Institute of Investigations in Genetic Engineering and Molecular Biology, National Council of Scientific and Technological Research, 1428 Buenos Aires, Argentina.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48105, USA.
Mol Metab. 2020 Apr;34:43-53. doi: 10.1016/j.molmet.2020.01.007. Epub 2020 Jan 11.
Regulation of food intake and energy balance depends on a group of hypothalamic neurons that release anorexigenic melanocortins encoded by the Pomc gene. Although the physiological importance of central melanocortins is well appreciated, the genetic program that defines the functional identity of melanocortin neurons and assures high levels of hypothalamic Pomc expression is only beginning to be understood. This study assessed whether the transcriptional regulator PRDM12, identified as a highly expressed gene in adult mouse POMC neurons, plays an important role in the identity and function of melanocortin neurons.
We first determined the cellular distribution of PRDM12 in the developing hypothalamus. Then we studied mutant mice with constitutively inactivated Prdm12 to evaluate possible changes in hypothalamic Pomc expression. In addition, we characterized conditional mutant mice specifically lacking Prdm12 in ISL1-positive or POMC neurons during development. Finally, we measured food intake, body weight progression up to 16 weeks of age, adiposity, and glucose tolerance in adult mice lacking Prdm12 selectively from POMC neurons.
PRDM12 co-expressed with POMC in mouse hypothalamic neurons from early development to adulthood. Mice lacking Prdm12 displayed greatly reduced Pomc expression in the developing hypothalamus. Selective ablation of Prdm12 from ISL1 neurons prevented hypothalamic Pomc expression. The conditional ablation of Prdm12 limited to POMC neurons greatly reduced Pomc expression in the developing hypothalamus and in adult mice led to increased food intake, adiposity, and obesity.
Altogether, our results demonstrate that PRDM12 plays an essential role in the early establishment of hypothalamic melanocortin neuron identity and the maintenance of high expression levels of Pomc. Its absence in adult mice greatly impairs Pomc expression and leads to increased food intake, adiposity, and obesity.
摄食和能量平衡的调节依赖于一组下丘脑神经元，这些神经元释放由 Pomc 基因编码的厌食性黑素细胞激素。尽管中枢黑素细胞激素的生理重要性已得到充分认识，但定义黑素细胞激素神经元功能特征并确保下丘脑 Pomc 表达高水平的遗传程序才刚刚开始被理解。本研究评估了转录调节因子 PRDM12 是否在成年小鼠 POMC 神经元中高度表达，在黑素细胞激素神经元的特征和功能中发挥重要作用。
我们首先确定了 PRDM12 在发育中的下丘脑中的细胞分布。然后，我们研究了 Prdm12 持续失活的突变小鼠，以评估下丘脑 Pomc 表达可能发生的变化。此外，我们对发育过程中特异性缺失 ISL1 阳性或 POMC 神经元中的 Prdm12 的条件性突变小鼠进行了特征描述。最后，我们在成年小鼠中选择性地从 POMC 神经元中缺失 Prdm12，测量了其摄食量、16 周龄前的体重进展、肥胖程度和葡萄糖耐量。
PRDM12 与 POMC 在从小鼠下丘脑神经元的早期发育到成年期共同表达。缺乏 Prdm12 的小鼠在发育中的下丘脑中 Pomc 表达大大减少。ISL1 神经元中 Prdm12 的选择性缺失阻止了下丘脑 Pomc 的表达。仅限于 POMC 神经元的 Prdm12 的条件性缺失大大减少了发育中下丘脑和成年小鼠中 Pomc 的表达，导致摄食量增加、肥胖和肥胖。
总之，我们的研究结果表明，PRDM12 在早期建立下丘脑黑素细胞激素神经元特征和维持高水平 Pomc 表达中发挥着重要作用。其在成年小鼠中的缺失大大降低了 Pomc 的表达，并导致摄食量增加、肥胖和肥胖。
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