Human Molecular Genetics, 2001, Vol. 10, No. 14 1465-1473
© 2001 Oxford University Press
Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus
Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal, Quebec, H3T 1C5, Canada, 1Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada and 2Department of Embryology, Carnegie Institution of Washington, 115 West University Parkway, Baltimore, MD, USA
Received February 23, 2001; Revised and Accepted May 2, 2001.
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ABSTRACT |
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The bHLH-PAS transcription factor SIM1 is required for the development of the paraventricular nucleus (PVN) of the hypothalamus. Mice homozygous for a null allele of Sim1 (Sim1–/–) lack a PVN and die perinatally. In contrast, we show here that Sim1 heterozygous mice are viable but develop early-onset obesity, with increased linear growth, hyperinsulinemia and hyperleptinemia. Sim1+/– mice are hyperphagic but their energy expenditure is not decreased, distinguishing them from other mouse models of early-onset obesity such as deficiencies in leptin and melanocortin receptor 4. Quantitative histological comparison with normal littermates showed that the PVN of Sim1+/– mice contains on average 24% fewer cells without a selective loss of any identifiable major cell type. Since acquired lesions in the PVN also induce increased appetite without a decrease in energy expenditure, we propose that abnormalities of PVN development cause the obesity of Sim1+/– mice. Severe obesity was described recently in a patient with a balanced translocation disrupting SIM1. Pathways controlling the development of the PVN thus have the potential to cause obesity in both mice and humans.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Obesity results from an imbalance between energy intake and energy expenditure that leads to a pathologic accumulation of adipose tissue. An increase in energy intake and/or a decrease in energy expenditure can be documented in obese individuals (1). Classical lesion experiments have shown that discrete regions of the hypothalamus act as key regulators of these two processes (reviewed in 2–4). The relevance of these hypothalamic centers as regulators of energy balance has gained support from a great body of physiological studies (2–4).
Several lines of evidence indicate that the paraventricular nucleus (PVN) of the hypothalamus is a critical regulator of appetite. First, lesions selectively created in the PVN lead to hyperphagia and obesity (5–10). Secondly, microinjection of several orexigenic signals into the PVN stimulates feeding, whereas injection of anorexigenic signals suppresses feeding (11,12). Thirdly, the PVN receives axonal projections which have been associated with the regulation of appetite through the secretion of NPY and MSH (13–15). Electrophysiological studies have shown that individual neurons of the PVN are capable of detection and integration of these NPY and MSH signals (11). Fourthly, a number of key regulators of energy balance, including Crh (16), Tubby (17), Galanin (Gal) (18) and 5-HT-2c receptor (19), are expressed in the PVN. However, the physiological functions of these factors in the PVN remain to be clarified. Axonal projections of the PVN to preganglionic autonomic neurons located in the brainstem appear to mediate its effects on appetite (5,20).
SIM1, a transcription factor characterized by the presence of bHLH and PAS domains, is strongly expressed in the PVN during development and after birth (21). The PVN fails to develop in mice homozygous for a null allele of Sim1 (21). Analyses of mutant embryos have shown that SIM1 functions during PVN development by controlling the final stages of the differentiation of several neuronal cell types. Heterodimerization with ARNT2 is required for SIM1 function in the developing hypothalamus (22).
Whereas Sim1 homozygous mice (Sim1–/–) die perinatally, presumably from the PVN developmental defect, here we show that Sim1 heterozygous mice (Sim1+/–) survive and develop early-onset obesity with increased linear growth, hyperinsulinemia and hyperleptinemia. Sim1+/– mice are hyperphagic but their energy expenditures are not significantly decreased. Moreover, we show that the PVN of Sim1+/– mice is hypocellular. In view of the critical function of the PVN for the regulation of appetite, we propose that hypodevelopment of the PVN is responsible for the obesity of the Sim1+/– mice. Our study supports the hypothesis that SIM1 haploinsufficency causes the obesity of patients with rearrangements of chromosome region 6q16, which contains SIM1 (23–26).
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Mice heterozygous for a targeted null allele of Sim1 (21) are viable, fertile and grow normally until 4 weeks of age. However, after 4 weeks, increased weight gain was observed in both female and male heterozygotes (Fig. 1A and B), particularly during the phase of rapid growth between 4 and 12 weeks. We have recently confirmed that mice heterozygous for a different null allele of Sim1 have similar weight curves (unpublished data). The obesity of Sim1+/– mice is similar in severity to that of heterozygous melanocortin-receptor 4 (McR4)-deficient mice (27) or ob/ob (28) mice which lack leptin.
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After 4 weeks, greater naso-anal length (Fig. 1C and D) and increased body mass index (BMI) (Fig. 1E and F) were detectable in Sim1+/– mice, in comparison with control littermates. Moreover, at 8 and 24 weeks of age, the masses of white (WAT) and brown adipose tissue (BAT) deposits were increased in Sim1+/– compared with littermate controls (Fig. 2A–H). Histologically, the WAT adipocytes of Sim1+/– and Sim1+/+ were indistinguishable (Fig. 3A and B). In the absence of adipocyte hypertrophy, the WAT of heterozygous animals must therefore be hyperplastic in order to account for its increased abundance. BAT histology revealed increased adipocyte diameter in Sim1+/– mice (Fig. 3C and D), indicating that adipocyte hypertrophy contributes to the increased BAT content.
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0.05.
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Blood glucose and plasma insulin were analyzed in 8- and 24-week-old Sim1+/– and control mice. Although blood glucose levels of these animals were not different (Fig. 4A and B), plasma insulin levels of Sim1+/– mice were significantly increased at 24 weeks but not at 8 weeks (Fig. 4C and D). This finding suggests that older Sim1+/– animals maintain normal blood glucose levels by compensating with increased insulin levels.
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Leptin is a hormone produced by the adipocytes. An increase in the adipose mass results in an increased production of leptin which then feeds back in the hypothalamus and possibly in peripheral tissues to decrease food intake and increase energy expenditures (29). Sim1+/– mice at 24 weeks of age were found to have increased plasma leptin levels as compared with littermate controls (Fig. 4E and F). Increased plasma leptin levels were also found in 8-week-old female but not in male Sim1+/– mice (Fig. 4E and F). This increase in leptin is consistent with the increased adipose mass found in Sim1+/– mice.
In order to define the physiological basis of obesity in Sim1+/– mice, we compared their energy intake and expenditure with that of littermate controls. At 4–5 weeks of age, prior to the onset of obesity, the food intake of Sim1+/– mice was significantly increased (Fig. 5A). This hyperphagia was sustained, as 35-week-old Sim1+/– males and females ate 39 and 30% more than controls, respectively. Measurements at 4–5 weeks of age of weight loss after 3 days on an energy-restricted diet (30) (Fig. 5B) and of feeding efficiency (Fig. 5C) were comparable in Sim1+/– and control mice, suggesting a normal level of energy expenditure in the former. Of note, locomotor activity of 8-week-old Sim1+/– males was comparable with that of controls (Fig. 5D). At 8 weeks of age, we also observed that Sim1+/– females, but not the males, displayed a better maintenance of body temperature upon exposure to cold (Fig. 5E and F). The basis of this observation remains unclear but could represent different estrogen/progestogen status (31), regulation of vasoconstriction (32) or an adaptive response to the increased food intake in Sim1+/– mice. At 8 weeks of age, when Sim1+/– mice become obese, oxygen consumption was increased in Sim1+/– males (Fig. 5G and H). A similar observation was made in 20–23-week-old males. We suspect that this increased oxygen consumption is related to the increased body size of Sim1+/– mice. Measurements of cold-induced temperature and oxygen consumption are consistent with a normal or increased energy expenditure in Sim1+/– mice, indicating that a subnormal level of energy expenditure is not involved in the development of their obesity. We conclude that increased food intake, and not decreased energy expenditure, causes the obesity of Sim1+/– mice.
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Consistent with the absence of modification of visceral energy metabolism in Sim1+/– mice, we could not detect Sim1 expression in adult liver, pancreas, muscle, WAT or BAT using an RT–PCR approach (data not shown). In contrast, Sim1 and its dimerization partner Arnt2 are expressed in the PVN during its development and in adult life (21,22; and data not shown). Since lesions in the PVN also induce increased appetite without decrease of energy expenditure (8,10) and Sim1 is crucial for PVN differentiation (21), we hypothesized that Sim1+/– mice may have detectable changes in the PVN. Indeed, on simple visual inspection of histological sections, the PVN of 15/18 Sim1+/– mice showed a subtle decrease of cell density and/or anterior–posterior length when compared with littermate controls (Fig. 6A and B). In order to formally evaluate this difference, we performed a quantitative histological analysis. Nuclear profile counts were decreased by an average of 24% in the PVN of Sim1+/– mice (Fig. 6C). Moreover, the area occupied by the PVN (Fig. 6D) or by the nuclei within the PVN (Fig. 6E) was reduced in Sim1+/– mice. Nuclear profile counts in another hypothalamic center regulating energy balance, the ventromedial nucleus (VMN), were not significantly different between Sim1+/– mice and littermate controls (Fig. 6F). The hypocellularity is therefore specific to the PVN of Sim1+/– mice, strongly suggesting that a developmental defect involving the PVN underlies the obesity of Sim1+/– mice. Since a significant proportion of PVN cells are absent, we next assessed whether any of the major cell types of the PVN is selectively eliminated. Vasopressin (Avp), Oxytocin (Ox), Gal, Crh, Trh, 5HT-2cR and Tubby expressing cells were all present in the PVN of Sim1+/– mice (not shown), suggesting that its hypocellularity does not result from a selective ablation of a major PVN cell type but from a reduction of neuronal pools.
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DISCUSSION |
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Sim1 haploinsufficiency causes early-onset obesity, increased linear growth, hyperleptinemia and hyperinsulinemia in mice. Hyperphagia, with no reduction of energy expenditure, underlies this increased weight gain. A balanced translocation interrupting SIM1 was recently found in a 6-year-old child with a similar phenotype (23). Like Sim1+/– mice, this child has early-onset obesity, increased linear growth, and hyperphagia with no decrease of energy expenditure. It was unclear whether the translocation results in loss- or gain-of-function of SIM1 or of another gene located near the breakpoints. Our mouse model supports the hypothesis that SIM1 haploinsufficiency is responsible for the obesity in this child. The description of morbid obesity in children with chromosomal deletions in the 6q16 region, which contains SIM1, further strengthens this conclusion (24–26).
An absence of Sim1 abolishes the development of several major cell types of the PVN (21). Here we show that partial Sim1 deficiency results in hypodevelopment of the PVN. Although we cannot formally exclude the absence of specific cell types within the PVN of Sim1+/– mice, our cell count and marker analyses suggest instead a reduction of the neuronal pool. We propose that PVN hypocellularity causes the hyperphagia of mice and humans with SIM1 haploinsufficiency. The fact that a minimal number of PVN neurons is required for correct regulation of appetite was also suggested by lesion experiments (5–10). Our study provides genetic evidence of this relationship. Of note, hypocellularity of the arcuate nucleus (AN), a critical center for the regulation of energy balance, has been associated with obesity in mice with a loss of the transcription factor NHLH2 (33). Reducing the number of cells in hypothalamic centers therefore has the potential to cause obesity. Since the regulation of appetite appears sensitive to the number of PVN cells, it is plausible that a modest decrease of Sim1 activity may be associated with a milder degree of obesity in humans or mice.
In view of the relationship between hypocellularity of the PVN and hyperphagia, it will be important to test whether other genetic factors involved in PVN development such as Arnt2 (22), Brn2 (34,35) and Otp (36,37) may also represent potential causes of obesity through the modification of eating behavior. Interestingly, pathological analysis suggests that the PVN of patients with Prader–Willi syndrome (PWS), a genetic condition characterized by hyperphagia and obesity, has fewer cells (38). Also, mice bearing a mutation in Necdin, which is contained in the PWS critical region, show variable perinatal lethality and a 29% decrease of PVN cells expressing oxytocin (39). However, the relationship between the PVN anomalies of PWS patients and Necdin mutant mice with the regulation of energy balance remains to be clarified, as Necdin mutant mice surviving the neonatal period do not develop obesity.
Experimentally and genetically induced hypocellularity of the PVN is specifically associated with hyperphagia without important decrease of energy expenditure. However, these observations do not preclude the possibility that the PVN participates in the control of energy expenditure. In fact, injections of NPY or CART into the PVN have been shown to decrease BAT thermogenesis (40,41). Some experimental evidence suggest that the PVN pathways that regulate feeding and thermogenesis are distinct, acting through different axonal projections to the autonomic system of the brainstem (42). Sim1 haploinsufficency appears to specifically affect the feeding pathway without interfering with the thermogenesis pathway.
In contrast to Sim1+/– mice, other mouse models of early-onset obesity, like McR-4- (27,43) and leptin-deficient mice (44), are characterized by both increased food intake and decreased energy expenditure. Leptin functions in the AN but also in other areas of the hypothalamus (45), whereas MSH, a ligand of MCR4, is synthesized in AN neurons. Axonal projections of the AN to the PVN and the lateral hypothalamus area are involved in the regulation of energy balance by leptin and MSH (11,45). In contrast, Sim1 is not expressed in other areas of the hypothalamus that have been associated with the regulation of appetite, nor does the PVN project to hypothalamic neurons associated with this process. Sim1 appears to affect a smaller set of pathways within the hypothalamus than do leptin and Msh, accounting for its distinctive effects on energy balance. Sim1+/– mice thus provide an important animal model for defining the role of the PVN in the regulation of appetite and for studying its interaction with other centers controlling energy balance.
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MATERIALS AND METHODS |
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Mice
The production and genotyping of Sim1 heterozygous mice have been described previously (21). Mice were weaned at 3 weeks and maintained in a daily cycle of 12 h light (06:00–18:00) and 12 h darkness (18:00–06:00). They were allowed free access to chow containing 9% crude fat (Purina). Control littermates were used in all experiments. Weight and naso-anal length were measured by the same person. BMI is calculated as g/cm2, obtained by dividing body mass by the square of the naso-anal length. Mice were maintained on a mixed C57BL/6-129/Sv background.
Blood analysis
Blood was drawn by cardiac puncture between 09:00 and 10:00 in anesthetized animals after an overnight fast. Blood glucose levels were measured with a glucose sensor device (Precision QID). Plasma insulin and leptin levels were measured by radioimmunoassay with commercial kits (Linco).
Food consumption and energy expenditures
Measurements of energy intake or expenditure were performed after mice had been housed individually in cages for 5 days. For measurements of food intake, 4–5-week-old mice were fed ad libitum. Food consumption was recorded daily for a period of 5 days. Feeding efficiency was calculated by dividing the total weight gain over a 7 day period by the total food intake (in g) during this period. Rate of weight loss when food intake was restricted was measured as described by Ohki-Hamazaki et al. (30). Briefly, mice were fed 5% body weight of chow and their weight was measured daily for 3 days. The initial weight of Sim1+/– and control mice used in this experiment was not significantly different (P > 0.05).
Oxygen consumption and carbon dioxide production were measured in a Columbus Instruments Oxymax Economy System. This indirect open circuit calorimeter was upgraded to simultaneously assess four mice. The control, measurement, display and storage of data were performed by a personal computer using software provided with the system. Chambers were contained in a controlled temperature incubator (VWR) equipped with timed light controls. Mice were placed into the chamber at the beginning of the light phase and oxygen consumption was measured continuously for 24 h. Mice had free access to chow and water. The chamber was maintained at 24°C, and a 12 h light–dark cycle (lights on at 06:00) was used.
Temperature was measured using an electronic thermometer equipped with a rectal probe (Ret-3, Physitemp). Temperature in cold conditions was examined by measuring rectal temperature of mice housed individually at 4°C every hour for the first 8 h and then at 24 h. Locomotor activity was measured using the infrared Digiscan system (Accuscan). Mice were housed individually in cages and the number of infrared beam breaks was monitored every minute for 360 min during the light period and for 360 min during the dark period. Results are expressed as the number of beam breaks/period of 360 min.
Histology, cell counts and expression analyses
For RT–PCR, 1 µg of total RNA of each tissue was used in a standard RT–PCR reaction. The reaction was carried out at 94°C for 1 min, 56°C for 1 min and at 72°C for 1 min for 35 cycles (Sim1) or 27 cycles (G3PDH). The primers used were: Sim1, 5'-GGAGCCCGAGACACGATGAAAG; Sim1, 3'-AAGGGGCTGGTCCGACTGGTGT; G3PD, 5'-ACCACAGTCCATGCCATCAC; G3PDH, 3'-TCCACCACCCTGTTGCTGTA.
For histology and in situ hybridization, pairs of 8-week-old heterozygous and wild-type littermates with a weight difference of at least 5 g (median 11.3 g) were used. These mice were anesthetized and perfused via cardiac puncture with saline and then 4% paraformaldehyde. Whole brains were rapidly removed, post-fixed overnight and then processed to generate four sets of 20 µM adjacent sections. After hybridization with various radioactive probes, the sections were counterstained with hematoxylin. For morphometric studies of the PVN, one set of these sections was used. Cell number was estimated by counting all nuclear profiles within the PVN on each side of the brain. The Image PRO Plus software was used to calculate the area occupied by the PVN or by its nuclei. Nuclear profile counts within the VMN on one side of the brain were performed on eight alternating sections starting from its most posterior end. These sections originated from the same brains as those used for the PVN studies. In situ hybridization was performed, as described previously (46). Sim1 (21), Arnt2 (22), Crh (16) and Trh (21) probes have been described previously, as indicated. Probes for Avp, Ox, 5Ht-2cR, Gal and Tubby were generated by RT–PCR. The sequences of the primers used to amplify these fragments are available upon request.
Statistical analysis
Results were expressed as means ± SEM. Student’s unpaired t-tests were used to compare means. Two-way (time x group) repeated-measures ANOVA was used to test differences between groups for the evolution across time of continuous variables. In the case of a significant time x group interaction, slice effect (also known as simple effect) analyses were then performed, i.e. difference between groups was analyzed at each time point.
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ACKNOWLEDGEMENTS |
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We thank Rachel Fastaff, Linghe Pan and Denise Carrier for technical assistance, François Harel and Charles Dupont for their help with statistical analysis and Drs Doug Koshland and Jim Wilhelm for critical reading of the manuscript. We are grateful to Dr Andrew Zinn for sharing data before publication. J.M. is a clinician-scientist of the Medical Research Council of Canada (MRC). This work was supported by grants from the MRC and NIH (R01-HD35596).
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 514 345 4727; Fax: +1 514 345 4766; Email: jmichaud@justine.umontreal.ca
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