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Division of Energy Balance and Obesity, Rowett Research Institute, Aberdeen Centre for Energy Regulation and Obesity, Bucksburn, Aberdeen AB21 9SB, Scotland
2To whom correspondence should be addressed. E-mail: zaa{at}rri.sari.ac.uk.
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ABSTRACT |
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10 d after weaning gained less weight than littermates fed a nonpurified (14 kJ/g) diet. Despite an initial hyperphagia following the change in diet, HE rats also consumed less energy. Although they exhibited reduced weight gain, HE rats were relatively obese; fat pad weights were elevated for all 4 dissected depots. HE-fed rats exhibited symptoms of developing metabolic syndrome with elevated plasma concentrations of glucose, triglycerides, nonesterified fatty acids, insulin, and leptin. In addition, leptin receptor gene expression in the hypothalamic arcuate nucleus (ARC) and ventromedial nucleus of HE rats was reduced. Consistent with the elevated serum leptin and other peripheral signals in HE rats, hypothalamic gene expression for the orexigenic neuropeptides, neuropeptide Y (ARC and dorsomedial nucleus), and agouti-related peptide (AgRP), was reduced. This reduction in orexigenic signaling and decline in energy intake is consistent with an apparent attempt to counter the further development of an obese state in rats consuming an energy-dense diet. The juvenile Sprague-Dawley rat has potential in the development of a model of childhood diet-induced obesity.
KEY WORDS: • leptin • ghrelin • neuropeptide Y • melanocortins • high-fat diet
The growing world-wide obesity epidemic (1,2) continues to increase the demand for effective treatment strategies. In particular, the need to develop safe and effective drug treatments that are based on a sound science foundation continues to power advances in our understanding of the mechanistic underpinnings of energy homeostasis and obesity in laboratory animal models (3). To date much of this work involved laboratory rodents carrying spontaneous or engineered genetic mutations that lead to obesity or wild-type animals that are subjected to manipulations leading to negative energy balance. This work identified genes that are critical to normal mammalian body weight regulation, some of which have subsequently been implicated as the causative genetic lesion in relatively small numbers of obese human subjects. For example, up to 6% of cases of severe early onset obesity carry mutations in the melanocortin-4 receptor gene (Mc4R),3 making this the most common known cause of monogenic human obesity (4,5). Nevertheless, it is generally recognized that most human obesity is polygenic and represents the interaction between multiple genes and environment, of which diet is a major component (3). Accordingly, rodent models of diet-induced obesity (DIO) are coming under increasing scrutiny.
The Sprague-Dawley rat has a number of attributes that make it an attractive model of DIO for mechanistic studies. Transfer of rats from a normal diet to a high-energy (HE) diet that is relatively high in fat and simple carbohydrates gives rise to obesity within the population. However, within any group, individuals have different body weight trajectories indicative of variation in relative susceptibility or resistance to weight gain (6–9). As for humans (10,11), the development of obesity on HE diets is not inevitable, raising the possibility of defining molecular diagnostics of susceptibility to obesity. A number of elegant studies (7,12) also demonstrated the differential effect of the HE diet and the liquid diet, Ensure, on the level of body weight that will be defended, providing an experimental route into these mechanisms.
A particularly worrying trend within the human obesity epidemic is the increasing prevalence of obesity and associated comorbidities in children and adolescents. Children have access to much the same diet as adults, namely one that is high in fat, calories, and sugar (2). This dietary regime undoubtedly contributes to the alarming rise in the prevalence of childhood obesity and there is a current need to develop animal models of this problem. Most studies of DIO in rodents have involved adult animals. The effect of such diets on juvenile animals is less well studied. So, we examined the consequences for body weight and composition, blood metabolites, and hormones and hypothalamic gene expression in juvenile Sprague-Dawley rats fed an HE diet not unlike the diet consumed by children and adolescents in the developed world (13). We tested the hypothesis that provision of an HE diet to juvenile rats will lead to the early development of obesity and characteristics of the metabolic syndrome. Furthermore, we examined whether the development of obesity, and associated comorbidities in juvenile rats, would result in perturbations to the energy balance regulatory circuits, including those in the hypothalamus.
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MATERIALS AND METHODS |
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Circulating hormones and metabolites. Serum leptin concentrations were measured using a commercially available rat-specific radioimmunoassay kit from Linco (Catalog No. RL-83K, Biogenesis). The sensitivity of the assay is reported at 0.5 µg/L, and the intra-assay CV was 1.7%. Plasma insulin was measured using radioimmunoassay (14) as described previously (9). Total immunoreactive ghrelin was measured using a commercially available rat-specific radioimmunoassay kit from Phoenix Pharmaceuticals (Catalog No. RK 031–31). The sensitivity of the assay is reported at 0.001 µg/L, and the intra-assay CV was 9.9%. Plasma glucose, nonesterified fatty acids (NEFAs), and triglyceride concentrations were determined using the fully automated KONE analyzer methods (15–17). The sensitivity of the assays was 0.34, 0.04, and 0.06 mmol/L, respectively. The intra-assay CVs were 0.35, 2.0, and 2.9%, respectively.
Hypothalamic gene expression. Hypothalamic gene expression for a number of energy balance related neuropeptides and receptors was quantified using in situ hybridization techniques, which are described in detail elsewhere (18). Riboprobes complementary to partial fragments of AgRP, pro-opiomelanocortin (POMC), cocaine- and amphetamine-regulated transcript, melanocortin-3 receptor gene (Mc3R), and Mc4R were generated from cloned cDNAs as previously described (19,20). Neuropeptide Y (NPY) riboprobes were generated using a partial rat cDNA sequence provided by Dr. S. Sabol. Riboprobes for suppressors of cytokine signaling-3 (mSOCS-3) and leptin receptor (OB-R, short form) were generated using a partial mouse and rat cDNA sequences, respectively (21,22). Ghrelin receptor (GHS-R) cDNA fragments were cloned from rat hypothalamic cDNA with 35 cycles of 94°C for 30 s, 60°C for 30 s, and 68°C for 1 min and then finally 1 cycle at 72°C for 10 min. The DNA fragments were ligated into PCR-script Amp cloning vector (Stratagene) and transformed into JM 109 cells (Promega). Automated sequencing was performed to verify the sequence of interest. The 449-bp fragment of rat GHS-R was amplified using primers 5'-GCGCTCTTCGTGGTGGGCATCT-3' and 5'-GTGGCGCGGCATTCGTTGGT-3' (GenBank NM032075). Briefly, forebrain sections were collected from the very caudal extent of the arcuate nucleus (ARC) through to the rostral extent of the paraventricular nucleus (PVN) onto 3 sets of 10 slides. The first 2 sets of slides spanned the full extent of the ARC, approximating –4.52 to –2.30 mm, relative to Bregma, according to the atlas of the rat brain (23). The third set of slides continued through to –1.40 mm relative to Bregma and included both rostral and caudal extents of the PVN. Sections were fixed, acetylated, and hybridized overnight at 58°C using 35S-labeled antisense riboprobes (1–1.5 x 1010 dpm/L). Slides were treated with RNase A to remove unhybridized probe and then desalted with a final high-stringency wash in 0.1X SSC at 60°C for 30 min. The slides were air dried and apposed to Hyperfilm ß-max (Amersham Pharmacia Biotech UK). Autoradiographic images were quantified using the Image-Pro Plus system (Media Cybernetics). This determined the intensity and area of the hybridization signal on the basis of set parameters; the integrated intensity was then computed using standard curves generated from 14C autoradiographic microscales (Amersham UK). Depending on the probe used, image analysis was performed on 5 to 6 sections spanning the ARC or 2 to 3 sections from the PVN.
Statistical analysis. Mean values are reported ± SEM and the probability value used for statistical significance was P < 0.05. ANOVA was used (24) for analysis of food intake and body weight repeated-measures. Mean daily body weight gain and energy intake were calculated for each individual for each week and group means were compared between treatment groups C and HE using t tests. The trends in these variables over time appeared relatively linear and were therefore analyzed by comparing mean linear trend coefficients (regression slopes). Linear regression slopes were calculated for each rat for each variable over each week and confidence intervals for the regression slopes were used to assess whether values changed over time. Comparison of the linear regression slopes using t tests was undertaken to assess the difference in the trends between groups (treatment x time interaction). Data were analyzed by simple linear regression with groups, using Genstat Release 4.2 Lawes Agricultural trust supplied by VSN International. All other data were analyzed by t test.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Although the HE diet evoked a short-duration hyperphagia, due possibly to the presentation of a novel palatable diet, it did not give rise to excessive weight gain in young male Sprague-Dawley rats; indeed, body weights were actually lower. However, the striking finding was that this diet manipulation did result in obesity and in the development of characteristics of the metabolic syndrome, as evidenced by adipose tissue weights and blood metabolites and hormones (increases in leptin, insulin, glucose, triglycerides, and NEFAs). The lower body weight and increasing obesity may partially explain the decline in energy intake of the HE rats toward the end of the experiment. This model of underweight obesity may find parallels in observations of short stature and obesity in children (26). The observed changes in blood variables in the current study are typical of the metabolic profile observed in mice and rats following exposure to an HF diet that elevates both body adiposity and body weight (25,27,28). These adiposity-related signals were accompanied by changes in energy balance circuits that generally reflected the state of positive energy balance and an attempt to counter this.
The precise response of rats to HE diets may be dependent upon a variety of factors including diet composition and consistency. Thus, even the 1 broadly comparable study with the Sprague-Dawley rat using similarly aged animals (29) produced different results. The earlier study provided the base diet in powdered form and the HE diet presumably as a paste. Surprisingly, in contrast to the present study and our consistent observations with older rats [see for example (9)], they observed no hyperphagia with the HE diet. Furthermore, body weight trajectories were similar for the first 4 wk, after which body weight gain in rats fed the HE diet increased above that of rats fed the control diet, in marked contrast to the effects observed here. However, despite this, there were no differences in plasma insulin concentrations between rats in the 2 diet groups (29). Feeding an HE diet to adult rats for periods of up to 14 wk results in obesity but, despite hyperinsulinemia and hyperleptinemia, rats are normoglycemic (7,9). The evidence of developing hyperglycemia in the juvenile rats from the current study highlights another potentially important characteristic of the model, namely the development of diet-induced metabolic syndrome in early life. This model may be valuable for mechanistic investigation, and the current manuscript provides an initial characterization of this juvenile obesity model.
Various degrees of leptin insensitivity or "resistance" are a characteristic of many different rodent models of DIO (12,25,30–33). Both physiological and imposed manipulations of circulating leptin concentrations can affect the mRNA expression of the leptin receptor in the hypothalamus (e.g., 34,35). Transduction of the leptin signal via the hypothalamic receptor involves phosphorylation of Jak2 tyrosine kinase and activation of the transcription factor, STAT3 (signal transducer and activator of transcription). Once activated, STAT3 regulates the transcription of leptin-responsive target genes including SOCS3 [suppressor of cytokine signaling (36)], which suppresses receptor signaling by inhibiting the phosphorylation of STAT3. Consequently, SOCS3 has been identified as a potential mediator of central leptin resistance (37). In the juvenile rat fed the HE diet, although chronic high leptin levels in the circulation reach hypothalamic receptor fields and cause downregulation of receptor mRNA in both the ARC and the VMH, there was no effect of diet or hyperleptinemia on SOCS3 gene expression in the ARC. This suggests that SOCS3 is constitutively expressed irrespective of diet. This contrasts with the regulation of SOCS3 mRNA in circumstances of acute hypoleptinemia such as food deprivation (38). A previous study of DIO in mice fed an HF diet also reported no effect on SOCS3 mRNA levels (27), although there was no effect of diet on leptin levels either, in contrast to the present study.
If hyperleptinemia in HE rats is consistent with leptin being "a molecular signal of energy abundance" (39), then the nature of the signal conveyed by ghrelin in the current study is uncertain, because there is no evidence of a negative correlation with body fat (40,41), although this relationship might not be apparent in animals with unrestricted access to feed. Ghrelin levels were similar to those reported from inbred strains of DIO-susceptible and DIO-resistant Sprague-Dawley rats, where a 10-d HE diet was also without effect on plasma ghrelin (42).
In the present study we measured levels of expression of key hypothalamic energy balance genes in juvenile rats that consumed the HE diet for 5 wk. There are a number of studies of DIO in adult Sprague-Dawley rats (43–45) where gene expression has been examined in the context of subpopulations of rats that are relatively resistant or susceptible to obesity on an HE or HF diet, or which had been selectively bred toward these extremes. However, we are not aware of gene expression data for outbred juvenile rats receiving a similar dietary manipulation. In juvenile Sprague-Dawley rats, obesity in the face of reduced overall weight gain was associated with decreases in mRNA levels for the orexigenic neuropeptides, NPY and AgRP, in the ARC. The ARC probably constitutes the major site of leptin and other hormonal and metabolic feedback to the hypothalamus, and reduced expression of orexigenic peptides in this nucleus is consistent with published data in murine DIO models; C57BL/6J mice fed a HF diet for 8 or 26 wk had reduced NPY gene expression in the ARC (46), whereas a transient reduction in AgRP mRNA has been reported in the same mouse strain (27). These changes could represent a compensatory response to counteract the state of positive energy balance by suppressing food intake and increasing energy expenditure. A similar interpretation has been invoked from juvenile mouse studies where induction of POMC gene expression on an HF diet has been proposed to be a defense mechanism (27). However, the anorexigenic neuropeptide systems examined in the present study were unaffected by the HE diet. We also observed a reduction in NPY gene expression in the DMH, in contrast to longer term (6 mo) DIO trials in C57BL/6J mice, where NPY gene expression in the ARC was again reduced but mRNA levels in the DMH and VMH were increased (47). Interestingly, in long-term (6 mo) comparisons of extreme "resistant" and "susceptible" Sprague-Dawley rats, ARC NPY and AgRP mRNAs may be elevated in persistent obesity (45), although these differences may be present prior to diet manipulation in resistant and susceptible subpopulations (43).
Signaling through Mc4R has a major influence over energy homeostasis, whereas the involvement of Mc3R is less certain. Expression of Mc3R mRNA is reduced in the ARC of the juvenile DIO model and many of the physiological features of rats after HE feeding such as increased fat mass, reduced lean mass, hyperleptinemia, hyperinsulinemia, and hypophagia are consistent with the phenotype of the Mc3R knockout mouse (48,49). At present the significance of this finding is unclear, but is worthy of further investigation.
The obese but underweight juvenile rats feeding on the HE diet that is relatively high in both fat and sugar possess many of the characteristics of the early stages of diabetes and the metabolic syndrome. What was initially surprising was that these rats develop this phenotype despite reduced weight gain overall. The underlying causes of this phenomenon have still to be established, but the apparent deposition of adipose tissue at the expense of lean tissue indicates changes in nutrient partitioning. A decrease in dietary protein from 20 to 15% (in a diet where fat content is constant) increases food intake in growing Sprague-Dawley rats (50), presumably to meet protein demands. However, with the HE diet, excess energy intake may limit the ability of the rat to meet its protein requirement for normal lean tissue growth by increasing food intake. The body weight gain trajectories and energy intakes exhibited by the juvenile Sprague-Dawley rats are consistent with this scenario, making this an interesting model to study from a metabolic physiology perspective.
Juvenile Sprague-Dawley rats are profoundly affected by the HE diet. This diet leads to early development of obesity and metabolic syndrome, apparently through an inability to cope with the energy density of the diet. The macronutrient proportions in the diet are similar to those consumed by children in the western world. Considering the escalation of childhood obesity in developed countries, the juvenile Sprague-Dawley rat could be an important model in which to study the mechanistic underpinning of juvenile diet-induced obesity.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: AgRP, agouti related peptide; ARC, arcuate nucleus; C, controls; DIO, diet-induced obesity; DMH, dorsomedial hypothalamus; GHS-R, ghrelin receptor; HE, high energy; HF, high fat; IBAT, interscapular brown adipose tissue; Mc3R, melanocortin-3 receptor; Mc4R, melanocortin-4 receptor; NEFA, nonesterified fatty acid; NPY, neuropeptide Y; OB-R, leptin receptor; POMC, pro-opiomelanocortin; PVN, paraventricular nucleus; SOCS3 suppressors of cytokine signaling-3; STAT3, signal transducer and activator of transcription-3; VMH, ventromedial hypothalamus; WAT, white adipose tissue.
Manuscript received 5 November 2003. Initial review completed 3 January 2004. Revision accepted 4 March 2004.
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