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Melanin-Concentrating Hormone Is a Critical Mediator of the Leptin-Deficient Phenotype

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Melanin-Concentrating Hormone Is a Critical Mediator of the Leptin-Deficient Phenotype Melanin-concentrating hormone is a critical mediator of the leptin-deficient phenotype Gabriella Segal-Lieberman*†‡, Richard L. Bradley*†, Efi Kokkotou*†, Michael Carlson*, Daniel J. Trombly*, Xiaomei Wang*, Sarah Bates*†, Martin G. Myers, Jr.*†, Jeffrey S. Flier†§, and Eleftheria Maratos-Flier*†¶ *Research Division, Joslin Diabetes Center, Boston, MA 02215; §Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, MA 02215; and †Department of Medicine, Harvard Medical School, Boston, MA 02215 Communicated by C. Ronald Kahn, Harvard Medical School, Boston, MA, June 13, 2003 (received for review March 6, 2003) Energy homeostasis is regulated by a complex network involving null mice having an increased resting metabolic rate, a significant peripheral and central signals that determine food intake and increase in locomotor activity, and an improved ability to thermo- energy expenditure. Melanin-concentrating hormone (MCH) plays regulate in response to environmental cold exposure. These results an essential role in this process. Animals treated with MCH develop indicate that MCH is a key neuropeptide acting downstream of hyperphagia and obesity. Ablation of the prepro-MCH gene leads leptin and that MCH is required for manifestation of the full ob͞ob to a lean phenotype, as does ablation of the rodent MCH receptor, phenotype. In particular, MCH is an essential mediator of the MCHR-1. MCH is overexpressed in the leptin-deficient ob͞ob central neural circuit by which leptin deficiency suppresses energy mouse, and we hypothesized that ablation of MCH in this animal expenditure through effects on both resting metabolic rate and would lead to attenuation of its obese phenotype. Compared with locomotor activity. ob͞ob animals, mice lacking both leptin and MCH (double null) had a dramatic reduction in body fat. Surprisingly, the hyperphagia of Materials and Methods the ob͞ob mouse was unaffected. Instead, leanness was secondary Animals. All studies were approved by the Joslin Diabetes Center to a marked increase in energy expenditure resulting from both Animal Care and Use Committee. Male mice were weaned at 3–4 increased resting energy expenditure and locomotor activity. weeks of age, genotyped, and housed, two to four mice per cage, Furthermore, double-null mice showed improvements in other with access to 9% fat food (Purina Formulab 5008) and water ad PHYSIOLOGY parameters impaired in ob͞ob mice. Compared with ob͞ob mice, libitum at 24°C under an alternating 12-h light͞dark cycle. double-null animals had increased basal body temperature, im- proved response to cold exposure, lower plasma glucocorticoid Generation of MCH؊/؊ ob͞ob Mice. Mice deficient in both MCH and levels, improved glucose tolerance, and reduced expression of leptin were obtained by breeding MCHϪ/Ϫ (3), backcrossed for six stearoyl-CoA desaturase 1 (SCD-1). These results highlight the generations onto a C57BL͞6 background at Taconic Farms, to importance of MCH in integration of energy homeostasis down- C57BL͞6 ob͞ϩ mice (The Jackson Laboratory). To generate ob͞ob stream of leptin and, in particular, the role of MCH in regulation of mice lacking the MCH gene, MCHϪ/Ϫ males were first bred to energy expenditure. ob͞ϩ females to create compound heterozygotes (MCHϩ/Ϫ ob͞ϩ). In a second cross, compound heterozygotes were bred with each Ϫ Ϫ ϩ ϩ elanin-concentrating hormone (MCH), a 19-aa neuropep- other, and MCH / ob͞ϩ as well as MCH / ob͞ϩ offspring were Mtide, is the product of the prepro-MCH gene and is expressed identified. In a third set of crosses, MCHϪ/Ϫ ob͞ϩ mice were bred exclusively within the lateral hypothalamus. MCH neurons make to each other to produce MCHϪ/Ϫ ob͞ob animals and MCHϪ/Ϫ monosynaptic projections throughout the neuraxis including the OB͞OB animals. In parallel, MCHϩ/ϩ ob͞ϩ mice were bred to cortex and hindbrain, suggesting that MCH regulates complex each other to produce MCHϩ/ϩ ob͞ob as well as MCHϩ/ϩ OB͞OB motivated behaviors (1). A role for MCH in energy homeostasis (WT) mice. emerged from studies demonstrating differential MCH gene ex- pression in leptin-deficient ob͞ob mice, where MCH mRNA was Genotyping. Genotypes were confirmed by PCR amplification of overexpressed 2- to 3-fold compared with normal-weight litter- genomic DNA. In MCHϪ/Ϫ mice, primers targeting the PGK-neo mates, in both fed and fasted states (2). Furthermore, MCH cassette (3) were used for the PCR. The primers were: for MCH, administration into the lateral ventricle of rats caused an acute and 5Ј-GAATTTGGAAGATGACATAGTAT-3Ј (sense) and 5Ј- rapid increase in feeding (2, 4). Genetic evidence for a role of MCH CAGCCCGGTGAGTTACAAGATTCT-3Ј (antisense); for in energy balance was derived from a model of MCH gene ablation, PGK-neo, 5Ј-CGGGTAGGGGAGGCGCT-3Ј (sense) and 5Ј- which produced a lean phenotype associated with a decrease in GCGCAAGGAACGCCCGTCGTG-3Ј (antisense); for the OB feeding and an increase in resting energy expenditure (3), and also gene, 5Ј-GCCAATGACCTGGAGAATCTC-3Ј (sense) and 5Ј- from a model of transgene-derived eutopic overexpression, which AGGACGCCATCCAGGCTCTC-3Ј (antisense); and for the ob produced mild obesity (5). Recently, chronic infusions of MCH mutation, 5Ј-GCCAATGACCTGGAGAATCTCT-3Ј (sense) and were shown to produce hyperphagia and obesity in mice (6) and 5Ј-AGGACGCCATCCAGGCTCTC-3Ј (antisense). rats (7). Based on the foregoing evidence, we hypothesized that MCH Glucose Tolerance Tests. Mice were fasted overnight (1700–0800 contributed to the hyperphagia seen in ob͞ob mice (8) and pre- hours) and then injected i.p. with glucose (2 g͞kg of body weight). dicted that mice lacking both MCH and leptin would show an Tail blood was collected at Ϫ1, 15, 30, 60, and 120 min. Blood attenuated obesity phenotype secondary to decreased feeding. Therefore, we performed a series of crosses of MCHϪ/Ϫ mice and ob͞ϩ mice to generate mice lacking both leptin and MCH, i.e., Abbreviations: MCH, melanin-concentrating hormone; SCD-1, stearoyl-CoA desaturase 1; MCHϪ/Ϫ ob͞ob mice, designated double null. MCHR, MCH receptor; VO2, oxygen consumption; UCP-1, uncoupling protein 1; BAT, brown adipose tissue; AgRP, agouti-related peptide; NPY, neuropeptide Y; NEI, neuropeptide EI; Double-null mice had marked attenuation of obesity and asso- NGE, neuropeptide GE. ciated metabolic and endocrine abnormalities of leptin deficiency. ‡Present address: Institute of Endocrinology, Sheba Medical Center, Tel-Hashomer 52621, Remarkably, food intake was no different in ob͞ob mice vs. Israel. double-null animals, and the improvement in obesity resulted ¶To whom correspondence should be addressed at: Research Division, Joslin Diabetes exclusively from an increase in energy expenditure, with double- Center, 1 Joslin Place, Boston, MA 02215. E-mail: [email protected]. www.pnas.org͞cgi͞doi͞10.1073͞pnas.1633636100 PNAS ͉ August 19, 2003 ͉ vol. 100 ͉ no. 17 ͉ 10085–10090 Downloaded by guest on September 28, 2021 Fig. 1. Growth, body composition, and glucose tolerance. (A) Photograph showing body size of MCHϪ/Ϫ ob͞ob and ob͞ob mice at 16 weeks of age. (B) Weights of ob͞ob, MCHϪ/Ϫ ob͞ob, MCHϪ/Ϫ, and WT mice over the course of 17 weeks. (C) Dual-energy x-ray absorptiometry analysis of 16-week-old WT (black bar), ob͞ob Ϫ Ϫ (gray bar), and MCH / ob͞ob (white bar) mice showing lean tissue mass and fat tissue mass. *, P Ͻ 0.015 vs. WT; **, P Ͻ 0.0001 vs. WT; #, P ϭ 0.001 vs. ob͞ob. (D) Glucose tolerance test of ob͞ob (black diamonds) and MCHϪ/Ϫ ob͞ob (black squares) mice at the age of 18 weeks after being fasted from 1700 hours to 0800 Ϫ Ϫ hours. *, P Ͻ 0.05 vs. MCH / ob͞ob. glucose levels were measured by using a glucometer (Elite, Bayer, densitometer, General Electric Medical Systems, Madison, WI) as Mishawaka, IN). described by the manufacturer. The machine was calibrated daily by using a phantom provided by the manufacturer. The image- RIAs. Corticosterone was measured by using a commercially avail- acquisition time was Ͻ5 min. The interassay coefficient of variation able RIA kit (ICN) according to manufacturer instructions. was 0.22%. Before scanning, mice were injected i.p. with a 1:1 mixture of tribromoethanol͞tert-amyl alcohol (0.015 ml͞g of body Indirect Calorimetry. Metabolic rates were measured by indirect weight). calorimetry in 12- to 14-week-old male MCHϪ/Ϫ ob͞ob, ob͞ob, and WT mice by using an eight-chamber open-circuit Oxymax Cold Exposure. To determine thermoregulatory ability of 30-week- system component of the comprehensive laboratory animal old WT, ob͞ob, and MCHϪ/Ϫ ob͞ob mice, individual mice were monitoring system (Columbus Instruments, Columbus, OH). Ϸ ͞ placed in a 2-liter beaker with 1-inch-deep bedding. The beaker was Mice were maintained at 24°C under a 12-h light dark cycle placed on ice in an insulated chamber in which air temperature was (light period, 0800–2000 hours). Food and water were available 4°C. Temperature was measured at 15-min intervals for1hbyusing ad libitum. Animals were housed individually in specially built a rectal probe. Plexiglas cages (height, 5 inches; width, 4.5 inches; depth, 8.5 inches) through which room air was passed at a flow rate of Immunoblotting. Interscapular brown fat from 34-week-old mice Ϸ0.54 liters͞min. Exhaust air from each chamber was sampled (n ϭ 4 per group) was washed twice in cold buffer containing at 1-h intervals for a period of 1 min; O2 and CO2 content of ͞ exhaust was determined by comparison to O and CO content Hepes, EDTA, and sucrose (HES buffer: 20 mM Hepes, pH 7.4 1 2 2 mM EDTA͞255 mM sucrose͞1 ␮g/ml leupeptin͞10 ␮g/ml aproti- of standardized sample air. Mice were acclimatized to cages for ͞ 48 h before beginning recordings, weighed, and then underwent nin 1 mM phenylmethylsulfonyl fluoride), homogenized for 1 min 24 h of monitoring. in an equal volume of HES by using a polytron homogenizer, and centrifuged at 3,000 ϫ g for 10 min at 4°C, and supernatants Motor Activity.
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