Importance of Adult Dmbx1 in Long-Lasting Orexigenic Effect of Agouti-Related Peptide.
Dmbx1 is a brain-specific homeodomain transcription factor expressed primarily during embryogenesis, and its systemic disruption (Dmbx1(-/-)) in the ICR mouse strain resulted in leanness associated with impaired long-lasting orexigenic effect of agouti-related peptide (AgRP). Because spatial and temporal expression patterns of Dmbx1 change dramatically during embryogenesis, it remains unknown when and where Dmbx1 plays a critical role in energy homeostasis. In the present study, the physiological roles of Dmbx1 were examined by its conditional disruption (Dmbx1(loxP/loxP)) in the C57BL/6 mouse strain. Although Dmbx1 disruption in fetal brain resulted in neonatal lethality, its disruption by synapsin promoter-driven Cre recombinase, which eliminated Dmbx1 expression postnatally, exempted the mice (Syn-Cre;Dmbx1(loxP/loxP) mice) from lethality. Syn-Cre;Dmbx1(loxP/loxP) mice show mild leanness and impaired long-lasting orexigenic action of AgRP, demonstrating the physiological relevance of Dmbx1 in the adult. Visualization of Dmbx1-expressing neurons in adult brain using the mice harboring tamoxifen-inducible Cre recombinase in the Dmbx1 locus (Dmbx1(CreERT2/+) mice) revealed Dmbx1 expression in small numbers of neurons in restricted regions, including the lateral parabrachial nucleus (LPB). Notably, c-Fos expression in LPB was increased at 48 hours after AgRP administration in Dmbx1(loxP/loxP) mice but not in Syn-Cre;Dmbx1(loxP/loxP) mice. These c-Fos-positive neurons in LPB did not coincide with neurons expressing Dmbx1 or melanocortin 4 receptor but did coincide with those expressing calcitonin gene-related peptide. Accordingly, Dmbx1 in the adult LPB is required for the long-lasting orexigenic effect of AgRP via the neural circuitry involving calcitonin gene-related peptide neurons.
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Seiichiro
S
Hirono
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Eun Young
EY
Lee
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Shunsuke
S
Kuribayashi
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Takahiro
T
Fukuda
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Naokatsu
N
Saeki
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Yasuhiko
Y
Minokoshi
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Toshihiko
T
Iwanaga
Departments of Medical Physiology (S.H., E.Y.L., S.K., T.M.) and Neurological Surgery (S.H., N.S.), Chiba University Graduate School of Medicine, Chuo-ku, Chiba, 260-0856, Japan; Division of Neuropathology (T.F.), Department of Pathology, The Jikei University School of Medicine, Minato-ku, Tokyo, 105-0003, Japan; Department of Developmental Physiology (Y.M.), National Institute for Physiological Sciences, Myoudaijicho, Okazaki-City, 444-8585, Japan; and Laboratory of Histology and Cytology (T.I.), Hokkaido University Graduate School of Medicine, Kita-ku, Sapporo 060-8638, Japan.
Takashi
T
Miki
D054369:Agouti-Related Protein / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001069:Appetite Regulation / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D003433:Crosses, Genetic; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects; D056426:Genetic Loci / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051857:Otx Transcription Factors / Q000235:genetics / Q000378:metabolism*; D065823:Parabrachial Nucleus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology
D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D001067:Appetite Depressants; D015415:Biomarkers; D009419:Nerve Tissue Proteins; D051857:Otx Transcription Factors; C470836:Otx3 protein, mouse; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; C430443:agouti-related protein (86-132), human; D013629:Tamoxifen