasis without inducing metabolic dysfunction 56<\/sup>. Younger rats have also been reported to\nbe protected from the deleterious consequences of high fructose diets through\nsome adaptive mechanism that involves the increased efficiency of GLuT 4\ntransport proteins for glucose 57, 58<\/sup>.\nUp till weaning, the GLuT 5 fructose transporters in the small intestines are\nstill very few and immature 59-61<\/sup>\nand might not effectively ensure the absorption of fructose from the GIT.\nHowever, the fructose transporters may undergo precocious maturation if\nfructose is introduced early in life 62, 63<\/sup>,\nas we did in our study. Unfortunately, we did not assay for the GLuT 5\ntransporters in this study, and we therefore do not know whether their\nexpression was increased due to our neonatal fructose administration. Future\nstudies should explore this possibility. <\/p>\n\n\n\n

The\ndata on body mass gain and organ weights also support the safety of fenofibrate\nuse during suckling. This is because all the rats gained weight significantly from\ninduction through weaning and at termination of the study indicating there was\nno unfavourable impact on growth and development of the experimental animals. Moreover,\nthe masses of the organs that were weighed (liver, kidneys, pancreas) remained\nthe same irrespective of the treatments administered. The body mass and organ\nmasses of experimental animals are surrogate markers in the determination of\ntoxicity of administered chemicals and drugs 64<\/sup>. Moreover, alterations in weights of organs are usually\nassociated with treatment-related effects and can give information on potential\ntarget organs for the chemical or drug 65<\/sup>.\nHowever, changes in organ weights may actually be indicators of the overall\nbody mass changes induced by the chemical and not necessarily related to the\nspecific organ 66<\/sup>. Hence, the\nuse of relative masses of the organs to the overall body mass is more\nappropriate 67<\/sup>. In our study, relative\nmasses of the weighed organs were not different across treatments, suggesting\nthe safety of fenofibrate administration in neonates.<\/p>\n\n\n\n

Additionally,\nsimilar body mass of the rats drinking fructose solution compared to those\ndrinking tap water were observed. This is not surprising because it has been previously\nshown that fructose-induced changes in body mass usually appear during\nadulthood when the rats are around 100 days old 68<\/sup>. However, at the time of the rats were terminated,  they were 63 days old (late adolescence) and\ntherefore had not yet experienced that excess accumulation of fats. Moreover,\nit has been suggested that a combination of fructose and a high fat diet better\ndevelops the obese phenotype than the use of fructose alone 69<\/sup>. <\/p>\n\n\n\n

Fenofibrate\nhas been shown to be useful in preventing diabetes and its related\ncomplications. This is one of the reasons we used it with the aim of\nprogramming for protection against the development of a high-fructose-induced disruption\nof glucose homeostasis. Even though, there was no increase in fasting blood\nglucose concentration, fasting insulin and the computed HOMA-IR, we are unable\nto say that this is a result of the protective effects of fenofibrate. This is\nbecause the high fructose diet did not also produce any effects in the control\ngroups as earlier mentioned. Therefore, there is a need for further investigation\nusing a different model of metabolic syndrome, perhaps in older rats.<\/p>\n\n\n\n

Finally,\na gene expression study of some of the genes involved in carbohydrate and lipid\nmetabolism such as PPAR or fatty acid synthase (FAS) would probably have shed\nmore light on the impact of fenofibrate at the mechanistic level. Additionally,\nglobal DNA methylation or specific methylation studies would have provided\nevidence on whether fenofibrate programmed for metabolic function in the rats\nor not. Indeed, these are worthwhile investigations that should form the core\nof future research in this area. <\/p>\n\n\n\n

Conclusion\n<\/strong><\/p>\n\n\n\n

Neonatal\nadministration of fenofibrate did not subsequently adversely affect the health of\nthe adolescent rats with or without a high fructose diet and may therefore be\nsafe for use in neonates. <\/p>\n\n\n\n

Acknowledgements<\/strong><\/p>\n\n\n\n

We\nacknowledge the assistance we received from the members of the Nutrition and\nMetabolism Research Team of the School of Physiology during the termination of\nthe rats and sample collection. We are also grateful to the employees in the\nUniversity of the Witwatersrand Animal Research Facility (WRAF) for their help\nwith caring for the rodents.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The\nauthors declare that they have no conflict of interest.<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

KGI (Grant number: 001.251.8521101.5121105.000000. 0000000000.4550) was a recipient of grants from the Faculty of Health Sciences Research Committee of the University of the Witwatersrand, Johannesburg while KHE (Grant number: IRF 2010041900009) received grants from the National Research Foundation of South Africa).<\/p>\n\n\n\n

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