We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin–LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase–LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis–relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.
Carl de Luca, Timothy J. Kowalski, Yiying Zhang, Joel K. Elmquist, Charlotte Lee, Manfred W. Kilimann, Thomas Ludwig, Shun-Mei Liu, Streamson C. Chua Jr.
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JAK-STAT and feeding
SR Ladyman, DR Grattan |
JAK-STAT | 2013 |
Phenotypic Effects of an Induced Mutation of the ObRa Isoform of the Leptin Receptor
Z Li, G Ceccarini, M Eisenstein, K Tan, JM Friedman |
Molecular Metabolism | 2013 |
Astrocytic leptin-receptor knockout mice show partial rescue of leptin resistance in diet-induced obesity
B Jayaram, W Pan, Y Wang, H Hsuchou, A Mace, GG Cornelissen-Guillaume, PK Mishra, RA Koza, AJ Kastin |
Journal of applied physiology | 2013 |
A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction
CF Elias |
American Journal of Physiology - Regulatory, Integrative and Comparative Physiology | 2013 |
Diminished leptin signaling can alter circadian rhythm of metabolic activity and feeding
H Hsuchou, Y Wang, GG Cornelissen-Guillaume, AJ Kastin, E Jang, F Halberg, W Pan |
Journal of applied physiology | 2013 |
Adipocytes: impact on tumor growth and potential sites for therapeutic intervention
S Hefetz-Sela, PE Scherer |
Pharmacology & Therapeutics | 2013 |
Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching
MD Virgilio, E Callen, A Yamane, W Zhang, M Jankovic, AD Gitlin, N Feldhahn, W Resch, TY Oliveira, BT Chait, A Nussenzweig, R Casellas, DF Robbiani, MC Nussenzweig |
Science | 2013 |
NHLH2: at the intersection of obesity and fertility
DJ Good, T Braun |
Trends in Endocrinology & Metabolism | 2013 |
Serotonin and the regulation of mammalian energy balance
MH Donovan, LH Tecott |
Frontiers in neuroscience | 2013 |
Neuronal expression of glucosylceramide synthase in central nervous system regulates body weight and energy homeostasis
V Nordström, M Willershäuser, S Herzer, J Rozman, OB Halbach, S Meldner, U Rothermel, S Kaden, FC Roth, C Waldeck, N Gretz, MH de Angelis, A Draguhn, M Klingenspor, HJ Gröne, R Jennemann |
PLoS Biology | 2013 |
In vivo characterization of the role of tissue-specific translation elongation factor 1A2 in protein synthesis reveals insights into muscle atrophy
J Doig, LA Griffiths, D Peberdy, P Dharmasaroja, M Vera, FJ Davies, HJ Newbery, D Brownstein, CM Abbott |
FEBS Journal | 2013 |
Taf7l cooperates with Trf2 to regulate spermiogenesis
H Zhou, I Grubisic, K Zheng, Y He, PJ Wang, T Kaplan, R Tjian |
Proceedings of the National Academy of Sciences | 2013 |
Selective leptin insensitivity and alterations in female-reproductive patterns linked to hyperleptinemia during infancy
M Schroeder, N Kronfeld-Schor, A Weller |
PloS one | 2013 |
Blockade of the cerebral aqueduct in rats provides evidence of antagonistic leptin responses in the forebrain and hindbrain
MI Vaill, BN Desai, RB Harris |
American journal of physiology. Endocrinology and metabolism | 2013 |
Investigating the Role of Tbx4 in the Female Germline in Mice
NC Douglas, R Arora, CY Chen, MV Sauer, VE Papaioannou |
Biology of reproduction | 2013 |
A General Approach for Controlling Transcription and Probing Epigenetic Mechanisms: Application to the Cd4 Locus
M Wan, R Kaundal, H Huang, J Zhao, X Yang, BH Chaiyachati, S Li, T Chi |
Journal of immunology (Baltimore, Md. : 1950) | 2013 |
Melanocortin-3 Receptors and Metabolic Homeostasis
Begriche K, Girardet C, McDonald P, Butler AA |
Progress in molecular biology and translational science | 2013 |