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Division of Endocrinology (Y.C., C.H., C.-K.H., C.B., M.A., H.M.H., L.J.S., M.L.H., Y.S.), Division of Bio-Research Technologies and Proteins (Q.Z., N.F., D.D.Y.), Lilly Research Laboratories, Eli Lilly \|[amp ]\|Co., Indianapolis, Indiana 46285
Address all correspondence and requests for reprints to: Dr. Yuguang Shi, Lilly Research Laboratories, Endocrine Division, Lilly Corporate Center, DC 0545, Eli Lilly \|[amp ]\|Co., Indianapolis, Indiana 46285. E-mail: . shi_yuguang{at}lilly.com
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Introduction |
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An orphan G protein-coupled receptor, SLC1/GPR24, was identified as an MCH receptor (MCHR1) in 1999 (13, 14). MCHR1 is widely expressed in multiple regions of the brain including cortex, hippocampus, thalamus, midbrain, pons, olfactory bulb, and hypothalamus (15, 16). MCHR2 was identified recently on the basis of the sequence homology to MCHR1 (17, 18, 19, 20). The expression pattern of both receptor isoforms in the brain is similar, although MCHR2, unlike MCHR1, is not expressed in the pituitary (18). In particular, MCHR1 and MCHR2 are expressed in the hypothalamic areas such as the ventromedial, dorsomedial, and arcuate nuclei implicated in the control of energy homeostasis (19). To gain insight of the functional role of the MCHRs, we created a mouse model of MCHR1 deficiency by disrupting the MCHR1 gene locus using homologous recombination in embryonic stem cells. Homozygous MCHR1-/- mice exhibit hyperphagia and resistance to diet induced by obesity. Thus, MCHR1 appears to play an important role in the regulation of energy homeostasis mediated by MCH.
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Materials and Methods |
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). The targeting vector pKOMCHR1 was constructed by inserting a 2.5-kb XhoI/EcoRI fragment that contains the 5' promoter region and a 5.5-kb EcoRI/KpnI fragment that contains genomic sequences downstream from the 3' untranslated region (Fig. 1A).
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Mouse genotyping by PCR
Genotype analysis of large numbers of mice was facilitated by PCR. Two sets of primers were used in PCR to identify the presence of each allele. The following primer pairs lacked annealing site in the targeting vector and were used to detect WT allele: pair (A), WT1, 5'-TGTCAAGGGGATCCCTGCAGTC-3'; WT2, 5'-TGTGAGACCTTTCGAAAACGCTTGG-3'; and pair (B), WT3: 5'-GTCCCCGACATCTTCATCATC-3'; WT4, 5'-TCAGGTGCCTTTGCTTTCTGT-3'. The primer pairs for detection of mutant allele were: pair (A), pGKP1, 5'-CTCCAGACTGCCTTGGGAAAA-3'; KO1, 5'-CTCTGAGGCTACTGTCCATTCTA-3'; and pair (B), neo1, 5'-TTGGGAAGACAATAGCAGGC-3', KO2, 5'-AGAGTTACAGAAGCAATGTA-3'. PCR was performed using the PCR supermix from Life Technologies, Inc. (catalog no. 10572-014), each primer of 200 nM and crude DNA extract from mouse tail in the final volume of 50 µl. The PCR samples were run on a 2% agarose gel to check for the presence or absence of an amplified band specific to each primer pair.
Southern blot, Northern blot, and real-time PCR analyses
We used a 262-bp DNA fragment as a probe for Southern blot analysis to detect correctly targeted ES cells and to confirm mouse genotypes (Fig. 1B
). This probe is specific for a segment of the mouse genomic sequence upstream of the 5'-arm of the targeting vector. Targeted disruption of the MCHR1 gene with the PGK-neo cassette introduced two additional PvuII recognition sites. Consequently, the probe detected a PvuII fragment 5.5 kb in length with the WT allele(s) and a 4.0-kb PvuII fragment with the correctly targeted, mutant MCHR1 allele(s). Southern blot analysis was carried out according to Sambrook et al. (22). Northern blot analysis was carried out using total RNA isolated from the brain. Brains were removed from decapitated 2-month-old male WT (+/+), heterozygous (+/-), and homozygous (-/-) mice and immediately frozen on dry ice until total RNAs were extracted from them by TRIzol Reagent (Life Technologies, Inc.). The 835-bp cDNA fragment initially used to identify the genomic BAC clone was used as a probe. Probes used for expression analysis of MCH, NPY, and orexin genes were amplified by primers (MCH: 5'-GTCTGGCTGTAAAACCTTACC-3' and 5'-ACCAGCAGGTATCAGACTTGCC-3'; NPY: 5'-TCGTGTGTTTGGGCATTCTGG-3' and 5'-GTCTTCAAGCCTTGTTCTGG-3'; orexin: 5'-CTGTCGCCAGAAGACGTGTTC-3' and 5'-GCTAAAGCGGTGGTAGTTACGG-3') based on the cDNA sequences of each gene, respectively). Probe used for ß-actin gene expression analysis was purchased from CLONTECH Laboratories, Inc. Northern blot analyses were performed according to Sambrook et al. (22), and the same blot was stripped and reused for expression analysis of all the genes. Quantification of gene expression level from the Northern blots was carried out using phosphor imager and the expression level of each gene was normalized with the level of ß-actin. Real-time PCR analyses were carried out using Taqman PCR amplifier equipped with ABI PRISM 7700 sequence detector (Perkin-Elmer Corp., Foster City, CA). Fifty nanograms total RNA equivalent cDNA was used for Taqman PCR. Each sample was run in duplicate, and the expression levels of AgRP and proopiomelanocortin (POMC) were normalized with that of ß-actin, and then they were compared among MCHR1 knockout, heterozygous, and WT group. The primer and probe sequences for the ß-actin gene were 5'-CCGTGAAAAGATGACCCAGA-3' and 5'-TACGACCAGAGGCATACAG-3'; probe: 5'-TTTGAGACCTTCAACACCCCA-3'. The primer and probe sequences for the POMC gene were 5'-GGCGTCTGGCTCTTCTCG-3' and 5'-AGCAACCCGCCCAAGG-3'; probe: 5'-AGGTCATGAAGCCACCGTAACGCTTG-3'. The primer and probe sequences for the AgRP gene were 5'-GCTAGATCCACAGAACCGCG-3' and 5'-AGCAGGACTCGTGCAGCCT-3'; probe: 5'-TCTCGTTCTCCGCGTCGCTGTGT-3'.
Animal care
All experiments were performed in F2 (129 X B6 background) mice. Mice were maintained on a 12-h light, 12-h dark cycle (lights on 2200–1000 h). The animals were weaned and individually housed at 3 wk of age. All mice had free access to water and received standard mouse chow (Purina 5015 chow, Ralston Purina Co., St. Louis, MO). Mice used for experiments reported in Figs. 3–7 were switched to a high fat-chow (TD 95217, 40% calories from fat; Teklad, Madison, WI) at 4 wk of age. Mice were allowed 1 wk to acclimate to the environment. Body weight and food consumption was measured once a week at 0800 h from the fourth week after birth. All animal use in this study was conducted in compliance with approved institutional animal care and use protocols according to NIH guidelines (NIH Publication No. 86-23, 1985). Fat mass was analyzed by nuclear magnetic resonance using an Echo System (Houston, TX) instrument. Lean body mass was calculated by subtracting fat mass from total weight.
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Statistical analyses
Mixed-effects repeated-measures ANOVA models were used to analyze the continuous efficacy data. Models included the fixed, categorical effects of treatment, time of observation, and treatment-by-time interaction. The unstructured (co)variance structure was used to model the within-mouse errors in the analyses. This was based on visual inspection of the pair-wise correlations between time points and careful consideration of all (co)variance structure options (e.g. autoregressive, toeplitz, and compound symmetric structures, with and without heterogeneous variances). The Kenward-Roders approximation was used to estimate degrees of freedom for all significance tests. The appropriate treatment-by-time interaction contrast was used to assess the magnitude and significance of treatment group differences at each time point. Analyses were implemented using a likelihood-based repeated measures approach (SAS PROC MIXED).
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Results |
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). Two targeted mutant ES clones identified by PCR and confirmed by Southern blot were injected into C57BL/6 blastocysts and resulted in 12 male chimeric offspring that transmitted the disrupted MCHR1 allele through the germline. Heterozygous mutant mice were intercrossed to generate homozygous mutants that were identified by PCR and confirmed by Southern blot analyses of genomic DNA (Fig. 1B). The null mutation of MCHR1 was demonstrated by the absence of MCHR1 expression, as determined by Northern analysis of mRNA isolated from brain of WT (+/+), heterozygous (+/-), and homozygous mutant mice (-/-) (Fig. 1C).
Body weight and fat mass of MCHR1 knockout mice
The MCHR1-/- mice used in the current studies were generated by intercross of MCHR1+/- mice. Among the different genotypes, MCHR1-/- mice were born at the predicted Mendelian ratios without any obvious phenotypic abnormality. We also set up independent breeding colonies outside our animal facility by crossing male and female MCHR1-/- mice to each other. Under the breeding program, more than 100 homozygous MCHR1 knockout mice have been generated so far. There is no phenotypic defect observed from these mice to date. Both genders are fertile and born with equal ratios. When fed a regular mouse chow, both male and female MCHR1-/- mice gained less weight than WT mice at 7 wk of age. The effect is more apparent in male MCHR1 mice that had a significantly lower body weight and fat mass, compared with WT controls (Fig. 2).
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). In comparison, the mean body weight of the female MCHR1-/- mice trailed the WT mice during the first few weeks of study and began to show significant differences at 14 wk of age. At 14 wk of age, male MCHR1-/- mice weighed 15% less and female MCHR1-/- mice weighed 12% less than the corresponding control mice. The body weight of the MCHR1+/- mice was indistinguishable from that of their WT controls throughout the studies. As measured by nuclear magnetic resonance, fat mass was decreased 30% and 50% in female and male MCHR1-/- mice, respectively, at 15 wk of age (Fig. 3C). Hence, the reduced body weight in both male and female MCHR1-/- mice was a consequence of decreased body fat mass. There was no significant difference in fat mass between WT and heterozygous mice. Reduced fat mass was not associated with any change in lean mass (Fig. 3D).
Consistent with a lower fat content, leptin levels were significantly lower in male but not in female MCHR1-/- mice, compared with the control mice measured at 15 wk of age (Fig. 4A). We next calculated leptin/fat ratio that can be used as an indicator for leptin sensitivity. When leptin levels were normalized to body fat for all three genotypes and both genders (nanogram per milliliter leptin per gram fat mass), there was a reduced leptin/fat ratio in the MCHR1-/- mice, but it did not reach statistical significance (females MCHR1+/+: 2.09 ± 0.52, MCHR1+/-: 2.18 ± 0.33, MCHR1-/-: 1.46 ± 0.13; males MCHR1+/+: 2.5 ± 0.52, MCHR1+/-: 1.87 ± 0.16, MCHR1-/-: 1.5 ± 0.11). As a result of fat mass reduction, significantly lower insulin levels were observed in both female and male MCHR1-deficient mice, compared with the corresponding control mice (Fig. 4B). Although lower insulin levels suggest improved insulin sensitivity, a more complete assessment of insulin sensitivity and glucose metabolism needs to be performed. There were no significant differences in plasma glucose levels between the MCHR1-/- mice (females: 192.09 ± 11.38; males: 225.2 ± 16.53 mg/dl) and the WT controls (females: 168.45 ± 7.43; males: 219.09 ± 16.78 mg/dl).
Decreased body mass and fat mass did not result from hypophagia. In fact, MCHR1-/- mice consumed more calories per unit weight on a daily basis. Food intake was increased by 15% in female MCHR1-/- mice, compared with controls (MCHR1-/-, 101.0 ± 2.3 g/kg of body weight; MCHR1+/+, 88.4 ± 4.2 g/kg of body weight; P < 0.05) (Fig. 5A) at 14 wk of age. The difference (20%) was greater in male MCHR1-/- mice, compared with WT mice (MCHR1-/-, 95.3 ± 4.7 g/kg of body weight; MCHR1+/+, 78.8 ± 2.6 g/kg of body weight, P < 0.01) (Fig. 5B) at 14 wk of age.
We next invested the fuel efficiency of the MCHR1-deficient mice. Fuel efficiency has been calculated as body weight gain per kilocalorie food intake (mean ± SEM) of all the three genotypes of mice between 6 and 12 wk of age. As shown in Fig. 5C, male knockout mice had significantly lower fuel efficiency (11.79 ± 0.98 x 10-3 g/kcal) than WT (17.05 ± 2.01 x 10-3 g/kcal) and heterozygous mice (18.06 ± 1.06 x 10-3 g/kcal) of the same gender, P < 0.05. However, fuel efficiency of female knockout mice (8.48 ± 0.64 x 10-3 g/kcal) was not significantly different from WT (9.22 ± 0.91 x 10-3 g/kcal) and heterozygous (10.2 ± 0.64 x 10-3 g/kcal) mice.
Metabolic rate of MCHR1 knockout mice
To investigate whether the phenotype in MCHR1-/- mice results from changes in metabolic rate, indirect calorimetry was performed at 9–14 wk of age to study energy metabolism under high-fat diet. No significant differences in metabolic rate were observed between the MCHR1-/--deficient and the WT controls in both male (Fig. 6A) and female mice (data not shown) over a 24-h period at 9 wk of age. Consistent with slower weight gain observed in male MCHR1-/- mice, total fuel utilization of the MCHR1-/- male mice increased significantly over a 24-h period at 11 wk (Fig. 6B) and 14 wk of age (data not shown). Total energy expenditure was 28% higher (P < 0.05) in male MCHR1-/- over a 24-h period at 11 and 14 wk of age when expressed as a percentage of the controls (Fig. 6C). In contrast, no significant differences were observed in females between the MCHR1-/- and the WT controls in total energy expenditure throughout the study period (Fig. 6C). Some of the extra energy expenditure could be due to increased activities because ambulatory movement was slightly increased in the male MCHR1-/- mice during a period when increased energy expenditure was observed. However, the difference was not significant (data not shown).
Changes in body weight and energy expenditure in response to fasting
We next investigated the response of MCHR1-/- mice to food deprivation at 15 wk of age. Following a 24-h fast, the male MCHR1-/- mice lost significantly more body weight, compared with the WT controls (Fig. 7A). Body weight loss was 7.4% in WT and 9.9% in MCHR1 knockout animals, compared with the prefast value. Despite the energy deficit caused by fasting, the total energy expenditure of male MCHR1-/- mice was 11% higher than that of WT mice (242 ± 15 vs. 218 ± 7 kcal/kg per day) (Fig. 7B), suggesting increased metabolic rate caused by MCHR1 inactivation.
Effect of MCHR1 inactivation on expression of neuropeptide genes
Northern blot and quantitative PCR analyses were carried out on WT, heterozygous, and homozygous MCHR1-deficient mice to investigate possible feedback responses from other neuropeptides involved in energy balance. Northern blot analyses were carried out to study expression of MCHR1, MCH, neuropeptide Y, and orexin genes. The level of expression of each gene is quantified by phosphor imager and normalized with the expression level of ß-actin that is used as internal control. Real-time PCR analyses were carried out to study the expression of both AgRP and POMC genes. As expected, there was no expression of the MCHR1 gene in the knockout mice and a 50% reduction was observed in the heterozygous knockout mice, compared with the WT controls (Fig. 8). However, inactivation of the MCHR1 gene did not alter the expression levels of MCH, neuropeptide Y, orexin (Fig. 8), AgRP, and POMC genes (data not shown). The results suggest that the metabolic pathway regulated by MCH is different from metabolic pathways induced by those neuropeptides (26).
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Discussion |
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Both male and female MCHR1-/- mice had a significantly reduced body weight, compared with WT littermates. However, male MCHR1-/- mice showed a reduced weight gain at a much earlier age (7 wk old), and a fat mass reduction of up to 50% was observed at 15 wk of age. In comparison, the lean mass was maintained at a level similar to that observed in the WT mice, suggesting that MCHR1 inactivation did not cause pathophysiological weight loss such as muscle wasting. Despite increased food intake on a weight basis in the MCHR1-deficient mice, these mice were leaner than the heterozygous and the WT controls. This suggests that the decrease in weight gain is most likely because of an observed increase in metabolic rate in the MCHR1-/- animals. Consistent with the lower fat mass, both plasma leptin and insulin levels are significantly lower in male MCHR1-deficient mice than those from the WT controls. Although in both male and female MCHR1-/-mice, there was a reduced leptin/fat ratio, which is an indicator for leptin sensitivity, it did not reach statistical significance. While lower insulin levels often suggest improved insulin sensitivity, a more detailed metabolic study needs to be performed to confirm the effect. Even though the MCHR1-deficient mice experienced less positive energy balance because of poor fuel efficiency, there was no compensatory response in the MCH mRNA expression in the knockout mice. Similarly, no changes in mRNA levels were observed from other regulatory neuropeptides involved in energy balance, such as neuropeptide Y, orexin, AgRP, and POMC, suggesting that the metabolic pathway regulated by MCH is different from metabolic pathways induced by those neuropeptides (26).
Total fuel utilization is the sum of fuel used for basal processes, thermogenesis, and physical activities (27, 28). Daily fuel utilization of male MCHR1-/- mice was increased by 28% at 11 wk of age, compared with the WT controls. This is likely due to an increase in metabolic rate and physical activity. Indeed, we observed a slight increase in locomotion in male MCHR1-/- mice between 11 and 15 wk of age when energy expenditure was increased in MCHR1-/- mice (data not shown). Increased food intake in MCHR1-/- may also be a compensatory response to the hypermetabolic rate and poor fuel efficiency experienced in the male MCHR1-deficient mice. Thus, despite hyperphagia, the MCHR1-/- mice gain less fat mass than the WT mice. The recent observation that MCH inhibits the thyroid axis directly at the pituitary, which expresses MCHR1, may provide a possible mechanism for the hypermetabolic state (29). Although increased energy expenditure appears to be the mechanism contributing to reduced weight gain in the MCHR1-/- mice, it should be pointed out that early in the development of the phenotype significant reductions in body weight were seen in the absence of significant increases in energy expenditure. This likely is due to low sensitivity in measuring energy expenditure over a 24-h period and the fact that weight gain is an accumulative measurement over many weeks and is therefore less sensitive to daily fluctuation.
The phenotypic traits of MCHR1-/- mice generally reflect the phenotypes of MCH-/- mice, suggesting that MCH effects on fat storage and energy metabolism are primarily mediated by MCHR1. However, some phenotypic differences also exist between the MCHR1-deficient mice and the MCH knockout mice. Most notably, although both male and female MCH-/- mice are equally susceptible to weight reduction (6), MCHR1 inactivation results in a more pronounced effect on reduction in mean body weight and fat mass in male MCHR1-/- mice than that in the females. Other phenotypic differences are less comparable between the MCH-/- and MCHR1-/- mice because of differences in diet used in the two studies. Nevertheless, it is noted that in contrast to hypophagia observed in the MCH-/- mice, the MCHR1-/- mice are hyperphagic. Because the phenotype of MCH knockout mice should be equivalent to inactivation of all the MCH receptors, these differences may be attributable to the effect of the newly identified MCHR2 whose physiological function remains to be investigated. Alternatively, it is noteworthy that the phenotype of the MCH-/- mice is complicated by deletion of sequences encoding the neuropeptides EI (NEI) and GE (6). Physiological functions of NEI and neuropeptide GE are poorly understood; however, both MCH and NEI have been shown to inhibit TRH release from hypothalamic explants (29). NEI has also been implicated in antagonizing effects of MCH on the hypothalamic-pituitary-adrenal axis (30). Nevertheless, our current work with the MCHR1-deficient mice has firmly established a role of MCH in regulating energy homeostasis. Moreover, our data demonstrate that MCHR1 plays an important role in energy homeostasis mediated by MCH.
In conclusion, we have generated MCHR1 knockout mice and demonstrated that these mice are hyperphagic, hypermetabolic, and resistant to diet induced obesity. Our observations establish MCH as an important regulator of energy homeostasis; more importantly, inactivation of MCHR1 alone is able to counterbalance obesity induced by a high-fat diet. The ongoing increase in the incidence of obesity and its associated susceptibility of type 2 diabetes has drawn attention in identifying novel and innovative treatments to counteract these epidemics. Identification, generation, and development of compounds that specifically antagonize MCHR1 may provide useful new medicines in treating and/or preventing human obesity.
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Acknowledgments |
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Footnotes |
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Received January 31, 2002.
Accepted for publication March 18, 2002.
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D. G. Smith, E. T. Tzavara, J. Shaw, S. Luecke, M. Wade, R. Davis, C. Salhoff, G. G. Nomikos, and D. R. Gehlert Mesolimbic Dopamine Super-Sensitivity in Melanin-Concentrating Hormone-1 Receptor-Deficient Mice J. Neurosci., January 26, 2005; 25(4): 914 - 922. [Abstract] [Full Text] [PDF]
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A. Astrand, M. Bohlooly-Y, S. Larsdotter, M. Mahlapuu, H. Andersen, J. Tornell, C. Ohlsson, M. Snaith, and D. G. A. Morgan Mice lacking melanin-concentrating hormone receptor 1 demonstrate increased heart rate associated with altered autonomic activity Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R749 - R758. [Abstract] [Full Text] [PDF]
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M. Tetsuka, Y. Saito, K. Imai, H. Doi, and K. Maruyama The Basic Residues in the Membrane-Proximal C-Terminal Tail of the Rat Melanin-Concentrating Hormone Receptor 1 Are Required for Receptor Function Endocrinology, August 1, 2004; 145(8): 3712 - 3723. [Abstract] [Full Text] [PDF]
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D. Meyre, C. Lecoeur, J. Delplanque, S. Francke, V. Vatin, E. Durand, J. Weill, C. Dina, and P. Froguel A Genome-Wide Scan for Childhood Obesity-Associated Traits in French Families Shows Significant Linkage on Chromosome 6q22.31-q23.2 Diabetes, March 1, 2004; 53(3): 803 - 811. [Abstract] [Full Text] [PDF]
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 I.S. Farooqi and S. O'Rahilly Monogenic Human Obesity Syndromes Recent Prog. Horm. Res., January 1, 2004; 59(1): 409 - 424. [Abstract] [Full Text]
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C. R. Abbott, A. R. Kennedy, A. M. Wren, M. Rossi, K. G. Murphy, L. J. Seal, J. F. Todd, M. A. Ghatei, C. J. Small, and S. R. Bloom Identification of Hypothalamic Nuclei Involved in the Orexigenic Effect of Melanin-Concentrating Hormone Endocrinology, September 1, 2003; 144(9): 3943 - 3949. [Abstract] [Full Text] [PDF]
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G. Segal-Lieberman, R. L. Bradley, E. Kokkotou, M. Carlson, D. J. Trombly, X. Wang, S. Bates, M. G. Myers Jr., J. S. Flier, and E. Maratos-Flier Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype PNAS, August 19, 2003; 100(17): 10085 - 10090. [Abstract] [Full Text] [PDF]
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 G. Segal-Lieberman, D. J. Trombly, V. Juthani, X. Wang, and E. Maratos-Flier NPY ablation in C57BL/6 mice leads to mild obesity and to an impaired refeeding response to fasting Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1131 - E1139. [Abstract] [Full Text] [PDF]
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M. Ito, A. Gomori, A. Ishihara, Z. Oda, S. Mashiko, H. Matsushita, M. Yumoto, M. Ito, H. Sano, S. Tokita, et al. Characterization of MCH-mediated obesity in mice Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E940 - E945. [Abstract] [Full Text] [PDF]
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A. Gomori, A. Ishihara, M. Ito, S. Mashiko, H. Matsushita, M. Yumoto, M. Ito, T. Tanaka, S. Tokita, M. Moriya, et al. Chronic intracerebroventricular infusion of MCH causes obesity in mice Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E583 - E588. [Abstract] [Full Text] [PDF]
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, P < 0.001, compared with WT group. WT, MCHR1+/+; Het, heterozygote (MCHR1+/-); KO, knockout (MCHR1-/-).
