Postnatal feeding with high-fat diet induces obesity and precocious puberty in C57BL/6J mouse pups: a novel model of obesity and puberty

Abstract

Childhood obesity and obesity-related metabolic complications are induced by a high-fat postnatal diet. The lack of a suitable animal model, however, remains a considerable challenge in obesity studies. In the current study, we provided high-fat diet (HFD) to dams during lactation and to pups after weaning. We also developed a novel model of C57BL/6J mouse pups with HFD-induced postnatal obesity. Results showed that feeding with HFD induces fat deposition and obesity in pups. Furthermore, HFD more potently increased the body weight (BW) of male than female pups. HFD-fed female pups were obese, underwent precocious puberty, and showed increased kisspeptin expression in the hypothalamus. However, parental obesity and precocious puberty exerted no synergistic effects on the HFD-induced postnatal weight gain and puberty onset of the pups. Interestingly, some HFD-fed litters with normal BW also exhibited precocious puberty. This finding suggested that diet composition but not BW triggers puberty onset. Our model suggests good construction validity of obesity and precocious puberty. Furthermore, our model can also be used to explore the mutual interactions between diet–induced postnatal childhood obesity and puberty.

Keywords

postnatal HFD feeding / obesity / kisspeptin / HPG axis / precocious puberty

Introduction

Obesity, which is triggered by diet and lifestyle changes, is becoming pandemic [,]. Obesity is linked with various complications, such as diabetes, cardiovascular problems, several cancer types, osteoarthritis, metabolic disorders, and reproductive problems (for a review, see Ref.). Obesity interrupts the hormonal profile that affects reproductive functions [–], including puberty []. In this regard, our previous study reported a positive correlation among fatness, overweightness, and obesity with precocious puberty or early sexual maturation in females [].

Adult animal models have been developed [,] for exploring the underlying pathology of metabolic complications in obesity, including in high-fat diet (HFD)-induced obesity. No suitable animal model, particularly in rodents, represents HFD-induced postnatal obesity in children with precocious puberty. Although researchers have developed mouse pup models with HFD-induced obesity and precocious puberty, obesity was not induced in the pups until puberty onset [,]. The lack of a suitable animal model remains a considerable challenge in the exploration of HFD-induced postnatal childhood obesity and precocious puberty. Thus, the development of a prepubescent obese animal model is necessary to further explore HFD-induced postnatal childhood obesity, precocious puberty, and their mutual interactions.

HFD is a typical tool for causing metabolic imbalance in various mouse strains to induce adult-stage obesity and obesity-related complications []. Similarly, HFD intake during the peri- and postnatal periods affect metabolism and behavior in mouse pups [–]. Given that nutritional and de novo fats are present in breast milk, its fatty acid composition is affected by nutritional fats [–]. Furthermore, imbalanced breast milk composition induces metabolic complications in pups []. Interestingly, feeding with HFD during lactation changes the composition of fatty acids and increases the content of long-chain fatty acids (LFAs) in the breast milk of both lean and obese dams, including C57BL/6J dams [,–]. LFAs are implicated in obesity [–]. Feeding dams with HFD also causes hyperphagy in pups [,]. Based on the above findings, we hypothesized that feeding HFD to lactating dams and to weaned pups will collectively induce obesity and precocious puberty in pups.

Materials and methods

Animals and diets

C57BL/6J mice were used in the current study. Mice were housed in the animal facility of Zhejiang University under the standard conditions for air, humidity, and temperature on a 12 h light:12 h dark cycle (lights on at 6:00 A.M.). The animals had free access to food and water. Animals were handled in accordance with the rules of Animal Care and Use Committee of Zhejiang University. At the age of 14 weeks, male and female mice were paired for breeding. Two diets were used: HFD 60% fat (HFD, Research Diets Inc., New Brunswick, New Jersey, USA) and control chow (12% fat).

Experimental design

HFD feeding increases LFAs in the breast milk of dams [] and induces hyperphagy in pups [,]. As hyperphagy and LFAs are involved in obesity, HFD might be a suitable tool to induce obesity in pups. Therefore, we provided HFD to dams during lactation and to pups after weaning. HFD-induced maternal obesity and precocious puberty are two possibly important factors that synergistically contribute to HFD-induced postnatal obesity and precocious puberty in pups. Therefore, another group of obese dams that underwent precocious puberty was fed with HFD before, during, and after pregnancy. Three groups of pups were set up as follows: group 1, the chow-chow-chow-chow group (C-C-C-C), was designated as control [dams n = 3, pups (male n = 17, female= 11)]; group 2, the chow-chow-HFD-HFD group (C-C-H-H), was designated as obese [dams n = 3, pups (male n = 17, female n = 17)]; and group 3, the HFD-HFD-HFD-HFD group (H-H-H-H). The dams of H-H-H-H pups were already obese and underwent HFD-induced precocious puberty (dams n = 3, female pups n = 8). The C-C-C-C and C-C-H-H groups were used to compare the effects of HFD feeding on weight gain and puberty onset, whereas the H-H-H-H group was used to study the synergistic effects of parental obesity and precocious puberty on HFD-induced weight gain and precocious puberty in pups. We used two different methods to produce obese pups. In the first method, dams were fed control chow (12% fat) before and during pregnancy. During lactation, dams were fed with HFD (60% fat). In the second method, the dams were already obese and had undergone precocious puberty via HFD. These dams were fed with HFD before, during, and after pregnancy. Obese pups that were produced by the first and second methods were assigned as the C-C-H-H group and H-H-H-H group, respectively. Groups C-C-H-H and H-H-H-H pups were fed with HFD after weaning at P-21. Dams were fed with control chow food before, during, and after pregnancy. The pups born from these dams were assigned as the C-C-C-C group. Group C-C-C-C pups were fed with control chow during weaning. There were 6 pups per litter. The experimental design is summarized in Fig. 1.

Weight measurement and observation of vaginal canalization (VC)

Weight gain and VC were used as markers of obesity and puberty onset, respectively. Pups were regularly checked for weight gain from postnatal day 16 (P-16) to P-40. In this experiment, we selected male pups at P-19 and P-24 to study obesity. We selected female pups to study puberty. Given that obese female pups reached puberty at approximately P-28 and control pups at approximately P-33, we selected the weight of female pups at P-28 and P-33 for obese and control pups, respectively.

Tissue collection

The animals (control n = 4, HFD n = 4) were anesthetized with isoflurane. After sedation, the chest was opened and 15 ml 4% paraformaldehyde (PFA) solution in phosphate-buffered saline (PBS) was administered through the heart for tissue fixation. After perfusion, gonadal white adipose tissue (WAT) and brains were collected from male and female pups, respectively. The collected gonadal WAT weight weighed to determine fat deposition and obesity, whereas brains were used for the immunohistochemistry (IHC) analysis of kisspeptin.

Immunohistochemistry

Mice were deeply anesthetized and transcardially perfused with 4% PFA in PBS. Brains were extracted and postfixed in 4% PFA overnight and then transferred to 30% sucrose in PBS. After the brains were saturated (36 h), a freezing microtome (CM30503, Leica) was used to cut coronal brain sections at 30 mm. Sections were processed as free-floating sections. After blocking in PBS that contained 100% normal donkey serum (Jackson Immuno Research 017-000-121) and 0.2% Triton X-100 (Sigma-Aldrich) for 2 h at room temperature, tissue sections were incubated in the blocking solution with primary antibody against kisspeptin (1:50; Santa Cruz Biotechnology sc-18134), overnight at 4 °C. Tissue sections were washed with PBS (10 min, thrice) and incubated with the appropriate secondary antibody Alexa Fluor 488 donkey anti-goat IgG (1:1000; Thermo Fisher Scientific A-A-11055) for 1 h at room temperature. After washing with PBS thrice, sections were mounted on glass slides with ProLong® Gold Antifade Reagent (Thermo Fisher Scientific P36931) for fluorescent imaging. Images were captured using a Nikon A1 laser-scanning confocal microscope under fixed settings. Cell numbers were analyzed by MetaMorph (Molecular Devices) with a fixed set of parameters.

Statistical analyses

The data were analyzed as mean±standard deviation. Student’s unpaired t-test, one way ANOVA, and two-way ANOVA were used for different comparisons. P value less than 0.05 (P<0.05) was considered significantly different. Graph Pad Prism version 5 (Software Inc., San Diego, CA, USA) was used for data analysis.

Results

HFD feeding increases body weight (BW) in mice pups

HFD feeding induces obesity in adult mice [,30,]. To determine whether postnatal HFD feeding induces obesity in mice pups, we provided HFD to dams during lactation and to pups after weaning at P-21. The weights of the control and obese pups are shown in Table 1. Unpaired t-test analysis showed that the weights of HFD-fed and control pups were significantly different (P<0.0001 for P-19, P<0.0001 for P-24). Our present results are the first to demonstrate that feeding lactating dams and weaned pups with HFD successfully induces obesity before puberty onset in C57BL/6J pups. The results are shown in Fig. 2.

HFD more potently increases BW in male than female pups

Male mice are naturally heavier than females. Consistent with previously reported results [,], male pups in the current study were heavier than females at P-40. Then, we determined whether HFD feeding equally increases BW in both sexes. We compared the weights of HFD male pups with those of HFD female pups and the weights of control male pups with those of control female pups at P-40. We also compared the percent increase in the BW of HFD male pups with those of control male pups and the weights of HFD female pups with those of control female pups. Our results showed that at P-40, HFD male pups (n = 9) were 24.37% heavier than control male pups (n = 9), whereas HFD female pups (n = 9) were 19.63% heavier than control female pups (n = 9). Similarly, HFD male pups were 27.25% heavier than HFD female pups, whereas control male pups were 22.30% heavier than control female pups. The weight and different comparisons between the groups are shown in Table 2 and Fig. 3, respectively. Interestingly, the BWs of the male and female pups of the same group at P-19 and P-24 were not significantly different (Table 1 and Fig. 2). The BWs of the two sexes, however, were significantly different at P-40 (Fig. 3). Our data demonstrated that HFD more potently increases BW in male pups than in female pups.

HFD feeding increases the deposition of gonadal and subcutaneous WAT

Increased intra-abdominal/visceral fat is linked with various metabolic complications, including obesity [–]. In the present study, we utilized gonadal and subcutaneous WAT deposition as a marker of obesity. Our results showed that WAT deposition significantly (P-19 P = 0.0036, and P-24 P = 0.0001) increased (66.66% in P-19 and 284% in P-24) in HFD-fed pups compared with that in the control. The results are shown in Fig. 4. Moreover, as clearly seen from the figure, WAT deposition increases with time in HFD-fed, whereas WAT deposition remains nearly constant in the control.

HFD feeding induces precocious puberty in female pups

Although HFD feeding advanced VC in female C57BL/6J mouse pups, the pups were not obese []. To induce precocious puberty with obesity, we provided HFD to dams during lactation and to pups after weaning. Our results showed that HFD feeding induces precocious puberty (six days earlier P = 0.0001) and obesity (P = 0.0001) in female pups. Although various studies have induced early VC by feeding pups with HFD after weaning at P-21, the pups were not obese before or at puberty onset [,]. Therefore, we developed a novel model of HFD-induced postnatal obesity with precocious puberty. The results are shown in Fig. 5.

HFD feeding increases kisspeptin expression in female pups

Hypothalamic kisspeptin is the main factor that regulates puberty onset via the stimulation of hypothalamic pituitary gonadal (HPG) axis []. We performed IHC to determine the relationship between postnatal HFD-induced precocious puberty and hypothalamic kisspeptin expression. IHC results showed significantly increased kisspeptin expression in the hypothalamic arcuate nucleus (ARC) of HFD-fed female pups. Our results suggested that postnatal HFD feeding increases kisspeptin expression that stimulates the HPG axis to induce precocious puberty in female pups. The results are shown in Fig. 6.

HFD-induced parental obesity and precocious puberty exhibit no synergistic effects on obesity and precocious puberty in pups

To determine whether HFD-induced parental obesity and precocious puberty exhibit synergistic effects on obesity and puberty onset in pups, we compared the obesity and puberty indices of C-C-H-H (n = 9) and H-H-H-H (n = 8) female pups. We found no difference in the BW and day of VC between the two groups. Our results are the first to demonstrate that HFD-induced parental obesity and precocious puberty exert no synergistic effects on HFD-induced obesity and puberty onset in female pups. Parents (male and female) were from the same litters. The results are shown in Fig. 7.

Diet composition but not BW affects puberty onset

We found that regardless of age, pups from the control and obese groups underwent puberty at the BW of ≈14.5 g. Paradoxically, three HD-fed litters had lower average BW (11.01 g) than obese (14.52 g) and control (14.61 g) pups at the day of VC. We designated these pups as C-C-H-H-L (HFD with low BW). Moreover, regardless of low BW, the pups still underwent precocious puberty (VC) at approximately P-28. The weight and statistical analysis are shown in Table 3 and Fig. 8, respectively. These results suggested that under normal physiological conditions, puberty onset occurs at a specific weight and that HFD can also initiate puberty onset by stimulating HPG axis at low BW. Although the C-C-H-H-L females have significantly lower BW than C-C-H-H (HFD obese) and C-C-C-C (control) groups at the day of VC, their early onset of puberty is more similar to that of the C-C-H-H group than that of the C-C-C-C group. Our results suggested that the diet composition, not BW/fat, is the factor that triggers puberty onset and early VC during HFD feeding.

Discussion

In the current study, we found that feeding lactating C57BL/6J mouse dams with HFD induces obesity in pups. The energy content of the diet affects BW [,]. Consistent with the above statement, previous studies have reported that both HFD-fed (60% fat) male and female CD-1 adult mice became obese [,]. Paradoxically, although the mice consumed comparable amounts of energy when fed with either HFD or control chow, HFD-fed mice became obese []. This energy paradox can be explained by the fact that HFD exhibits high-energy proficiency [] and induces hypothalamic inflammation (for reviews, see Refs. and ), thus encouraging weight gain. Additionally, the composition of fat consumed early in life is a possible risk factor for childhood weight gain and obesity []. Furthermore, Saben et al. found high levels of LFAs in the breast milk of HFD-fed dams []. LFAs are implicated in obesity [–,]. Feeding lactating dams with HFD also increases the volume of breast milk consumed by their pups [,]. Based on the above results, we speculate that increased LFAs in dam breast milk and hyperphagy in pups resulted in the observed obesity in our pups. Furthermore, gender and dietary energy efficacy affect BW [–]. In the present study, obese male pups were heavier than obese female pups of the same litter at P-40. Consistent with our results, obese CD-1 adult male mice (24 g) [] were 7 g heavier than obese CD-1 adult female mice of the same age (17 g) []. In the above studies, adult CD-1 mice (age six weeks) were exposed to HFD (60% fat) for 12 weeks. The above paradoxical results suggested the differential response of mouse sexes to HFD feeding. Furthermore, sex differences in obesity onset exist in humans and other animal models [3,,]. Obesity is more prevalent in women than in men []. Unlike humans, female mice from different strains are less sensitive to HFD-induced obesity and obesity-related metabolic complications [,]. In the present study, obese HFD male pups were not significantly heavier than obese HFD female pups at P-19 and P-24 (before puberty) but become significantly heavier at P-40 (after puberty). Although validating the mechanism of sex-associated metabolic response to HFD is difficult, hormones, such as testosterone and estrogen, that are involved in puberty and reproduction may play important roles in obesity [3,,,]. Further studies are thus required to unveil the exact mechanism of sex-associated obesity.

Similarly, fat deposition is a principal outcome of HFD [,]. Mammals have two primary types of fats: brown adipose tissue and WAT. WAT is the main depot of energy storage and secretes various hormones and cytokines that regulate metabolism and insulin actions [–]. Obesity is caused by excessive WAT accumulation. We found that WAT deposition significantly increased (66.66% in P-19 and 284% in P-24) in obese HFD pups. Our results are consistent with those of a previous study that reported that HFD feeding increases WAT mass in CD-1 adult mice []. Our results suggest that HFD has the potential to trigger WAT deposition, thus inducing obesity both in adults and pups.

In the present study, obese HFD-fed female pups showed advanced VC. Similarly, although Brill and Moenter found advanced VC in HFD-fed C57BL/6J female pups, the pups were not obese []. One of the possible explanations of the above paradoxical results is that Brill and Moenter [] exposed pups to HFD (45% from fat) during weaning, whereas we exposed dams to HFD (60% from fat) during lactation and pups after weaning. The high percentage of fat in our diet (60%) and the long exposure (lactation and after weaning) of pups to HFD likely induced obesity in our pups. Thus, we developed a novel animal model of postnatal HFD-induced obesity and early canalization (precocious puberty) in C57BL/6J pups. Various endocrine and neuroendocrine factors regulate reproduction in which, some are responsible for the stimulation or restimulation of the HPG axis during puberty onset [–,]. Kisspeptin is an essential neuroendocrine stimulator of sexual maturation; the inactivating mutation of kisspeptin and its receptor prevents puberty onset, whereas the activating mutation of kisspeptin induces precocious puberty [–]. Kisspeptin is the afferent stimulator of GnRH expression [,]. GnRH triggers luteinizing hormone/follicle-stimulating hormone secretion from the pituitary gland [] that in turn regulates gametogenesis and steroidogenesis in the gonads []. In the current study, we found that kisspeptin expression significantly increased in ARC. More importantly, the reduced sensitivity of hypothalamic kisspeptin to the steroid inhibitory feedback is a hypothetical mechanism for the stimulation of HPG axis during puberty onset [,]. Additionally, obesity is linked with elevated androgen levels [–] and VC indicates increasing estradiol levels. Androgens are involved in decreased hypothalamic sensitivity to steroid inhibitory feedback in animal models [,], as well as hyperandrogenemic disorders in adults [,]. Elevated androgens also act as precursors for estrogens that advance VC in rats []. Based on the above findings, we posit that HFD-induced obesity induces the early production of ovarian androgens. Then, androgens decrease hypothalamic sensitization to steroid negative feedback during puberty transition, increase kisspeptin expression, and thus provide the adult profile of GnRH surge. Although we cannot exclude the importance of estrogens in advancing VC, the blocking of early VC by flutamide, an androgen-receptor blocker, directs the mechanism of androgen-dependent receptor signaling [].

The stage of reproductive development is related with BW but not with body fat []. In the current study, some HFD-fed litters exhibited equal to or lower BW than the control, as well as advanced VC that is similar to HFD-obese female pups. Bronson [] also reported that BW is a good predictor for the stages of reproductive development. Nevertheless, BW is not critical for puberty onset because VC is more advanced in females that were exposed to male mice or male pheromones than in isolated females. Furthermore, bisphenol A treatment induces precocious puberty in female mice at lower BW than the control []. Additionally, in our previous study, both obese and lean females showed central precocious puberty []. Our results and previous reports collectively suggest that diet composition, not obesity/BW, induces precocious puberty by advancing VC during HFD feeding. We also studied the synergistic effects of HFD-induced parental obesity and precocious puberty on obesity and puberty onset in pups. We found that parental obesity and early VC exert no synergistic effects on postnatal HFD-induced obesity and precocious puberty in pups.

In the current study, we introduced a novel animal model of postnatal HFD-induced obesity and early canalization (precocious puberty) in C57BL/6J pups. Our animal model fulfills the manifestation and construction validity of postnatal HFD-induced obesity and precocious puberty. Given that C57BL/6J mice can be used to represent a heterogeneous human population, the present experiment supports the use of this novel animal model for the detailed study of postnatal diet-induced childhood obesity, obesity-related metabolic complications, and precocious puberty.

References

[1] James PT, Leach R, Kalamara E, Shayeghi M. The worldwide obesity epidemic. Obes Res 2001; 9(S11): 228S–233S

[2] Malik VS, Willett WC, Hu FB. Global obesity: trends, risk factors and policy implications. Nat Rev Endocrinol 2013; 9(1): 13–27

[3] Mayes J, Watson G. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev 2004; 5(4): 197–216

[4] Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum Reprod Update 2003; 9(4): 359–372

[5] Robker RL. Evidence that obesity alters the quality of oocytes and embryos. Pathophysiology 2008; 15(2): 115–121

[6] Hussain MA, Abogresha NM, Hassan R, Tamany DA, Lotfy M. Effect of feeding a high-fat diet independently of caloric intake on reproductive function in diet-induced obese female rats. Arch Med Sci 2016; 12(4): 906–914

[7] Colmenares A, Gunczler P, Lanes R. Higher prevalence of obesity and overweight without an adverse metabolic profile in girls with central precocious puberty compared to girls with early puberty, regardless of GnRH analogue treatment. Int J Pediatr Endocrinol 2014; 2014(1): 1–7

[8] Dai YL, Fu JF, Liang L, Gong CX, Xiong F, Luo FH, Liu GL, Chen SK. Association between obesity and sexual maturation in Chinese children: a muticenter study. Int J Obes 2014; 38(10): 1312–1316

[9] Guyenet SJ, Schwartz MW. Regulation of food intake, energy balance, and body fat mass: implications for the pathogenesis and treatment of obesity. J Clin Endocrinol Metab 2012; 97(3): 745–755

[10] Tchernof A, Després JP. Pathophysiology of human visceral obesity: an update. Physiol Rev 2013; 93(1): 359–404

[11] Sánchez-Garrido MA, Castellano JM, Ruiz-Pino F, Garcia-Galiano D, Manfredi-Lozano M, Leon S, Romero-Ruiz A, Diéguez C, Pinilla L, Tena-Sempere M. Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges. Endocrinology 2013; 154(9): 3387–3400

[12] Brill DS, Moenter SM. Androgen receptor antagonism and an insulin sensitizer block the advancement of vaginal opening by high-fat diet in mice. Biol Reprod 2009; 81(6): 1093–1098

[13] West DB, Boozer CN, Moody DL, Atkinson RL. Dietary obesity in nine inbred mouse strains. Am J Physiol Regul Integr Comp Physiol 1992; 262(6): R1025–R1032

[14] Sullivan EL, Nousen EK, Chamlou KA. Maternal high fat diet consumption during the perinatal period programs offspring behavior. Physiol Behav 2014; 123: 236–242

[15] Borengasser SJ, Kang P, Faske J, Gomez-Acevedo H, Blackburn ML, Badger TM, Shankar K. High fat diet and in utero exposure to maternal obesity disrupts circadian rhythm and leads to metabolic programming of liver in rat offspring. PLoS One 2014; 9(1): e84209

[16] Benatti RO, Melo AM, Borges FO, Ignacio-Souza LM, Simino LAP, Milanski M, Velloso LA, Torsoni MA, Torsoni AS. Maternal high-fat diet consumption modulates hepatic lipid metabolism and microRNA-122 (miR-122) and microRNA-370 (miR-370) expression in offspring. Br J Nutr 2014; 111(12): 2112–2122

[17] Gorski JN, Dunn-Meynell AA, Hartman TG, Levin BE. Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance. Am J Physiol Regul Integr Comp Physiol 2006; 291(3): R768–R778

[18] Demmelmair H, Kuhn A, Dokoupil K, Hegele V, Sauerwald T, Koletzko B. Human lactation: oxidation and maternal transfer of dietary ¹³C-labelled a-linolenic acid into human milk. Isotopes Environ Health Stud 2016; 52(3): 270–280

[19] Neville MC, Picciano MF. Regulation of milk lipid secretion and composition. Annu Rev Nutr 1997; 17(1): 159–184

[20] Ohta T, Toriniwa Y, Ryumon N, Inaba N, Hirao T, Yamanaka S, Maeno T, Sakakibara W, Sumikawa M, Chiba K, Nakamura A, Miyajima K, Fatchiyah F, Yamada T.Maternal high-fat diet promotes onset of diabetes in rat offspring. Anim Sci J 2017; 88(1): 149–155

[21] Rolls BA, Gurr MI, Van Duijvenvoorde PM, Rolls BJ, Rowe EA. Lactation in lean and obese rats: effect of cafeteria feeding and of dietary obesity on milk composition. Physiol Behav 1986; 38(2): 185–190

[22] Saben JL, Bales ES, Jackman MR, Orlicky D, MacLean PS, McManaman JL. Maternal obesity reduces milk lipid production in lactating mice by inhibiting acetyl-CoA carboxylase and impairing fatty acid synthesis. PLoS One 2014; 9(5): e98066

[23] Wahlig JL, Bales ES, Jackman MR, Johnson GC, McManaman JL, MacLean PS. Impact of high-fat diet and obesity on energy balance and fuel utilization during the metabolic challenge of lactation. Obesity (Silver Spring) 2012; 20(1): 65–75

[24] Ge F, Walewski JL, Torghabeh MH, Lobdell H IV, Hu C, Zhou S, Dakin G, Pomp A, Bessler M, Schrope B, Ude-Welcome A, Inabnet WB, Feng T, Carras-Terzian E, Anglade D, Ebel FE, Berk PD. Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss. Obesity (Silver Spring) 2016; 24(1): 113–122

[25] Scaglioni S, Verduci E, Salvioni M, Bruzzese MG, Radaelli G, Zetterström R, Riva E, Agostoni C. Plasma long-chain fatty acids and the degree of obesity in Italian children. Acta Paediatr 2006; 95(8): 964–969

[26] Walewski JL, Ge F, Gagner M, Inabnet WB, Pomp A, Branch AD, Berk PD. Adipocyte accumulation of long-chain fatty acids in obesity is multifactorial, resulting from increased fatty acid uptake and decreased activity of genes involved in fat utilization. Obes Surg 2010; 20(1): 93–107

[27] Zhou SL, Kiang CL, Stump D, Bradbury M, Isola LM. Uptake of long chain free fatty acids is selectively up-regulated in adipocytes of Zucker rats with genetic obesity and non-insulin-dependent diabetes mellitus. J Biol Chem  1997; 272(13): 8830–8835

[28] Berk PD, Zhou SL, Bradbury M, Stump D, Kiang CL, Isola LM. Regulated membrane transport of free fatty acids in adipocytes: role in obesity and non-insulin dependent diabetes mellitus. Trans Am Clin Climatol Assoc 1997;108: 26–40

[29] Kojima S, Catavero C, Rinaman L. Maternal high-fat diet increases independent feeding in pre-weanling rat pups. Physiol Behav 2016; 157: 237–245

[30] Gao M, Ma Y, Liu D. High-fat diet-induced adiposity, adipose inflammation, hepatic steatosis and hyperinsulinemia in outbred CD-1 mice. PLoS One 2015; 10(3): e0119784

[31] Breslin WL, Strohacker K, Carpenter KC, Esposito L, McFarlin BK. Weight gain in response to high-fat feeding in CD-1 male mice. Lab Anim 2010; 44(3): 231–237

[32] Cnop M, Landchild MJ, Vidal J, Havel PJ, Knowles NG, Carr DR, Wang F, Hull RL, Boyko EJ, Retzlaff BM, Walden CE, Knopp RH, Kahn SE. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations. Distinct metabolic effects of two fat compartments. Diabetes 2002; 51(4):1005–1015

[33] Goodpaster BH, Leland Thaete F, Simoneau JA, Kelley DE. Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat. Diabetes 1997; 46(10): 1579–1585

[34] Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444(7121): 881–887

[35] Tena-Sempere M. Keeping puberty on time: novel signals and mechanisms involved. Curr Top Dev Biol 2013; 105: 299–329160;

[36] Vernarelli JA, Mitchell DC, Rolls BJ, Hartman TJ. Dietary energy density is associated with obesity and other biomarkers of chronic disease in US adults. Eur J Nutr 2015; 54(1): 59–65

[37] Crino M, Sacks G, Vandevijvere S, Swinburn B, Neal B. The influence on population weight gain and obesity of the macronutrient composition and energy density of the food supply. Curr Obes Rep 2015; 4(1): 1–10

[38] Iossa S, Lionetti L, Mollica MP, Crescenzo R, Botta M, Barletta A, Liverini G. Effect of high-fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats. Br J Nutr 2003; 90(5): 953–960

[39] Cai D, Liu T. Hypothalamic inflammation: a double-edged sword to nutritional diseases. Ann N Y Acad Sci 2011; 1243(1): E1–E39

[40] Cai D. Neuroinflammation and neurodegeneration in overnutrition-induced diseases. Trends Endocrinol Metab 2013; 24(1): 40–47

[41] Ailhaud G, Guesnet P. Fatty acid composition of fats is an early determinant of childhood obesity: a short review and an opinion. Obes Rev 2004; 5(1): 21–26

[42] Berk PD, Zhou S, Bradbury MW. Increased hepatocellular uptake of long chain fatty acids occurs by different mechanisms in fatty livers due to obesity or excess ethanol use, contributing to development of steatohepatitis in both settings. Trans Am Clin Climatol Assoc 2005; 116: 335–345

[43] Slavin JL. Dietary fiber and body weight. Nutrition 2005; 21(3): 411–418

[44] Noakes M, Keogh JB, Foster PR, Clifton PM. Effect of an energy-restricted, high-protein, low-fat diet relative to a conventional high-carbohydrate, low-fat diet on weight loss, body composition, nutritional status, and markers of cardiovascular health in obese women. Am J Clin Nutr 2005; 81(6): 1298–1306

[45] Mahgoub O, Lu CD, Early RJ. Effects of dietary energy density on feed intake, body weight gain and carcass chemical composition of Omani growing lambs. Small Rumin Res 2000; 37(1–2): 35–42

[46] Kanter R, Caballero B. Global gender disparities in obesity: a review. Adv Nutr 2012; 3(4): 491–498

[47] Garg N, Thakur S, Alex McMahan C, Adamo ML. High fat diet induced insulin resistance and glucose intolerance are gender-specific in IGF-1R heterozygous mice. Biochem Biophys Res Commun 2011; 413(3): 476–480

[48] Barron AM, Rosario ER, Elteriefi R, Pike CJ. Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer’s disease. PLoS One 2013; 8(10): e78554

[49] Wells JCK, Marphatia AA, Cole TJ, McCoy D. Associations of economic and gender inequality with global obesity prevalence: understanding the female excess. Soc Sci Med 2012; 75(3): 482–490

[50] Asarian L, Geary N. Sex differences in the physiology of eating. Am J Physiol Regul Integr Comp Physiol 2013; 305(11): R1215–R1267

[51] Woods SC, Seeley RJ, Rushing PA, D’Alessio D, Tso P. A controlled high-fat diet induces an obese syndrome in rats. J Nutr 2003; 133(4): 1081–1087

[52] Aldhahi W, Hamdy O. Adipokines, inflammation, and the endothelium in diabetes. Curr Diab Rep 2003; 3(4): 293–298

[53] Farmer SR. Transcriptional control of adipocyte formation. Cell Metab 2006; 4(4): 263–273

[54] Ronti T, Lupattelli G, Mannarino E. The endocrine function of adipose tissue: an update. Horumon To Rinsho 2006; 64(4): 355–365

[55] Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature 2006; 444(7121): 847–853

[56] Trayhurn P, Beattie JH. Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 2001; 60(03): 329–339

[57] Watanabe G, TerasawaE. In vivo release of luteinizing hormone releasing hormone increases with puberty in the female rhesus monkey. Endocrinology 1989; 125(1): 92–99

[58] Terasawa E, Guerriero KA, Plant TM. Kisspeptin and puberty in mammals. Adv Exp Med Biol 2013; 784: 253–273

[59] Apter D, Butzow TL, Laughlin GA, Yen SSC. Gonadotropin-releasing-hormone pulse-generator activity during pubertal transition in girls—pulsatile and diurnal patterns of circulating gonadotropins. J Clin Endocrinol Metab 1993; 76(4): 940–949

[60] Castellano JM, Tena-Sempere M. Metabolic control of female puberty: potential therapeutic targets. Expert Opin Ther Targets 2016; 20(10):1181–1193 

[61] Ullah R, Shen Y, Zhou YD, Huang K, Fu JF, Wahab F, Shahab M. Expression and actions of GnIH and its orthologs in vertebrates: current status and advanced knowledge. Neuropeptides 2016; 59: 9–20 

[62] d’Anglemont de Tassigny X, Fagg LA, Dixon JPC, Day K, Leitch HG, Hendrick AG, Zahn D, Franceschini I, Caraty A, Carlton MBL, Aparicio S, Colledge WH. Hypogonadotropic hypogonadism in mice lacking a functional Kiss1 gene. Proc Natl Acad Sci USA 2007; 104(25): 10714–10719

[63] Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MBL, Crowley WF Jr, Aparicio S, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med 2003; 349(17): 1614–1627

[64] de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA 2003; 100(19): 10972–10976

[65] Caraty A, Smith JT, Lomet D, Ben Said S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. Kisspeptin synchronizes preovulatory surges in cyclical ewes and causes ovulation in seasonally acyclic ewes. Endocrinology 2007; 148(11): 5258–5267

[66] Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: a potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA 2005; 102(6): 2129–2134

[67] Dhillo WS, Chaudhri OB, Patterson M, Thompson EL, Murphy KG, Badman MK, McGowan BM, Amber V, Patel S, Ghatei MA, Bloom SR. Kisspeptin-54 stimulates the hypothalamic-pituitary gonadal axis in human males. J Clin Endocrinol Metab 2005; 90(12): 6609–6615

[68] Matsui H, Takatsu Y, Kumano S, Matsumoto H, Ohtaki T. Peripheral administration of metastin induces marked gonadotropin release and ovulation in the rat. Biochem Biophys Res Commun 2004; 320(2): 383–388

[69] Schally AV, Arimura A, Kastin AJ, Matsuo H, Baba Y, Redding TW, Nair RMG, Debeljuk L, White WF. Gonadotropin-releasing hormone—one polypeptide regulates secretion of luteinizing and follicle-stimulating hormones. Science 1971; 173(4001): 1036–1038

[70] Themmen APN, Huhtaniemi IT. Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 2000; 21(5): 551–583

[71] Terasawa E, Fernandez DL. Neurobiological mechanisms of the onset of puberty in primates. Endocr Rev 2001; 22(1): 111–151

[72] Korhonen S, Hippeläinen M, Vanhala M, Heinonen S, Niskanen L. The androgenic sex hormone profile is an essential feature of metabolic syndrome in premenopausal women: a controlled community-based study. Fertil Steril 2003; 79(6): 1327–1334

[73] Barber TM, McCarthy MI, Wass JAH, Franks S. Obesity and polycystic ovary syndrome. Horumon To Rinsho 2006; 65(2): 137–145

[74] Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab 2006; 91(2): 492–497

[75] Pielecka J, Moenter SM. Effect of steroid milieu on gonadotropin-releasing hormone-1 neuron firing pattern and luteinizing hormone levels in male mice. Biol Reprod 2006; 74(5): 931–937

[76] Pielecka J, Quaynor SD, Moenter SM. Androgens increase gonadotropin-releasing hormone neuron firing activity in females and interfere with progesterone negative feedback. Endocrinology 2006; 147(3): 1474–1479

[77] Pastor CL, Griffin-Korf ML, Aloi JA, Evans WS, Marshall JC. Polycystic ovary syndrome: evidence for reduced sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 1998; 83(2): 582–590

[78] Eagleson CA, Gingrich MB, Pastor CL, Arora TK, Burt CM, Evans WS, Marshall JC. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J Clin Endocrinol Metab 2000; 85(11): 4047–4052

[79] Ramirez D, Sawyer CH. Advancement of puberty in the female rat by estrogen. Endocrinology 1965; 76(6): 1158–1168

[80] Bronson FH. Puberty in female mice is not associated with increases in either body fat or leptin. Endocrinology 2001; 142(11): 4758–4761

[81] Nah WH, Park MJ, Gye MC. Effects of early prepubertal exposure to bisphenol A on the onset of puberty, ovarian weights, and estrous cycle in female mice. Clin Exp Reprod Med 2011; 38(2): 75–81

[82] Fu JF, Liang JF, Zhou XL, Prasad HC, Jin JH, Dong GP, Rose SR. Impact of BMI on gonadorelin-stimulated LH peak in premenarcheal girls with idiopathic central precocious puberty. Obesity (Silver Spring) 2015; 23(3): 637–643

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