Journal
DIABETES
Volume 67, Issue 6, Pages 1093-1104Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db17-1395
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Funding
- Michigan Diabetes Research Center (National Institutes of Health) [P30-DK020572]
- Molecular Genetics, Animal Phenotyping, and Clinical Cores
- Michigan Mouse Metabolic Phenotyping Center
- American Diabetes Association
- Marilyn H. Vincent Foundation
- National Institute of Diabetes and Digestive and Kidney Diseases [DK056731, DK097861, GM007315, DK101357, DK088752]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [P30DK020572, R37DK056731, U2CDK110768, T32DK101357, R01DK056731, R01DK104999, F30DK097861, T32DK071212, R25DK088752] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007863, T32GM008322, T32GM007315] Funding Source: NIH RePORTER
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Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lep(ob/ob)) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3(LepRb)KO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.
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