Highly Conserved STAT3 Motifs Present in the Neuronal Pomc Enhancer nPE1 are Critical for Maximal Hypothalamic Pomc Expression
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View abstract on PubMed
Summary
This summary is machine-generated.Two STAT3 motifs in the Pomc gene enhancer nPE1 are crucial for maintaining normal hypothalamic Pomc expression levels. Deleting these motifs reduces Pomc mRNA but does not affect body weight or food intake in mice.
Area Of Science
- Neuroendocrinology
- Molecular Biology
- Genetics
Background
- Central melanocortins, regulated by the Pomc gene, are key controllers of food intake and adiposity.
- Hypothalamic Pomc expression is orchestrated by three enhancers: nPE1, nPE2, and nPE3, with nPE1 exhibiting the highest transcriptional activity.
Purpose Of The Study
- To investigate the functional significance of two conserved STAT3 motifs within the nPE1 enhancer on hypothalamic Pomc expression.
- To determine the impact of deleting these STAT3 motifs on Pomc mRNA levels, body weight, and feeding behavior.
Main Methods
- Comparative genomics identified two conserved STAT3 binding motifs in the nPE1 enhancer.
- CRISPR-Cas9 gene editing was used to create mutant mice with co-allelic deletions of both STAT3 motifs in nPE1.
- Quantitative real-time PCR (qRT-PCR) measured hypothalamic Pomc mRNA levels in homozygous mutant and wild-type littermates.
- Body weight, length, fat mass, and food intake were monitored, along with a fasting and refeeding test.
Main Results
- Mice with homozygous deletions of both STAT3 motifs in nPE1 showed a significant reduction in hypothalamic Pomc mRNA levels (approximately 25% lower than controls).
- Despite the reduced Pomc mRNA, homozygous mice exhibited normal body weight trajectories, body composition, and food intake patterns compared to wild-type littermates.
- Fasting and refeeding tests revealed no significant differences in daily food intake or body weight changes between mutant and control mice.
Conclusions
- The two identified STAT3 motifs within the Pomc enhancer nPE1 are essential for achieving maximal hypothalamic Pomc expression.
- While critical for Pomc expression levels, these specific STAT3 motifs may not be the sole determinants of long-term energy homeostasis regulation in mice.
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