| PART I:Postnatal feeding with high fat diet induces obesity and precocious puberty in C57BL/6J mouse pupsBackground:Perinatal overfeeding,induced by maternal obesity,maternal high fat diet(HFD)feeding during gestation and lactation and raring small litter size has been shown to induce obesity.However;the effects of purely postnatal HFD feeding on obesity and puberty in offspring were poorly known.The objective of the current study was to develop an animal model that can be used to study the effects of postnatal HFD feeding on obesity,puberty and their mutual interaction.Methods:We used three different groups in the current study.The dams and pups of one group were feeding on control chow during lactation and post-weaning respectively.This group was named as CNTRL.The dams and pups of the second group were feeding on HFD during lactation and post-weaning respectively.The pups of this group were named as HFD.Results:Our results showed that HFD feeding induces fat deposition and obesity in pups.Furthermore,HFD was more potent to increase body weight(BW)in male than female pups.Interestingly,female pups feeding on HFD were obese,underwent through precocious puberty and showed increased kisspeptin expression in the hypothalamus.Conclusion:Postnatal HFD feeding is capable to induce obesity and precocious puberty and is more potent to increase body weight in males compared to female pups.Thus we successfully developed a new model of postnatal HFD-induced obesity and puberty that has good face and construct validity of obesity and precocious puberty and it can be used to explore postnatal diet induced children obesity,puberty and their mutual interaction.PART II:Postnatal feeding with HFD induced precocious puberty independent of body weight,body fat and leptin signalingBackground:Puberty occurs when an individual has sufficient stored energy.Previous studies have reported that postnatal overfeeding,induced by small litter size or maternal high fat diet(HFD)feeding during gestation and lactation increases body weight(BW),body fat,plasma leptin levels and induces precocious puberty.The role of BW,body fat and leptin siganling in postnatal HFD-induced precocious puberty is poorly understood.In this study,we investigated the role of BW,body fat and leptin signaling in HFD-induced precocious puberty.Methods:Total five mice groups were used in the current experiment.The dams and pups of one group were feeding on control diet during lactation and post-weaning respectively.The number of pups per litter was 6 and the group was named as CNTRL.The rest of the three groups were feeding on HFD but differed in litter size or time to start feeding on HFD.The dams were feeding on control diet during lactation whereas the pups start to feed on HFD post-weaning.The number of pups per litter was 6 and the group was names as HFD A.The dams and pups of the other group were feeding on HFD during lactation and post-weaning respectively.The number of pups per litter was 11 and the group was named as HFD B.The fourth group was similar to HFD B,however the number of pups per litter was 6,this group was named as HFD C.Different litter size and time to start feeding on HFD was used to produce pups with different BW and body fat before puberty.To investigate the role of HFD feeding during neonatal stage(first week of lactation),dams were exposed to HFD during first week of lactation and transferred to control chow thereafter.The pups were also feeding on control chow post-weaning.The number of pups per litter was 6 and the group was named as HFD D.Body weight,body fat and plasma hormones levels were checked at different time points.Results:Our results showed that postnatal HFD feeding increases BW and body fat and induces adipocytes hyperplasia and precocious puberty.HFD C were significantly heavier at postnatal day 24(P24)compared to CNTRL,HFD A and HFD B;however,the BW of CNTRL,HFD A and HFD B were comparable.Furthermore,BW of all the HFD groups was significantly higher compared to CNTRL at P-28;however the BW of HFD A and HFD B were lower than HFD C.Interestingly,regardless of different BW at P-24 and P-28,all the HFD groups showed earlier puberty onset compared to CNTRL.Likewise body fat deposition in all the HFD groups were significantly higher compared to CNTRL;however fat deposition in HFD groups were significantly different from one another with highest in HFD C and lowest in HFD A.Furthermore,adipocytes size was significantly large in HFD C compared to CNTRL,HFD A and HFD B;however adipocytes size was comparable among CNTRL,HFD A and HFD B.Regardless of different body fat deposition and adipocytes size,all the HFD groups showed earlier puberty compared to CNTRL.Next we measured plasma leptin levels and found that plasma leptin levels were comparable among all the groups,however,HFD C showed elevated but non-significant plasma leptin.Regardless of similar leptin levels compared to CNTRL,all the HFD groups showed earlier puberty onset.Similarly,plasma LH,FSH and estradiol(E2)levels were also comparable in all the groups except HFD A that showed elevated plasma LH and FSH levels.Plasma leptin in HFD D mouse pups at P-7 was similar to CNTRL.Furthermore,HFD D mouse pups were significantly heavier than CNTRL at P-7.At P-24 and P-28,HFD D showed lower BW compared to HFD C;however the BW of HFD D were comparable with CNTRL.Regardless of different BW,HFD D showed earlier puberty similar to other HFD groups.Conclusion:Our results collectively suggest that postnatal HFD feeding induces precocious puberty independent of BW,body fat and plasma leptin levels.Although,we have not checked but our results suggest that postnatal HFD feeding makes some permanent changes in neuronal circuits in the hypothalamus that mediates postnatal HFD-induced precocious puberty;however;further studies are required to prove it.PART III:Postnatal high fat diet feeding impairs hypothalamic POMC and AGRP neurocircuitry and metabolism in C57/BL6 mouse pupsBackground:Childhood obesity increases the risk for adult stage obesity and related metabolic complications.Overnutrition during early developmental stages permanently programs energy homeostasis that supports metabolic complications in adult stages.However,postnatal high fat diet(HFD)-induced altered hypothalamic circuitry and its role to support HFD-induced adult stage metabolic abnormalities,remain unexplored.Methods:Seven groups were used in the current experiment.The dams and pups of one group were feeding on control chow during lactation and post-weaning respectively.The group was considered as control and named as CNTRL.The dams and pups of another group were feeding on HFD during lactation and post-weaning respectively.This group was named as HFD.HFD of the HFD group was replaced by control chow at postnatal day 34(P34)and continued for next two months,the group was named as HC.The control pups(CNTRL group)were still feeding on control chow for next two months and the group was named as CC.To investigate the effect of postnatal HFD feeding on adult stage impaired metabolism in response to HFD feeding,we provided both CC and HC groups with HFD for next 10 weeks and the groups were named as CHH and HCH groups respectively.Control group was still feeding on control chow for next 10 weeks and the group was named as CCC group.Body weight,body fat,body length,food intake,total calories intake and POMC and AGRP expression were checked at P34(HFD and CNTRL group),at the age of 3 months(HC and CC groups)and at the age of 5.5 months(HCH,CCH,and CCC groups).The number of pups per litter during lactation was 7.Results:Our results showed that postnatal feeding with HFD up to P34,decreases POMC expression,accelerates body growth and induces obesity by increasing body weight,body fat deposition and adipocytes size.At the age of three months,both POMC and AGRP expression was increased,however body weight and total food and calories intake were comparable between the HC and CC groups.After 10 weeks feeding on HFD,various metabolic parameters were checked.HCH group showed reduced POMC and increased AGRP expression compared to CCH and CC group.However,the altered POMC and AGRP expression were significantly differ from CCH group but do not form CCC.Body growth,body weight,body fat and adipocytes size in CCH and HCH groups were significantly increased compared to CCC group;however these parameters were comparable between CCH and HCH groups.Average food and calories intake were also comparable between CCH and HCH groups.Paradoxically plasma leptin levels were reduced in CCH and HCH groups compared to CCC group;however plasma insulin levels were non-significantly increased in CCH and HCH groups compared to CCC group.Interestingly,plasma glucose levels were significantly increased in CCH and HCH groups compared to CCC group with more elevation in HCH group.Conclusion:Our results demonstrate that postnatal HFD-induced altered hypothalamic POMC and AGRP circuitry persist up to adult stage and exacerbate adult stage HFD-induced metabolic complications.Interestingly,this altered circuitry do not increases average calories intake and suggests that these exacerbated HFD induced adult stage metabolic complications are due to reduced metabolism,increased sensitivity to HFD or reduced behavioral activities;however further studies are required to investigate the aforementioned. |
PDF Full Text Request